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Biomedical subjects

R C Bast

Publications and source records attributed to R C Bast.

At least 289 records · Page 16Linked to original sources
PubMed1971

Heterogeneity of the cellular immune response. I. Kinetics of lymphocyte stimulation during sensitization and recovery from tolerance.

Lymph node cells from guinea pigs immunized with HSA in complete Freund's adjuvant were grown in cultures containing different concentrations of specific antigen. Stimulation of thymidine incorporation was induced with progressively lower concentrations of HSA at successive intervals after sensitization. Moreover, the intensity of delayed skin reactions and the magnitude of stimulation in vitro increased over the same interval. These events are considered compatible with an evolution of the cellular immune response resulting from the selection of lymphoid cells by decreasing concentrations of antigen in vivo. Cells from animals rendered tolerant to HSA failed to respond to specific antigen in culture. As tolerance waned, stimulation was achieved at high but not low antigen concentrations. Tolerance, measured by cutaneous reactivity or by lymphocyte stimulation, was less readily induced in animals sensitized with adjuvant containing a reduced concentration of mycobacteria. Lymph nodes from these animals contained a large population of cells reactive at high antigen concentration, presumably less susceptible to the toleragenic effect of intravenous antigen. The dissociation of delayed hypersensitivity and antibody formation observed early in the immune response and upon recovery from tolerance has permitted correlation of lymphocyte stimulation with delayed hypersensitivity and cutaneous basophil hypersensitivity respectively.

Animals↗
PubMed1971

Heterogeneity of the cellular immune response. II. The role of adjuvant, lymphocyte stimulation in cutaneous basophil hypersensitivity.

Antigen-mediated stimulation of thymidine incorporation was demonstrated in lymph node cells from guinea pigs immunized with 100 microg human serum albumin in either Freund's incomplete or Freund's complete adjuvant. Animals receiving HSA in IFA exhibited both cutaneous basophil (Jones-Mote) hypersensitivity and lymphocyte stimulation at 1, but not at 6 wk after immunization. Significant stimulation required >/= 10 microg HSA/ml of culture. Sensitization with HSA in CFA produced delayed hypersensitivity and permitted lymphocyte stimulation at both 1 and 6 wk. Stimulation was observed with as little as 0.1 microg HSA/ml at the later interval. Administration of 5 mg HSA intravenously at the time of sensitization with 100 microg HSA in IFA reduced but did not eliminate both CBH and lymphocyte stimulation at 1 wk. Antigen-specific inhibition of macrophage migration could be demonstrated with exudates from animals immunized with HSA in CFA, but not with HSA in IFA at 3 wk after sensitization. HSA was cleared from depots of CFA and IFA at similar rates, but significantly more antigen appeared in the plasma and subsequently in the draining lymph nodes following administration in IFA. Conversely, accumulated antigen disappeared more rapidly following CFA immunization.

Albumins↗
PubMed1967

In vitro assay of endotoxin by the inhibition of macrophage migration.

A quantitative in vitro technique was used to compare the ability of different endotoxins to inhibit the migration of macrophages from explants of rabbit spleen cultured in a coagulated plasma medium. The order of potency was different from that observed in chick embryo assays, and in assays with mice, of the same endotoxins. In general, however, the sensitivity of the macrophage inhibition test was comparable to that of other bioassay methods. A highly purified endotoxin from Salmonella enteritidis (Ribi) in a concentration of 0.004 mug/ml regularly inhibited macrophage migration. The in vitro method was used to detect a progressive loss of biological activity in fractions obtained during acid hydrolysis of the purified endotoxin. The selective toxicity of very low concentrations of endotoxin for mammalian macrophages was important in estimating the degree of specificity of the reaction. The pattern of cellular response in explant cultures made it possible to differentiate endotoxic damage from the specific cytotoxic action of antigen associated with delayed hypersensitivity.

Animals↗
PubMedDate not supplied

Targeted therapy for epithelial ovarian cancer: current status and future prospects.

