Biomedical subjects

D M Lubaroff

Publications and source records attributed to D M Lubaroff.

At least 19 recordsLinked to original sources

PubMed2001

Immunization with type 5 adenovirus recombinant for a tumor antigen in combination with recombinant canarypox virus (ALVAC) cytokine gene delivery induces destruction of established prostate tumors.

Prostate-specific antigen (PSA) is expressed by prostate epithelial cells and has a highly restricted tissue distribution. Prostatic malignancies in 95% of patients continue to express PSA, making this antigen a good candidate for targeted immunotherapy. The goals of our studies are to generate a recombinant PSA adenovirus type 5 (Ad5-PSA) that is safe and effectively activates a PSA-specific T-cell response capable of eliminating prostate cancer cells, and to characterize the immunologic basis for this rejection. Here we show that immunization of mice with Ad5-PSA induced PSA-specific cellular and humoral immunity that was protective against a subcutaneous challenge with RM11 prostate cancer cells expressing PSA (RM11psa), but not mock-transfected RM11 tumor cells (RM11neo). Mice immunized with recombinant adenovirus type 5 encoding beta-galactosidase (Ad5-lacZ) did not generate protective immunity. Antitumor activity was predominantly mediated by CD8(+) T lymphocytes. Although Ad5-PSA immunization prior to RM11psa challenge was protective, Ad5-PSA immunization alone was not able to control the growth of existing RM11psa tumors. In contrast, established RM11psa tumors ranging in size from 500 to 1,000 mm(3) were efficiently eliminated if Ad5-PSA priming was followed 7 days later by intratumoral injection of recombinant canarypox viruses (ALVAC) encoding interleukin-12 (IL-12), IL-2, and tumor necrosis factor-alpha. In this case, antitumor immunity was still dominated by CD8(+) T lymphocytes, but natural killer cells became necessary for a maximal response. These data provide information on the effector cell populations in a protective immune response to prostate cancer and demonstrate the utility of an Ad5-PSA vaccine combined with cytokine gene delivery to eliminate large established tumors that are refractory to other interventional methods.

Adenoviridae↗

PubMed2001

Cutting edge: restoration of the ability to generate CTL in mice immune to adenovirus by delivery of virus in a collagen-based matrix.

Viruses are commonly used for the delivery of genes coding for tumor-associated Ags to elicit tumor-specific immune responses. The success of viral vectors has been limited in preclinical and clinical trials in part because of antiviral immunity. We investigated the ability of a collagen-based matrix (Gelfoam; Pharmacia and Upjohn, Kalamazoo, MI) to improve CTL activation by recombinant adenovirus. The data show that coinjection of Gelfoam with type 5 adenovirus recombinant for prostate-specific Ag (Ad5-PSA) enhanced CTL activation. Ad5-PSA priming in Gelfoam also abrogated the inhibitory effects of adenoviral immunity on CTL activation in mice naive to PSA but immune to adenovirus. Finally, Gelfoam enhanced immunization in a self-Ag model using type 5 adenovirus recombinant for membrane-bound OVA (Ad5-mOVA) in rat insulin promoter (RIP)-mOVA-transgenic mice. Thus, Gelfoam enhances CTL activation by recombinant viral vectors in a setting where preformed Ab to the virus is present and also in a tolerant self-Ag model.

Adenoviruses, Human↗

PubMed2001

Effects of housing relocation on immunocompetence and psychosocial functioning in older adults.

