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R S Weiner

Publications and source records attributed to R S Weiner.

At least 19 recordsLinked to original sources
PubMed1992

Identification of assembled epitopes on the alpha-subunit of human follicle stimulating hormone.

In order to characterize further the antigenic structure of human follitropin (hFSH), BALB/c mice were immunized with hFSH and anti-hFSH monoclonal antibodies (mAbs) were generated. The hFSH subunit specificity of the mAbs was assessed by a solid-phase enzyme-linked immunosorbent assay (ELISA) and a solution-phase radioimmunoassay (RIA), each using hFSH, hFSH alpha, and hFSH beta. Five mAbs bound hFSH and hFSH alpha in the ELISA and the RIA. In addition, some mAbs recognized hFSH beta, albeit to a much lower degree, as demonstrated by displacement of [125I]hFSH binding to the mAbs by hFSH beta, in the solution-phase RIAs. Next, synthetic peptides corresponding to the hFSH alpha-subunit sequence were used to identify sequences specific to the epitopes of each of the five mAbs. Using this epitope mapping strategy, two assembled epitopes were identified. mAbs 3A and 4B distinguish one discontinuous epitope comprised minimally of sequences alpha-16-21 and alpha-66-92, whereas mAbs 5F and 2E distinguish a second discontinuous epitope comprised minimally of sequences alpha-40-50 and alpha-66-72.

Amino Acid Sequence↗
PubMed1992

A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group Study.

PURPOSE: A randomized clinical trial was undertaken to compare the therapeutic effectiveness of idarubicin (IDR) to daunorubicin (DNR), and both were given in combination with cytarabine (CA) in acute myelogenous leukemic (AML) patients. PATIENTS AND METHODS: Newly diagnosed patients were given a daily infusion of CA (100 mg/m2) for 7 days and were assigned randomly to receive DNR (45 mg/m2) or IDR (12 mg/m2) daily for the first 3 days. Those patients who achieved a complete remission (CR) were given three consolidation courses that consisted of CA (100 mg/m2 intravenously [IV]) and thioguanine (TG; 100 mg/m2 orally) every 12 hours for 5 days and either DNR (50 mg/m2) or IDR (15 mg/m2) on the first day of each cycle. After consolidation, patients received late intensification, which consisted of the same drugs used for induction except that the CA was given for 5 days and the anthracycline for 2 days. Four courses were planned at 13-week intervals. RESULTS: The CR rates were 75 of 105 (71%) on the IDR arm and 65 of 113 (58%) on the DNR arm (P = .03). The median survival and median remission durations were 297 and 433 days, respectively, on the IDR arm. The median survival and median remission durations were 277 and 328 days, respectively, on the DNR arm. Six deaths occurred during late intensification, five on IDR and one on DNR; this approach was abandoned after 47 patients were entered. The median survival was significantly longer for patients who received late intensification. CONCLUSION: This trial demonstrated that IDR was more effective than DNR in remission induction in AML.

Adolescent↗
PubMed1992

Biochemical analyses of proteolytic nicking of the human glycoprotein hormone alpha-subunit and its effect on conformational epitopes.