Despite advances in surgery and chemotherapy, less than 20% of patients with stage III or IV ovarian cancer survive long-term. In the past, cytotoxic regimens have been developed empirically, combining active agents at maximally tolerated doses, often without a clear rationale for their interaction. Advances in understanding the biology of ovarian cancer have identified multiple molecular targets that differ in normal and malignant cells. Targets include cell cycle regulators, growth factor receptors, signal transduction pathways, molecules that confer drug resistance, and angiogenic mechanisms. A number of targeted agents have entered clinical trials. Small molecular weight inhibitors, monoclonal antibodies, and antisense and gene therapy are all being evaluated alone and in combination with cytotoxic drugs. In contrast to earlier studies, the impact of each agent on the designated target can be assessed and agents can be matched to the genotype and phenotype of malignant and normal cells. In the long run, this should facilitate individualization of more effective, less toxic therapy for women with ovarian cancer.

Angiogenesis Inhibitors↗
PubMedDate not supplied

New tumor markers: CA125 and beyond.

A variety of biomarkers have been developed to monitor growth of ovarian cancer and to detect disease at an early interval. CA125 (MUC16) has provided a useful serum tumor marker for monitoring response to chemotherapy, detecting disease recurrence, distinguishing malignant from benign pelvic masses, and potentially improving clinical trial design. A rapid fall in CA125 during chemotherapy predicts a favorable prognosis and could be used to redistribute patients on multiarmed randomized clinical trials. Several studies now document that CA125 can serve as a surrogate marker for response in phase II trials. Serial measurement of CA125 might also provide a useful marker for monitoring stabilization of disease with cytostatic targeted therapeutic agents. The greatest potential for serum markers may be in detecting ovarian cancer at an early stage. A rising CA125 can be used to trigger transvaginal sonography (TVS) in a small fraction of patients. An algorithm has been developed that calculates risk of ovarian cancer based on serial CA125 values and refers patients at highest risk for TVS. Use of the algorithm is currently being evaluated in a trial with 200,000 women in the UK that will test critically the ability of a two-stage screening strategy to improve survival in ovarian cancer. Whatever the outcome, as 20% of ovarian cancers have little or no expression of CA125, additional serum markers will be required to detect all patients in an initial phase of screening. More than 30 serum markers have been evaluated alone and in combination with CA125 by different investigators. Some of the most promising include: HE4, mesothelin, M-CSF, osteopontin, kallikrein(s), and soluble EGF receptor. Two proteomic approaches have been used: one examines the pattern of peaks on mass spectroscopy and the other uses proteomic analysis to identify a limited number of critical markers that can be assayed by more conventional methods. Both approaches are promising and require further development. Several groups are placing markers on multiplex platforms to permit simultaneous assay of multiple markers with very small volumes of serum. Mathematical techniques are being developed to analyze combinations of marker levels to improve sensitivity and specificity. In the future, serum markers should improve the sensitivity of detecting recurrent disease as well as facilitate earlier detection of ovarian cancer.

Biomarkers, Tumor↗
PubMedDate not supplied

Clinical application of oxaliplatin in epithelial ovarian cancer.

Platinum remains the most active drug class in ovarian cancer treatment; however, new single-agent and combination therapies are needed to improve the clinical outcome of ovarian cancer therapies. Oxaliplatin, a third-generation platinum derivative, has shown effective antitumor activity and a favorable toxicity profile in epithelial ovarian cancer. Preclinical evidence of the synergistic cytotoxic effect of oxaliplatin in combination with several other chemotherapeutic agents and clinical evidence of the absence of any dose-limiting hematologic toxicity associated with this agent have made oxaliplatin an attractive compound for combination agent therapy. This article reviews the current status of the clinical application of oxaliplatin alone and in a combination regimen in epithelial ovarian cancer treatment.

Antineoplastic Agents↗
PubMedDate not supplied

Pathogenesis of ovarian cancers.