BACKGROUND: The psychological and physical response to moderate life stressors among older adults has not been well characterized. This research examines effects of voluntary housing relocation on distress and immune function in healthy older adults as a model for studying the effects of moderate life stress. METHODS: Thirty older adults moving to congregate living facilities were assessed 1 month premove, 2 weeks postmove, and 3 months postmove. Twenty-eight nonmoving control subjects were assessed at similar time points. Subjects completed psychosocial questionnaires and had early morning blood draws in their homes. Blood samples were assayed for natural killer cell cytotoxicity (NKCC), interleukin-6 (IL-6), and IgG antibody titers to the Epstein Barr virus (EBV) viral capsid antigen. RESULTS: Movers demonstrated decreased vigor and elevated thought intrusion 1 month premove and 2 weeks postmove. By the 3-month follow-up, vigor increased, and intrusion decreased to levels commensurate with the controls. Averaged across all time points, movers showed lower NKCC than controls; however, post-hoc analyses indicate that by the 3-month follow-up time point, these differences were no longer significant. There were no differences between groups in IL-6 or in EBV antibody titers. Independent of the effects of group, higher levels of vigor were associated with greater NKCC at all assessments and with lower EBV titers at 2 weeks postmove. CONCLUSIONS: Findings suggest that in general, healthy older adults recover well psychologically from moderate. temporary life stressors such as moving. Whereas movers showed generally lower NKCC than controls, IL-6 and EBV antibody titers appeared not to be strongly affected by the stress of moving.

Adaptation, Psychological↗

PubMed2000

Macropinocytosis as a mechanism of entry into primary human urethral epithelial cells by Neisseria gonorrhoeae.

Gonococcal entry into primary human urethral epithelial cells (HUEC) can occur by macropinocytosis. Scanning and transmission electron microscopy revealed lamellipodia surrounding gonococci, and confocal laser scanning microscopy analysis showed organisms colocalized with M(r) 70,000 fluorescein isothiocyanate-labeled dextran within the cells. Phosphoinositide 3-kinase inhibitors and an actin polymerization inhibitor prevented macropinocytic entry of gonococci into HUEC.

Actins↗

PubMed1999

Suppression of prostate cancer invasive potential and matrix metalloproteinase activity by E-cadherin transfection.

Our previous studies have demonstrated the heterogeneous expression of E-cadherin in a Dunning rat prostate tumor model. From this model, cloned E-cadherin-negative cells exhibited enhanced invasive and metastatic potential when compared with E-cadherin-positive cells. In this report, we examined the invasion suppressor function of E-cadherin in these prostate tumor cell clones. The E-cadherin gene was stably transfected into E-cadherin-negative Dunning clones. E-cadherin transfection resulted in the up-regulation of the three major catenins (alpha-, beta-, and gamma-catenin) and enhanced Ca2+-dependent cellular cohesiveness. Morphological analyses of E-cadherin transfectants revealed a reversion from a fibroblastic, motile phenotype to a more stationary epithelial phenotype. Matrix metalloproteinase 2, an important marker associated with invasive and metastatic potential, was reduced in all six stable transfected lines. A concomitant decrease in cellular invasiveness was observed, as assessed in vitro by the ability of the transfected cells to invade biological matrices. These results lend further support to the hypothesis that in this experimental system, E-cadherin plays a central role in reducing the cellular invasiveness of prostatic adenocarcinoma, due in part to the down-regulation of matrix metalloproteinase 2 activity. Moreover, the data shed additional light on the possible mechanisms involved in E-cadherin-dependent modulation of invasion.

Adenocarcinoma↗

PubMed1999

A novel immunological model for the study of prostate cancer.

The Dunning R-3327 rat prostatic adenocarcinoma is a widely accepted model for in vivo experimental studies of prostate cancer. We have previously derived phenotypically distinct cell lines from a s.c. tumor resulting from the inoculation of the R-3327-5 subclone into Copenhagen rats. In this study, we report studies using a gelatin sponge model for the delivery of tumor cells and the retrieval of tumor-specific leukocytes responsive to different prostatic cell lines. S.c. preimplanted sponges were inoculated with tumor cells previously selected for differential properties of tumor formation and metastasis and examined for leukocyte content at time points of 1, 3, and 5 weeks after tumor cell inoculation. Cytospin and flow cytometric analyses revealed fewer tumor-associated leukocytes present in sponges inoculated with tumorigenic R-3327-5' and R-3327-5'B lines, with lesser sponge degradation, than in experiments with the nontumorigenic R-3327-5'A line, suggestive of a tumor cell-induced immunomodulatory mechanism. Morphological studies indicate an intermittent tumor growth pattern that gradually disappears in sponges inoculated with the nontumorigenic R-3327-5'A cells but a robust growth pattern in sponges inoculated with the tumorigenic cell lines. Cytokine analyses show the secretion of higher levels of active transforming growth factor-beta by the more invasive and metastatic lines. Total transforming growth factor-beta levels are higher in the epithelial, tumorigenic R-3327-5'B line. Additionally, the more tumorigenic lines secrete interleukin 10, a potent immunosuppressive molecule. In this report, we demonstrate the ability to retrieve viable leukocyte populations from a prostate tumor line bearing sponges, which offers an important model for further in vitro and in vivo manipulations and holds promise for testing adoptive immunotherapeutic strategies.

