Anticancer efficacy of cisplatin and trichostatin A or 5-aza-2'-deoxycytidine on ovarian cancer.

BACKGROUND: To evaluate the anticancer efficacy of the combination of epigenetic modifiers and cisplatin in human ovarian cancer. METHODS: The effect of trichostatin A (TSA) and 5-aza-2'-deoxycytidine alone or in combination with low-dose cisplatin was evaluated on human ovarian cancer cell lines in vitro. We measured drug interaction by MTS assay, migration by transwell assay, expression of epithelial to mesenchymal transition (EMT) markers (Twist, Snail, Slug, E-cadherin, and N-cadherin), pluripotency markers (Oct4, Sox2, and Nanog), and epigenetic markers (DNMT3A, LSD1 and H3K4me2, H3K4me3, H3K9me2, and H3K9me3) by western blot, and the impact on and characteristics of spheroid growth when exposed to these drugs. Mouse xenografts were used to evaluate the anticancer effect of sequential drug treatment. RESULTS: Combination treatment had greater efficacy than single drugs and significantly suppressed cell viability, migration, and spheroid formation and growth. Sequential treatment of cisplatin (1 mg kg(-1)) followed by TSA (0.3 mg kg(-1)) significantly suppressed tumorigenicity of HEY xenografts through inhibition of EMT and decreased pluripotency of ovarian cancer cells. CONCLUSION: Epigenetic modifiers potentiate the anticancer efficacy of low-dose cisplatin in ovarian cancer through regulation of EMT and pluripotency, and may provide a promising treatment for ovarian cancer patients.

The potential of biologic network models in understanding the etiopathogenesis of ovarian cancer.

Ovarian cancer is one of the most common gynecologic malignancies and is the 5th leading cause of cancer mortality in women in the United States. Understanding the biology and molecular pathogenesis of ovarian epithelial tumors is key to developing improved prognostic indicators and effective therapies. The selection of ovarian serous carcinomas as one of the three cancer types for extensive genomic and proteomic characterization of The Cancer Genome Atlas (TCGA) project offers an important opportunity to extend our knowledge of ovarian cancer. The data portal includes molecular characterization, high throughput sequencing, and clinical data. Models to determine which of these genes act as "key drivers" of ovarian carcinogenesis and which are innocent "passengers" are needed. Standard statistical approaches often fail to differentiate between these driver and passenger genes, given that the correlation between sets of genes or genes and endpoints alone does not establish causality. As contrasted to basic correlations analyses, biological network models offer the ability to resolve causality by elucidating the directional linkages between genetics, molecular characterizations of the system, and clinical measures. This article describes the use of a novel, supercomputer-driven approach named REFS to learn network models directly from the TGCA ovarian cancer data set and simulate these models to learn the "key drivers" of ovarian carcinogenesis. The model can be validated by out-of-sample testing, and may provide a powerful new tool for ovarian cancer research.

Ovarian neoplasm development by 7,12-dimethylbenz[a]anthracene (DMBA) in a chemically-induced rat model of ovarian failure.

OBJECTIVES: The objectives were to determine the time course for ovarian failure in rats caused by 4-vinylcyclohexene diepoxide (VCD) and develop a model for ovarian cancer in which ovarian neoplasms were chemically induced in an animal that was follicle depleted, but retained residual ovarian tissue. METHODS: Initially, female Fisher 344 rats were treated with VCD (to induce ovarian failure) or vehicle control (sesame oil). Three or 6 months after treatment, ovaries were collected and processed for histological evaluation for confirmation of ovarian failure. A further set of female rats was assigned to four groups exposed to combinations of vehicle control, VCD and/or DMBA (directly applied to the ovary) in a novel model for examining early stages of ovarian neoplasia. RESULTS: Three and 6 months following VCD dosing there was a significant reduction of ovarian weight and follicle number. Treatment with DMBA subsequent to VCD resulted in tumors in 42% of animals at 3 months and 57% at 5 months. All neoplasms were classified Sertoli-Leydig cell tumors (SLCT). No tumor occurred in animals treated with vehicle or DMBA alone. CONCLUSIONS: These studies demonstrate that the VCD-treated rat can be used as a model for peri- and post-menopause. DMBA induction of ovarian neoplasms was greater in those rats treated with VCD. Whether this increase was due to tumor initiation by VCD or was the result of ovarian failure cannot be distinguished from these results. This represents the only animal model to date for sex cord stromal tumors.

Controlled study of the antiparkinsonian activity and tolerability of cabergoline.