Conformational features of two epitopes on the glycoprotein hormone alpha-subunit were investigated using two antihuman FSH (anti-hFSH) monoclonal antibodies (mAbs) 3A and 5F that recognize different epitopes and are specific for alpha-subunit. These mAbs were used to investigate whether the conformation of these epitopes was different in heterodimeric hFSH, hTSH, hLH, or hCG. Any differences in the mass of hormone in each preparation were accounted for by sodium dodecyl sulfate-polyacrylamide gel electrophoresis/Western blot analysis of all hormone preparations used in this study. Rabbit anti-hFSH alpha-(11-27) antipeptide antisera and [125I]protein-G were used in the Western blot analysis. Radioactivity associated with each band was determined and used to normalize the mass of alpha-subunit in each reference preparation used in the displacement assays. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis was also performed in order to examine the integrity of each of the hormone reference preparations. hTSH alpha and, to a lesser extent, hLH alpha preparations contained an internal nick in the polypeptide chain. RIA analysis performed using heterodimeric glycoprotein hormones as competitors revealed that an average 100-fold difference in the ED50 values for hFSH compared to the other glycoprotein hormones was seen with mAb 3A. Therefore, the conformation of 3A epitope appeared to be different in hFSH than in hTSH, hLH, or hCG. In comparison, the epitope recognized by mAb 5F only had an average 7-fold difference in reactivity (ED50 values) for hFSH compared to hTSH, hLH, and hCG. Likewise, competition assays using the respective alpha-subunits and mAb 5F revealed a pattern of competition similar to that observed with heterodimers, with an average 4-fold difference in the ED50 values for hFSH alpha compared to those for hTSH alpha, hLH alpha, and hCG alpha. Therefore, the conformation of the 5F epitope appears unaffected by association of alpha-subunit with beta-subunit. Accordingly, any differences in the conformation of the four alpha-subunits, as demonstrated by these small differences in ED50 values, appear to be inherent to each alpha-subunit. In fact, the 5F epitope appears to be quite rigid, since nicked alpha-subunit preparations could compete with [125I]hFSH for binding to 5F with comparable potency to non-nicked alpha-subunits. These findings support the concept that epitopes on heterodimeric hFSH alpha may have different conformational features. Some are specific for heterodimeric hFSH alpha, and we refer to these as conformationally active (flexible). Others are common to the four human glycoprotein hormone alpha-subunits, suggesting that they are conformationally constrained (rigid).

Amino Acid Sequence↗
PubMed1991

Epitope mapping of human follicle stimulating hormone-alpha using monoclonal antibody 3A identifies a potential receptor binding sequence.

Five monoclonal antibodies (mabs) were generated (3A, 4B, 5F, 2E, 1E) by immunizing BALB/c mice with human (h) FSH. The mabs were used to relate antigenic structures (epitopes) to function (receptor binding). All five mabs could immunoneutralize (inhibit binding to receptor) hFSH and could be placed into two groups based on potency (degree of neutralization). Group I mabs (5F, 2E, 1E) were less potent than group II mabs (3A, 4B) even though group I mabs had a 2-fold higher average affinity constant than group II. Those data suggested that group II mabs recognize an epitope near or in the receptor binding site of hFSH. Immunoradiometric epitope cross-matching demonstrated that group I and group II mabs recognize different epitopes. Further characterization of 5F and 3A (representative of group I and group II, respectively) utilized an enzyme-linked immunosorbent assay (ELISA) and a RIA. In the ELISA, both mabs bound hFSH and hFSH alpha but not hFSH beta. In the RIA, 3A bound [125I]hFSH and [125I]hFSH alpha but not [125I]hFSH beta. In contrast, 5F bound only [125I]hFSH. hFSH effectively competed with [125I]hFSH for 5F and 3A. In contrast, hFSH alpha competed with [125I]hFSH for 5F but not for 3A even though 3A could bind hFSH alpha in the ELISA and the RIA. These results suggest that 3A and 5F recognize different epitopes. The epitope recognized by 3A is unique in that its conformation appears to be dependent on association with hFSH beta. Since 3A was a more potent inhibitor of receptor binding than 5F, its epitope specificity was characterized further by epitope mapping. This was accomplished utilizing a peptide ELISA and by affinity chromatography. The results from epitope mapping demonstrated that 3A recognizes sequences 61-78 and 73-92 with binding to 73-92 being 4-fold greater than to 61-78. Thus, the epitope comprised of sequence 73-92 (and to a lesser extent 61-78) appears to be important for receptor binding.

Antibodies, Monoclonal↗
PubMed1990

Myelodysplastic syndromes presenting in pregnancy. A report of five cases and the clinical outcome.

Five female patients, ranging in age between 22 and 36 years, presented with myelodysplastic syndromes during pregnancy between June 1982 and March 1987. Three of these five cases evolved into acute leukemia. A bone marrow transplant was attempted in the fourth. It is suggested that the association of myelodysplastic syndromes during pregnancy is more than coincidental and that acute leukemia evolves in a majority of these cases. Furthermore, refractory macrocytic anemias in pregnancy need to be carefully evaluated for a primary myelodysplastic state.

Adult↗
PubMed1990

Topographic analysis of the alpha-subunit of human follicle-stimulating hormone using site-specific antipeptide antisera.