Adenocarcinoma↗

PubMed1999

Sense of coherence moderates the relationship between life stress and natural killer cell activity in healthy older adults.

A sense of coherence (SOC) has been found to be a strong predictor of health outcomes and life satisfaction in older adults. This study investigated mood and immune effects of anticipated voluntary housing relocation in 30 healthy older adults and 28 age-matched controls and examined whether SOC would buffer effects of relocation on natural killer (NK) cell activity. Movers completed assessments and had blood drawn 1 month before relocation to congregate living facilities; controls were assessed concurrently. Compared with the control group, movers showed decreased positive mood and NK activity and elevated thought intrusion. Positive mood mediated the relationship of moving with NK activity, whereas SOC moderated this relationship. Low SOC movers had the poorest NK activity; that of high SOC movers was less compromised. These findings are consistent with possible salutogenic contributions of SOC and positive mood to immune function in older adults facing stressful life transitions.

Adult↗

PubMed1999

Life stress, mood disturbance, and elevated interleukin-6 in healthy older women.

BACKGROUND: Although adverse effects of severe chronic stress on immunocompetence and physical well-being in older adults have been reported, the immune response to less severe life stress among healthy older adults, particularly among women, is not well understood. Interleukin-6 (IL-6) has been considered a good overall indicator of immune functioning in older adults because of its contribution to the pathogenesis of several age-related conditions such as osteoporosis. Regulation of IL-6 is impaired in elderly adults, and levels of IL-6 increase with stress and depression. This research cross-sectionally examined levels of IL-6 in three groups of healthy older women with varying levels of life stress and mood disturbance and a healthy group of young women. METHODS: Subjects included 18 caregivers of Alzheimer's patients, 17 older women assessed one month before relocation of their residence, 15 nonmoving and noncaregiving older women, and 20 younger women. Subjects completed the Profile of Mood States (POMS) and had early morning blood draws. RESULTS: Alzheimer's caregivers reported significantly greater distress than women of all other groups. IL-6 levels in caregivers were significantly higher than those of all other women. The older women had significantly higher IL-6 than young controls, but there were no significant differences in IL-6 between movers and older controls. Among all women, greater depression and distress were related to higher levels of IL-6. CONCLUSIONS: These findings suggest that in older women, chronic stressors are associated with significant elevations in IL-6 over and above the elevations associated with normal aging, but that moderate stressors may not be related to appreciable elevations in IL-6.

Aged↗

PubMed1998

Alterations in constituent urinary proteins in response to bladder outlet obstruction in rats.

PURPOSE: Benign prostatic hyperplasia, resulting in bladder outflow obstruction, induces well recognized clinical symptoms and morphologic bladder changes. Despite these phenomenon, relatively little is known with regard to the precise molecular events occurring in the bladder as a consequence of obstruction. In an effort to screen for alterations in bladder gene expression induced by obstruction, and/or alterations in uroepithelial integrity, this study compared pre- and post-obstructive constituent urinary proteins in an animal model. MATERIALS AND METHODS: Outlet obstruction was created using a previously established model system. Experimental animals were surgically obstructed for either 2 or 7 days, at which time the urine was aspirated and the bladders removed and weighed. Urinary proteins were separated using 2-D PAGE. Following comparison of sham versus experimental animals, microsequencing was performed on proteins that were down regulated. RESULTS: Duplicate experiments confirmed the presence of outflow obstruction. Statistically significant increases (p <0.01) in bladder weights were seen at 2 and 7 days in the obstructed groups as compared with both sham and control groups. 2-D PAGE demonstrated a down regulation of three urinary proteins post-obstruction. Microsequencing identified these proteins as prostatic steroid-binding protein C3 precursor (pI=5.5, MW=15000), glandular kallikrein 9 (S3) precursor (pI=6.2, MW=19000), and glandular kallikrein 8 (P1) precursor (pI=6.2, MW=33000). CONCLUSIONS: Bladder outflow obstruction alters constituent urinary protein composition in an animal model system. The precise etiology of these alterations remains to be defined.