OBJECTIVE: To review our current understanding of the molecular genetic events involved in the development of epithelial ovarian cancers. METHODS: Molecular biologic techniques have been used to examine the role of growth-stimulatory genes (oncogenes) and -inhibitory genes (tumor suppressors) in ovarian cancer. RESULTS: A number of different peptide growth factors and their receptors are expressed by normal and malignant ovarian epithelial cells. However, the role, if any, of growth factors in ovarian carcinogenesis or maintenance of the transformed phenotype remains unknown. Amplification and overexpression of the HER-2/neu and c-myc oncogenes occur in a significant fraction of epithelial ovarian cancers (20-30%). Overexpression of HER-2/neu has correlated with poor survival in some studies, whereas c-myc amplification is more common in serous cancers. Mutation of the K-ras oncogene frequently occurs in borderline ovarian tumors, but is less common in invasive epithelial ovarian cancers. Mutation of the p53 tumor suppressor gene occurs in approximately half of advanced (stage III/IV) ovarian cancers and in 15% of early (stage IA/IB) cases. Most recently, preliminary studies have focused on the role of other tumor suppressor genes, cyclins, WAF1, and DNA mismatch repair genes. CONCLUSIONS: An understanding of the molecular events involved in the pathogenesis of epithelial ovarian cancer is beginning to evolve. Improvements in early diagnosis, treatment, and prevention of this deadly disease are dependent on further progress in this area.

Carcinoma↗
PubMedDate not supplied

Tumor antigen NB/70K and CA 125 levels in the blood of preoperative ovarian cancer patients and controls: a preliminary report of the use of the NB12123 and CA 125 radioimmunoassays alone and in combination.

The NB12123 and CA125 radioimmunoassays, murine monoclonal antibody assays for measuring circulating levels of human ovarian tumor associated antigens NB/70K and CA 125, respectively, have been previously described. In the present study, preoperative serum samples were obtained from patients undergoing laparotomy for benign neoplastic ovarian tumors (N = 16), cancer of the cervix (N = 22), cancer of the uterus (N = 20), and cancer of the ovary (N = 47). Controls (N = 50) were obtained from healthy blood bank donors. No correlation was observed between the levels of NB/70K and CA 125 in these samples (r2 = .079, linear regression analysis). In general, increasing levels of both antigens were present with increasing tumor burden and higher histological grade. In addition, both markers were most elevated in the serum of ovarian cancer patients with serous and unclassified adenocarcinomas. Using 40 AU and 35 unit cut-offs for the NB/70K and CA 125 assay, respectively, overall specificity for healthy controls and patients with benign diseases approaches 100%. The combined sensitivity of the assays for ovarian cancer patient sera in this study indicates that the assays may be helpful in establishing a pre operative diagnosis of ovarian cancer. Complementarity of the NB/70K and CA 125 assays has been demonstrated, indicating that one or both assays may be used to monitor as many as 85% of ovarian cancer patients.

Adenocarcinoma↗
PubMedDate not supplied

OVX1 and CEA in patients with colon carcinoma, colon polyps and benign colon disorders.

The OVX1 tumor marker promises to complement CA125 for detection of early stage ovarian carcinoma. OVX1 has also been shown to be elevated in colon cancer patients. This study is designed to assess serum OVX1 levels in patients with specific stages of colon cancer, colon polyps or other GI disorders. Serum OVX1 and CEA were measured by radioimmunoassay or enzyme immunoassay for 206 patients at the time of colonoscopy or staging for colon carcinoma. In patients with stage I, II, III, or IV colon carcinoma, serum OVX1 was positive in 37%, 48%, 74% and 63%, respectively. Fifty-three percent of patients with colon polyps had elevated OVX1 levels, while OVX1 levels were positive in only 7% of healthy controls. If both OVX1 and CEA were considered, at least one of these markers was elevated in 36%, 60%, 79% or 89% of patients with stage I, II, III or IV colon carcinoma, respectively. The majority of patients with inflammatory bowel disease or diverticulosis also had elevated OVX1 levels. Both markers were positive in 27% of patients with colon carcinoma, and not in any patients with a normal colonoscopy or with a diagnosis of diverticulosis or hemorrhoids. In conclusion, serum OVX1 improves the sensitivity of CEA for detecting colon polyps and colon cancer; however, the use of OVX1 in this setting is hindered by its elevation in non-malignant colonic processes.

Antigens, Tumor-Associated, Carbohydrate↗
PubMedDate not supplied

CA 125: the past and the future.