Structure-function investigations were undertaken to increase understanding of the surface topology of the alpha-subunit of human FSH (hFSH). The objectives were to determine which sequences of the alpha-subunit of hFSH are surface-oriented (exposed to antibody) and to identify which of these surface-oriented sequences are in contact with the beta-subunit of hFSH in the alpha/beta heterodimer. Seven overlapping synthetic peptides spanning the primary structure of hFSH alpha were used for immunizing rabbits to generate site-specific antipeptide antisera. The antisera were characterized with respect to their reactivity to the seven synthetic peptides, as well as hFSH, hFSH alpha, hFSH beta, and hFSH alpha r/a (reduced and alkylated), using an enzyme-linked immunosorbent assay. All of the peptides successfully generated antipeptide antisera with titers that range from 1:1,600 to 1:80,000. Anti-1-15 bound exclusively to hFSH alpha. Anti-11-27 and anti-33-58 bound to hFSH alpha to a much greater extent than to hFSH. In contrast, anti-73-92 had only slightly higher binding to hFSH alpha than to hFSH. Anti-22-39, anti-51-65, and anti-61-78 all failed to bind to either hFSH or hFSH alpha. With the exception of anti-22-39, all of the remaining antisera bound to hFSH alpha r/a. None of the antisera bound to hFSH beta. These data strongly suggest the following. Sequences 1-15, 11-27, and 33-58 contain residues that are masked by hFSH beta and are thus in or near the alpha/beta-subunit interface. In addition, sequences 11-27 and 33-58 contain other distinct residues that are surface-oriented in the hFSH heterodimer. In contrast, sequence 73-92 appears to be surface-oriented in the hFSH heterodimer. Lastly, sequences 51-65 and 61-78 appear to be buried within the native alpha-subunit and, thus, are unable to interact with antibodies. These results agree with and extend previous findings and will prove useful to those currently investigating the surface topology and structure-function relationships of the glycoprotein hormones.

Amino Acid Sequence↗
PubMed1989

Protective effects of IL-1 on human hematopoietic progenitor cells treated in vitro with 4-hydroperoxycyclophosphamide.

Based on recently published data, IL-1 has been shown to provide radioprotective effects when given to mice 20 h before a lethal dose of irradiation and to enhance granulocyte recovery in mice treated with cyclophosphamide. In this study, we have investigated whether IL-1 can provide protection for human bone marrow colony-forming cells treated with high doses of 4-hydroperoxycyclophosphamide (4-HC), a potent derivative of cyclophosphamide. We have established an in vitro model system which demonstrates that prior incubation with IL-1 protects early human hematopoietic progenitor cells from the lethal effects of high doses of 4-HC. These early progenitors give rise to blast cell colonies which appear late in the culture and are characterized by their ability to give rise to different types of secondary colonies when replated. Furthermore, prior incubation with IL-1 was shown not to protect HL-60 or K562 leukemic cells from the lethal effects of 4-HC. We conclude that IL-1 is able to protect early human hematopoietic progenitors from a non-cell cycle-specific chemotherapeutic agent such as 4-HC, whereas providing no protection for the leukemic cell lines HL-60 and K562.

Adult↗
PubMed1989

Diagnostic and therapeutic utility of monoclonal antibodies in urologic oncology.

Remarkable advances in the treatment of urologic malignancies have recently been made. Monoclonal antibodies selective for a variety of normal and malignant urologic tissues have been useful in defining normal antigens and tumor-associated antigens and have potential as diagnostic and immunotherapeutic agents. In renal cancer, monoclonal antibodies can define serum markers, radiolabel tumor xenografts, and assist in specific tissue diagnosis. Additionally, there is potential for these antibodies either alone or as conjugates to localize and kill tumors. Monoclonal antibodies to bladder cancer associated antigens are able to demonstrate differential antigen expression on superficial versus invasive tumors, to refine urinary cytologic diagnosis of bladder cancer, and to predict invasive recurrence of superficial cancer. Monoclonal antibodies have localized bladder tumor xenografts and can inhibit tumor growth when conjugated to radioisotopes or toxins. In prostate cancer monoclonal antibodies to prostate antigens are not usually tumor specific. Monoclonal antibodies to prostate antigen (PA) and prostatic acid phosphatase (PAP) are able to localize prostate cancer metastases. Chemotherapy-conjugated anti-PAP monoclonal antibodies have demonstrable inhibition on human prostate cancer xenografted tumor growth. Monoclonal antibodies have defined normal and tumor-associated antigens in urologic cancers and are expected to be useful in immunodiagnosis and cancer therapy in the near future.