Androgen-Binding Protein↗

PubMed1997

Fine structural studies of induced tumors arising within the prostatic complex of Lobund-Wistar rats.

BACKGROUND: Morris Pollard, Phyllis Luckert, and colleagues have reported the occurrence of spontaneously arising tumors of the prostatic complex in aged Lobund-Wistar (L-W) rats, and have also shown that the genesis of such tumors may be accelerated by means of intravenous administration of methylnitrosourea, followed by androgen supplementation. METHODS: Light and electron microscopic investigations of the tumors arising under this regime were conducted, with the objective of documenting morphological changes attending the transformation process; 10 tumor samples were used for the electron microscopic studies. RESULTS: All tumors studied were adenocarcinomas arising within the prostatic complex of induced animals. These tumors varied in size, degree of differentiation, and invasiveness. Foci of prostatic intraepithelial neoplasia were noted in light microscopic studies as well. Consistent fine structural features exhibited by cells of the induced adenocarcinomas included a large nuclear to cytoplasmic ratio; large irregular nuclei with heavily marginated chromatin; conspicuous nucleoli; abundant ribosomes and polysomes and a paucity of rough endoplasmic reticulum; and numerous cytoplasmic vesicles and lipid inclusions. Numerous, short microvilli extended from the cell surface into a copious surrounding extracellular matrix. CONCLUSIONS: Thus, these tumors shared many of the fine structural features characteristic of the Dunning (rat) and human prostatic adenocarcinomas.

Adenocarcinoma↗

PubMed1997

Association of smoking, body mass, and physical activity with risk of prostate cancer in the Iowa 65+ Rural Health Study (United States).

Smoking, obesity, alcohol, and physical activity can modulate the endocrine system, and therefore have been hypothesized to play a role in the etiology of prostate cancer. At baseline in 1982, 80 percent (n = 3,673) of the noninstitutionalized persons age 65+ in two rural Iowa (United States) counties were enrolled into the Iowa 65+ Rural Health Study. Follow-up for mortality was complete through 1993, and cancer experience was determined by linkage to the State Health Registry of Iowa cancer database for the years 1973-93. We analyzed data on 1,050 men aged 65 to 101 years (mean age 73.5) with a full interview in 1982 and with no documented cancer in the 10 years prior to baseline. Through 1993 (8,474 person-years of follow-up), there were 71 incident cases of prostate cancer. In a multivariate model, age, cigarette smoking (relative risk [RR] = 2.9 for currently smoking 20 or more cigarettes per day compared with never smoking; P trend = 0.009), greater body mass index (BMI) (wt/ht2) (RR = 1.7 for BMI > 27.8 kg/m2 compared with < 23.6; P trend = 0.1), and greater level of physical activity (RR = 1.9 for high activity level cf inactive; P trend = 0.05) were independent predictors of prostate cancer, and these associations were stronger for regional or disseminated disease at diagnosis. Percent change in BMI from age 50 to baseline was associated positively with risk (P trend = 0.01), and this association appeared to be stronger in heavier men. There were no data on diet. These findings suggest that smoking, overweight, and weight gain in later life are risk factors for prostate cancer and support a hormonal etiology; the positive association for physical activity confirms some previous reports, but remains without a credible biologic mechanism.

Age Distribution↗

PubMed1995

Survival of human prostate carcinoma, benign hyperplastic prostate tissues, and IL-2-activated lymphocytes in scid mice.