Over the last 15 years, substantial progress has been made in understanding the potential and the limitations of the CA 125 assay. More than 2000 papers have been published concerning laboratory and clinical studies of CA 125. The original CA 125 assay utilized the OC 125 antibody that recognizes the CA 125 epitope on a high molecular weight glycoprotein. Despite repeated attempts, the gene encoding the peptide component has not yet been cloned. Monoclonal antibodies have been raised against other epitopes expressed by this molecule, leading to the development of the CA 125-II assay that exhibits less day-to-day variation. Using either assay, elevated levels of CA 125 are detected in a number of benign conditions, including endometriosis. CA 125 is most consistently elevated in epithelial ovarian cancer, but can be expressed in a number of gynecologic (endometrial, fallopian tube) and non-gynecologic (pancreatic, breast, colon and lung) cancers. The best established application of the CA 125 assay is in monitoring ovarian cancer. The rate of decline in CA 125 during primary chemotherapy has been an important independent prognostic factor in several multivariate analyses. Persistent elevation of CA 125 at the time of a second look surgical surveillance procedure predicts residual disease with > 95% specificity. Rising CA 125 values have preceded clinical detection of recurrent disease by at least 3 months in most, but not all studies. Given the modest activity of salvage chemotherapy, this information has not yet impacted on survival. Rising CA 125 during subsequent chemotherapy has been associated with progressive disease in more than 90% of cases. CA 125 may serve as an effective surrogate marker for clinical response in phase II trials of new drugs. CA 125 levels can aid in distinguishing malignant from benign pelvic masses, permitting effective triage of patients for primary surgery. Early detection of ovarian cancer remains the most promising application of CA 125. An algorithm has been developed that estimates the risk of ovarian cancer (ROC) based upon the level and trend of CA 125 values. A major trial has been initiated that uses the ROC algorithm to trigger transvaginal sonography and/or subsequent laparotomy. Such a trial could demonstrate improvement in survival through early detection. This strategy should provide adequate specificity, but sensitivity for early stage disease may not be optimal. In the future, improved sensitivity may be attained using multiple markers and neural network analysis. Most serum tumor markers have been proteins or carbohydrates, but lipid markers such as lysophosphatidic acid deserve evaluation. Genomic and proteonomic technologies should identify additional novel markers.

Antibodies↗
PubMedDate not supplied

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.

Female↗
PubMedDate not supplied

Recombinant leukocyte alpha interferon in advanced ovarian carcinoma.

Recombinant leukocyte alpha interferon (rIFN-alpha A; Hoffmann-La Roche, Inc) was administered to 15 patients with recurrent or persistent ovarian carcinoma. All patients had been previously treated with surgery and combination chemotherapy including cyclophosphamide (15 patients), doxorubicin (14), and cisplatin (14). Three patient had also previously undergone radiation therapy. At the start of therapy the largest tumor size was less than or equal to 2 cm in four patients and greater than 2 cm in 11. Interferon was administered in three times weekly for 8 weeks at a dose of 20 X 10(6) units/m2, with average drug levels of 2267 pg/ml 6 hours after im injection. In three patients (20%), the dose had to be reduced by 50% because of drug toxicity. Side effects included fever (greater than 101 degrees F) in 12 patients, fatigue in ten, headache in two, diarrhea in two, and reversible myelosuppression in five. Of the 15 patients, one had mixed response lasting 12 weeks, two had stable disease of 8 weeks' duration, and 12 had disease progression.

Adenocarcinoma↗
PubMedDate not supplied

Spectral differences between epitopes in the cronomes of salivary CA130 and CA125.

Ovarian tumor markers CA125 and CA130 are here investigated in the search for harbingers of an elevated cancer risk or pre-cancer. A circadian rhythm of large amplitude is demonstrated for salivary CA125 and CA130 of a clinically healthy 28-year-old woman (AP). The circadian rhythms of both markers found in AP have a pattern similar to that of a patient (EH) with a müllerian cancer involving the ovary, with high values in the early morning and low values in the afternoon. Whereas acrophases occur approximately at the same circadian stage in both AP and EH, the MESOR and circadian amplitude are higher in EH as compared to AP. The circadian rhythm of salivary CA130 of AP is similar to that of other clinically healthy women. CA130 concentrations are lower than CA125 concentrations in unstimulated saliva (before rinsing of the mouth) in this clinically healthy woman (AP), and in other women studied herein. This difference between CA130 and CA125 concentrations is observed irrespective of circadian stage and irrespective of the concentration range of CA125 at the outset. After rinsing of the mouth, a statistically significant decrease in both CA130 and CA125 concentration is observed in AP and in another healty woman (GC) who collected saliva both before and after rinsing of the mouth.

Adult↗