Acid Phosphatase↗
PubMed1989

Risk factors for interstitial pneumonia following bone marrow transplantation for severe aplastic anaemia.

Data from 547 patients with aplastic anaemia who received bone marrow transplants from HLA-identical siblings were analysed to determine factors associated with the risk of interstitial pneumonia (IPn). IPn developed in 92 patients (17%). 37% of cases were associated with cytomegalovirus infection and 22% with other organisms; in 41% of cases no organism was identified. The case fatality rate was 64%; the mortality rate due to IPn was 11%. In multivariate analysis, four factors were associated with an increased probability of interstitial pneumonia: use of methotrexate rather than cyclosporine after transplantation (relative risk, 2.8; P less than 0.0008); occurrence of moderate to severe acute graft-versus-host disease (relative risk, 2.2; P less than 0.002); inclusion of total body radiation in the pretransplant preparative regimen (relative risk 2.2, P less than 0.004); and patient age greater than 20 (relative risk 1.7, P less than 0.002). The probability of IPn ranged from 4% for patients with none of these adverse risk factors to 51% (relative risk of 13.4) for patients with all four. The incidence of IPn decreased significantly between 1978 and 1985, paralleling a decrease in the use of total body radiation pretransplant for immune suppression and methotrexate post-transplant for prophylaxis against graft-versus-host disease.

Adolescent↗
PubMed1989

Effects of lipoxygenase and glutathione pathway inhibitors on leukemic cell line growth.

We have examined the effects of various inhibitors of the lipoxygenase pathway of arachidonic acid metabolism on the growth of three well-characterized human leukemia cell lines, HL-60, K-562, and KG-1. An intact lipoxygenase pathway, and the synthesis of leukotriene C4 (LTC4), which requires reduced glutathione, is essential for in vitro growth of normal myeloid progenitors (CFU-GM). We tested the effects of nordihydroguiaretic acid (NDGA) and caffeic acid (CA), inhibitors of lipoxygenase; buthionine sulfoximine (BSO), which inhibits glutathione synthesis; and Acivicin, a glutamine antagonist, on these cell lines and compared the effects with those seen on CFU-GM. In semisolid culture, all three cell lines were inhibited by NDGA, CA, and BSO in a dose-dependent manner similar to that in CFU-GM but were relatively resistant to Acivicin. In liquid culture, all three cell lines exhibited relative resistance to inhibition by both BSO and Acivicin, with KG-1 also demonstrating relative resistance to inhibition by NDGA and CA. The inhibition of HL-60 by CA could be completely reversed by the addition of exogenous leukotriene D4. The dependence on the lipoxygenase pathway may be altered to varying degrees in different leukemic lines and may depend on culture conditions. Whether these changes may contribute to the pathogenesis of leukemia or merely represent secondary metabolic changes is yet to be determined.

Buthionine Sulfoximine↗
PubMed1989

Temporal relationships between the major complications of bone marrow transplantation for leukemia.

Data from 3113 patients receiving HLA-identical sibling bone marrow transplants for leukemia were analysed to determine the time course of the major causes of treatment failure. The median interval from transplant to onset of acute graft-versus-host disease (GVHD) was 17 days, interstitial pneumonitis 63 days, and chronic GVHD 111 days. The median interval from transplant to relapse was 3.3 months for patients transplanted in relapse of acute leukemia or blast phase of chronic myelogenous leukemia (CML), 6.4 months when transplants were performed in second or subsequent remission of acute leukemia or accelerated phase of CML, and 7.8 months for patients transplanted during first remission of acute leukemia or while in the first chronic phase of CML. Shorter intervals from transplant to onset of interstitial pneumonitis or chronic GVHD were associated with a significantly lower probability of 2-year survival. The temporal relationships between these complications are displayed graphically and demonstrate the overlapping and competing causes of death following allogeneic bone marrow transplantation.

Adolescent↗
PubMed1989

The role of interleukin 3 and interleukin 6 in the protection from 4-hydroperoxycyclophosphamide and the proliferation of early human hematopoietic progenitor cells.