Mice, homozygous for the mutation severe combined immunodeficiency (scid) and also segregating for the mutation hypogonadal (hpg), were tested for their potential use as an in vivo model system for studying the growth of human prostate cancer and benign hyperplastic prostate tissue grafts. Fresh human prostate cancer or benign hyperplastic prostate tissue was implanted subcutaneously into androgen-replete C.B. 17 scid/scid males, and into androgen-deficient hpg/hpg scid/scid or androgen-replete +/? scid scid males. The tissue grafts grew in both androgen-replete and androgen-deficient host mice. When dihydrotestosterone (DHT) was administered at tissue grafting, both the incidence and size of the tissue grafts increased. Histology of tissue from tumors in the androgen-deficient hpg/hpg scid/scid host showed either undifferentiated tumors or adenocarcinomas with few glandular structures. These data suggest the androgen deficient environment selected for growth of androgen-independent tumor tissue. Finally, when interleukin-2 (IL-2)-activated tumor-infiltrating lymphocytes were injected into scid/scid hosts, the cells were found to survive and could be identified in the spleen of the recipient mice. These results indicate that growth of human prostate tissues and IL-2-activated lymphocytes in scid/scid mice is a viable model system for in vivo studies of prostatic disease.

Adenocarcinoma↗

PubMed1994

Gross and microscopic pathology of induced prostatic complex tumors arising in Lobund-Wistar rats.

The necessity for additional animal models for prostate cancer has recently been stressed. The Pollard model of chemically induced prostate cancer has received attention in this regard although the histiogenetic origin of these tumors has come under question. We independently studied this model for the development of tumors in the prostate region. The tumors, all of which were adenocarcinomas, first became grossly evident 5 months after induction and ultimately occurred in 71% of the animals. Seventy-three % of the tumors involved only the seminal vesicle, 22% involved other portions of the prostatic complex as well as the seminal vesicle, and 5% were located in the coagulating gland (anterior prostate). Although the majority of tumors arose in or involved the seminal vesicle, this may still be a useful model for the study of human prostate cancer because the tumors are adenocarcinomas, occur in the large majority of animals, are hormonally induced, and have the propensity to metastasize.

Adenocarcinoma↗

PubMed1993

Localization of LAK cells and IL-2-stimulated regional lymph node lymphocytes by regional arterial infusion in renal tumor-bearing rats.

We describe the results of a traffic assay of the regional arterial administration of either lymphokine-activated killer cells or recombinant interleukin-2-activated regional lymph node lymphocytes in tumor-bearing rats in comparison with the results of systemic or intracardiac administration. The lymphocytes were labeled with 51Cr before infusion. The distribution and localization of these cells were serially evaluated by counting the radioactivity of the removed tissues. Concerning arterial administration, the labeled cells were directly infused into the abdominal aorta just proximal to the left renal artery. In the systemic or intracardiac route, the labeled cells preferentially localized to the lung, spleen and liver 2 h after injection. Radioactivity of the lung decreased thereafter and that of the spleen increased. In contrast, regional arterial administration yielded a remarkable accumulation of radioactivity in the left renal parenchyma 2 and 6 h after injection, similar to other distal organs tested. In the renal tumor model, the percentage radioactivity of the tumor tissue (% injectate recovered/g tissue) obtained at 6 h after injection in the arterial administration group ranged from 0.40 to 1.33, which was significantly higher (p < 0.05) than that in the systemic administration group. However, the radioactivity rapidly decreased from the tumor tissue 18 h after the injection. This study raises the essential issue on the mechanism of tumor destruction by lymphokine-activated killer lymphocytes in adoptive immunotherapy.

Animals↗

PubMed1992

Identification of functional T cell subsets and surface antigen changes during activation as they relate to RT6.

The functional and phenotypic heterogeneity of the rat peripheral T lymphocyte antigen RT6 has been examined. The in vivo popliteal graft-vs-host reaction (GvHR), in vitro MLR, and the generation and effector populations of cytotoxic T lymphocyte were used to examine the response of RT6-positive (RT6+) or -negative (RT6-) subsets of CD4 and CD8 T cells to alloantigen. T lymphocytes with the CD4+RT6+ surface phenotype are necessary and sufficient for inducing a strong GvHR. T lymphocytes with the CD4+RT6-, CD8+RT6+, and CD8+RT6- surface phenotypes do not contribute or induce a strong GvHR. Both the CD4+RT6+ and the CD4+RT6- T cells proliferate in the MLR assay. CTL precursors are a mixture of CD8+RT6+ and CD8+RT6- phenotypes, but only cells bearing the RT6- phenotype are potent CTL effector cells. Data presented in this paper also demonstrate that the RT6.1 alloantigen, present on the majority of rat T cells, modulates on cortisone-resistant thymocytes (CRT) and peripheral T cells. Although freshly isolated CRTs do not express the RT6.1 epitope, RT6+ cells develop when CRTs are placed into culture. Peripheral T cells that are RT6- will also become RT6+ in culture. Stimulation of T cell cultures with a mitogen causes the loss of the RT6.1 antigen, as detected by the DS4.23 mAb. The effect is more pronounced in cultures of CRTs than peripheral T cells. Following a return to a nonactivated state, the T cells reexpress RT6. The loss and reexpression of RT6 may be related to activation and/or differentiation of T cells.