Cabergoline, a new ergoline derivative, is a D2-specific dopaminergic agonist that is more potent and longer-acting than other agonist agents. We conducted a randomized, double-blind study of increasing doses of cabergoline taken once a day. Twenty-five patients with Parkinson's disease taking stable doses of levodopa began cabergoline at 0.5 mg. The dose was escalated at weekly intervals to 1.0 mg in 19 patients, 1.5 mg in 14 patients, 2.0 mg in nine patients, and 2.5 mg in four patients. Treatment continued for 8 weeks after titration. Unified Parkinson's Disease Rating Scale scores, Hoehn and Yahr stage of disease, and computerized measures of motor performance improved significantly with cabergoline treatment. Dose-response effects were not significant. No serious adverse experiences occurred during the 13-week trial, and the side-effect profile mirrored other dopaminergic agonists. Cabergoline appears to be a promising agent in the treatment of Parkinson's disease.

Prevalence of tremor and Parkinson's disease.

To determine the prevalence of essential tremor (ET) and Parkinson's disease (PD) in a retirement community, all residents of Carefree, Arizona, aged over 65 years were contacted. All participants completed validated questionnaires for PD and ET, and were examined using the Unified Parkinson's Disease Rating Scale. Of 356 individuals evaluated, 155 (43.5%) had tremor; 73 (20.5%) had ET; 26 (7.3%) had PD; and 56 (15.7%) had postural tremor (PT). Thus, a large percentage of individuals were found to have tremor, in the plurality of whom it could be classified as ET. The number of individuals with Parkinson's disease exceeded our expectations.

Prevention of ovarian cancer.

Chemoprevention trials with OCP and retinoids will be important to determine if these drugs are effective in selected populations. Further work will be critical to understanding the mechanism of action of OCP in preventing ovarian cancer and if this protective effect will be upheld in the high-risk population. Initial results in the Milan study are promising for the retinoids in prevention of ovarian cancer and will be used in chemoprevention trials both alone and in combination with OCP's to determine if there might be an additive effect with these drugs. As yet, little is known about preinvasive changes in the ovary to predict which women are at risk for developing ovarian cancer. We can now identify high-risk women by genetic counseling and testing, yet ultrasound and serum markers are the only modality available to evaluate these women. Research is focusing on developing ways of evaluating women, particularly those at high risk for ovarian cancer, to better understand the neoplastic process in the ovary and thus identify these women prior to their developing advanced ovarian cancer. Research is also focusing on understanding chemoprevention for ovarian cancer so that women can receive the optimal chemopreventive agent when diagnosed as high risk. Prognosis with advanced disease is so poor that early diagnosis and chemoprevention are the only methods at the current time to significantly improve survival in epithelial ovarian cancer.

Enzyme conversion of lignocellulosic plant materials for resource recovery in a Controlled Ecological Life Support System.

A large amount of inedible plant material composed primarily of the carbohydrate materials cellulose, hemicellulose, and lignin is generated as a result of plant growth in a Controlled Ecological Life-Support System (CELSS). Cellulose is a linear homopolymer of glucose, which when properly processed will yield glucose, a valuable sugar because it can be added directly to human diets. Hemicellulose is a heteropolymer of hexoses and pentoses that can be treated to give a sugar mixture that is potentially a valuable fermentable carbon source. Such fermentations yield desirable supplements to the edible products from hydroponically-grown plants such as rapeseed, soybean, cowpea, or rice. Lignin is a three-dimensionally branched aromatic polymer, composed of phenyl propane units, which is susceptible to bioconversion through the growth of the white rot fungus, Pluerotus ostreatus. Processing conditions, that include both a hot water pretreatment and fungal growth and that lead to the facile conversion of plant polysaccharides to glucose, are presented.

Human ovarian tumour-derived chaperone-rich cell lysate (CRCL) elicits T cell responses in vitro.

Tumour-derived chaperone-rich cell lysate (CRCL), which is made up of numerous heat shock proteins, has been used successfully to generate tumour-specific T cell responses and protective immunity against a wide range of murine tumours. In this study, we have investigated the potency of human ovarian cancer-derived CRCL to activate dendritic cells (DC) and to generate tumour-specific T cells in vitro. CRCL was generated from primary ovarian cancers and SKOV3-A2, a HER2/neu, Wilm's tumour gene 1 (WT1) and human leucocyte antigen (HLA)-A2 positive human ovarian tumour cell line. Peripheral blood mononuclear cells from both HLA-A2(+) healthy donors and HLA-A2(+) ovarian cancer patients were stimulated weekly with autologous DC loaded with ovarian tumour-derived CRCL. After four to six stimulations in vitro, specific cytokine secretion and cytotoxicity were measured. CRCL promoted interleukin (IL)-12 secretion and enhanced the immunostimulatory capacity of DC. T cells from healthy controls and from ovarian cancer patients secreted higher amounts of interferon-gamma following in vitro restimulation with ovarian cancer-derived CRCL than with HER2/neu or WT1 peptide-pulsed DC. We were also able to generate cytotoxic T lymphocyte activity against cancer-specific antigens such as HER2/neu and WT1 from all healthy donors, but from only one of the four ovarian cancer patients with bulky disease. These preliminary results substantiate further the concept that CRCL may prove to be a potent adjuvant for women suffering from ovarian cancer and that this personalized vaccine may be a promising approach for active immunotherapy.