Previous reports have shown that interleukin 1 (IL-1) has radioprotective effects when given to mice 20 h before a lethal dose of irradiation and enhances granulocyte recovery in mice treated with cyclophosphamide. We have recently reported that IL-1 can provide protection for human bone marrow colony-forming cells including blast colony-forming cells (B1-CFC) treated with high doses of 4-hydroperoxycyclophosphamide (4-HC). In view of the recent reports that IL-1 induces interleukin 6 (IL-6) in fibroblasts and macrophages and that IL-6 and interleukin 3 (IL-3) are the main growth factors for B1-CFC, we have examined the ability of these interleukins to protect early human hematopoietic progenitor cells from the cytotoxic effects of 4-HC. In addition, we have also studied the ability of IL-3 to promote colony formation by 4-HC-treated bone marrow cells with or without IL-1 preincubation. In this study, we report that preincubation of bone marrow mononuclear cells with IL-3 or IL-6 prior to 4-HC results in no protection and, in fact, may be detrimental to early hematopoietic progenitor cells. On the other hand, addition of IL-3 to 5637-conditioned medium and erythropoietin enhanced colony formation by early progenitors following 4-HC treatment. These findings suggest that IL-3 and IL-6 are not responsible for the protection of early progenitor cells from 4-HC seen with IL-1, but that IL-3 does promote colony formation following 4-HC treatment.

Cell Division↗
PubMed1988

High-risk Ewing's sarcoma: end-intensification using autologous bone marrow transplantation.

Because of retrospective analysis showing survival to be related to primary tumor size, in February 1982 a study to test this hypothesis prospectively was begun at the University of Florida. Patients with primary tumors 8 cm or less in maximum diameter and no metastases received adjuvant chemotherapy consisting of vincristine, cyclophosphamide, doxorubicin, and dactinomycin plus radiotherapy or surgery (standard-risk protocol). All others received a similar regimen followed by end-intensification with high-dose melphalan and autologous bone marrow transplantation (Protocol HR-2). Because of poor results of HR-2, another high-risk protocol (HR-3) was initiated in January 1985. Patients on HR-3 received 2 cycles of chemotherapy containing vincristine, cyclophosphamide, and doxorubicin followed by local radiation therapy and maintenance chemotherapy. At the end of this therapy, autologous bone marrow transplantation (ABMT) was performed, using a preparatory regimen of total body irradiation and intensive chemotherapy. The 2-year disease-free survival rate was 70% for the standard-risk protocol, 20% for HR-2, and 80% for HR-3. The follow-up on HR-3 is still short, but the results are promising enough to warrant further clinical trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Identification and screening of women at high risk of breast cancer.

First- and second-order female relatives of newly treated breast cancer patients who received their care by private practice surgeons were contacted to determine the feasibility of identifying an at-risk population, to ascertain screening practices, and to promote breast cancer screening. Utilizing the breast cancer patient as the primary contact, 42% of relatives participated. Only 32% of relatives reported ever having had a mammogram (40% of those 50 years of age and over), and 52% practiced monthly breast self-examination (BSE). Screening practices correlated with race, with having been taught BSE, and with income; 73% of relatives planned to be screened subsequent to contact. The results of this study indicate a low use of established screening modalities such as BSE and mammography.

Adult↗
PubMed1987

Impact of air filtration on nosocomial Aspergillus infections. Unique risk of bone marrow transplant recipients.

Bone marrow transplant recipients were found to have a 10-fold greater incidence of nosocomial Aspergillus infection than other immunocompromised patient populations (p less than 0.001) when housed outside of a high-efficiency particulate air (HEPA) filtered environment. Multivariate analysis demonstrated that number of infections, age, and graft-versus-host disease severe enough to require treatment were independent risk factors for development of nosocomial Aspergillus infection in this group. The use of whole-wall HEPA filtration units with horizontal laminar flow in patient rooms reduced the number of Aspergillus organisms in the air to 0.009 colony-forming units/m3, which was significantly lower than in all other areas of the hospital (p less than or equal to 0.03). No cases of nosocomial Aspergillus infection developed in 39 bone marrow transplant recipients who resided in this environment throughout their transplantation period compared with 14 cases of nosocomial Aspergillus infection in 74 bone marrow transplant recipients who were housed elsewhere (p less than 0.001). Thus, although bone marrow transplant recipients had an order-of-magnitude greater risk of nosocomial Aspergillus infection than other immunocompromised hosts, this risk could be eliminated by using HEPA filters with horizontal laminar airflow.

Air Microbiology↗