ADP Ribose Transferases↗

PubMed1991

The in vivo effect of regional hyperthermia on dunning R3327 prostatic tumor.

This report describes the in vivo effect of regional hyperthermia on male Copenhagen rats implanted with Dunning R3327 prostatic carcinoma. In six rats, a 22-gauge 1.5-cm needle was inserted into the tumor and heated to 46.5 degrees C for 2 hr. Two hyperthermia treatments were administered 48 hr apart. In a separate group of six rats, the needle was inserted into the tumor, but not heated. After treatment, serial measurements of tumor volume and body weight were made twice a week for 4 weeks. From the first day of measurement to day 22, the tumor size in the treated group compared to control was significantly smaller, P = 0.02. In the first 12 days following treatment, the mean value of body weight in the treated and control groups decreased 7% and 3%, respectively. Following this, body weights increased to baseline levels by the end of the study. No other side effects related to hyperthermia were observed and no immediate mortality occurred. In the control group, two rats died from lung metastasis of the prostatic carcinoma after day 22. In the treated group, no lung metastases were found and no rats died before being sacrificed on day 29. Our experiments show that local elevation of the temperature of the Dunning tumor results in the death of tumor cells; at 46.5 degrees C for 2 hr there is marked tumor damage while the rats tolerated the hyperthermia well.

Adenocarcinoma↗

PubMed1990

Social support and immune function among spouses of cancer patients.

This study investigated whether social support was related to immune function among spouses of cancer patients. Effects of depression and negative life events were examined as potential mediators. Results showed evidence of greater immunocompetence on 2 of 3 dynamic measures: natural killer cytotoxicity and proliferation response to phytohemagglutinin among spouses who reported high levels of social support. All six components of social support assessed by the Social Provisions Scale (Cutrona & Russell, 1987) were strongly related to these indices of immune function. No evidence was found for mediation by either life events or depression.

Adult↗

PubMed1990

Regional hyperthermia combined with high energy shock wave treatment on Dunning prostate tumors.

Male Copenhagen rats implanted with Dunning R3327 prostate carcinoma were treated with regional hyperthermia and high energy shock waves (HESW). Twenty-four rats were divided into four equal groups. All rats in one group were matched with the corresponding rats in the other three groups according to tumor size. Hyperthermia was created by the resistive heating of a 22-gauge 1.5-cm needle; HESW were generated by the Dornier XL-1 experimental lithotripter. In two hyperthermia treatments administered 48 hours apart, the tumor was heated to 46.5 degrees C for 2 hours; HESW treatment involved 1,600 shocks at 18 kV. Twenty-nine days after initiation of this study, animals were sacrificed and tumor growth calculated. Tumor growth in group 1 (combined hyperthermia and HESW) was significantly delayed between the 7th and 29th day (p = 0.05). In group 2 (HESW alone), tumor growth was significantly delayed between the 7th and 22nd day (p = 0.01), while tumor growth in group 3 (hyperthermia alone) was delayed between the 3rd and 22nd day (p = 0.02). On day 22, mean percent change in tumor growth in the control group exceeded that of group 1 by 449% (p = 0.015) as well as that of groups 2 and 3, by 350% (p = 0.034) and by 268% (p = 0.049), respectively. As previous reports demonstrate the efficacy of hyperthermia in combination with irradiation or chemotherapy for the treatment of prostate carcinoma, our results indicate hyperthermia in combination with HESW may also be a useful treatment modality.

Animals↗