Bacille Calmette-Guérin immunization in normal healthy adults.

Bacille Calmette-Guérin (BCG) vaccine was administered to 20 purified protein derivative (PPD) skin test-negative and human immunodeficiency virus serology-negative, healthy adults 18-65 years old. Local adverse reactions were monitored and intermediate-strength PPD skin test responses were evaluated 2 months and 1 year after vaccination. All vaccinees developed erythema, induration, and tenderness at the vaccination site. Muscular soreness was reported by 15 subjects, local ulceration with drainage by 14, and tender regional adenopathy by 2. BCG organisms were isolated from the ulcer of the only vaccinee who was cultured. PPD skin tests revealed induration in all subjects. Normal healthy adults at risk of occupational exposure to tuberculosis and considering BCG immunization should be fully informed about the local reactions seen after BCG administration and the high rate of persistent PPD skin test responses. Since viable organisms can be recovered from ulcer drainage, vaccination sites should be covered to reduce nosocomial transmission of the vaccine strain.

Metastatic uterine papillary serous carcinoma to the pericardium.

BACKGROUND: Uterine papillary serous carcinoma is an aggressive tumor with a high propensity for distant spread. Metastases to the heart or pericardium are rare in gynecologic malignancies and usually fatal. CASE: A 64-year-old African American woman was diagnosed with recurrent uterine papillary serous carcinoma metastatic to the pericardium. Her case at presentation was significant for an elevated serum CA-125, evidence of metastatic disease to the liver, and massive cardiomegaly. Cytologic analysis of fluid obtained by pericardiocentesis confirmed recurrence. Despite treatment with paclitaxel and a pleuropericardial window, the patient succumbed to her disease. CONCLUSION: The prognosis for patients whose recurrent uterine papillary serous carcinoma has metastasized to the heart or pericardium is extremely poor. Effective adjuvant and salvage therapies are essential.

Molecular, microscopic, microstructural and mechanical methods of analyzing pseudoneointimal linings within partial artificial hearts in man and the calf.

Ex vivo molecular, microscopic (cellular), microstructural and mechanical methods have been utilized to evaluate biologic, blood-interfacing linings (pseudoneointimal) formed on textured, fibril-flocked pumping surfaces within abdominal left ventricular assist devices (ALVADs) on partial artificial hearts. Thus far, seventeen human and twenty bovine pseudoneointimal linings (1--28 day pumping durations) have been evaluated by these methods. The results indicate that pseudoneointima begins developing within 24 hours after contact of the pumping surface with blood and is well developed at five days. The linings exhibit surface immunofluorescent fibrinogen activity, viable surface macrophages and histiocytes and scattered erythrocytes at ALVAD removal. Structurally similar linings (20 micrometer to 500 micrometer in thickness) develop in calves and in man. Mechanically, pseudoneointima is a stable, adherent, highly compliant, isotropic structural material. It is linearly elastic and strain-rate independent, with small viscous energy losses under physiologic strains. The methods employed for the evaluation of pseudoneointima provide useful information to determine the suitability of textured or rough surfaces for blood interfacing. The cumulative results indicate that the textured surface approach is useful for intermediate-term clinical ALVAD utilization.

Intra-aortic balloon pumping: theory and practice. Experience with 325 patients.

Intra-aortic balloon pumping to support the failing circulation is now an accepted therapeutic modality. The device is simple. Insertion can be accomplished rapidly and efficiently in emergency rooms, coronary care units, cardiac catheterization suites and operating rooms, preoperatively, intraoperatively and postoperatively. The hemodynamic effects are immediate and predictable, and the accruing clinical results show increasing survival and hospital discharge rates. In these institutions, mechanical support of the circulation by this and more advanced methods has been formalized within the responsibility of a Circulatory Support Service. The purpose of this report is to summarize some observations and analyses which have been made during care of 325 consecutive postcardiotomy and/or postinfarction cardiogenic shock patients. Historical, theoretical, basic, and applied aspects and current results are included. Foremost are the straightforward concepts of considering the heart as a pump, the failing heart as a failing pump and intra-aortic balloon pumping as a temporary intravascular, auxiliary pump, capable of stabilizing or reversing that failure if utilized early in its evolution.