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Biomedical subjects

W H Wilson

Publications and source records attributed to W H Wilson.

At least 19 recordsLinked to original sources

A conserved genetic module that encodes the major virion components in both the coliphage T4 and the marine cyanophage S-PM2.

Sequence analysis of a 10-kb region of the genome of the marine cyanomyovirus S-PM2 reveals a homology to coliphage T4 that extends as a contiguous block from gene (g)18 to g23. The order of the S-PM2 genes in this region is similar to that of T4, but there are insertions and deletions of small ORFs of unknown function. In T4, g18 codes for the tail sheath, g19, the tail tube, g20, the head portal protein, g21, the prohead core protein, g22, a scaffolding protein, and g23, the major capsid protein. Thus, the entire module that determines the structural components of the phage head and contractile tail is conserved between T4 and this cyanophage. The significant differences in the morphology of these phages must reflect the considerable divergence of the amino acid sequence of their homologous virion proteins, which uniformly exceeds 50%. We suggest that their enormous diversity in the sea could be a result of genetic shuffling between disparate phages mediated by such commonly shared modules. These conserved sequences could facilitate genetic exchange by providing partially homologous substrates for recombination between otherwise divergent phage genomes. Such a mechanism would thus expand the pool of phage genes accessible by recombination to all those phages that share common modules.

Base Sequence↗

Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia.

BACKGROUND: Hairy-cell leukemia that is resistant to treatment with purine analogues, including cladribine, has a poor prognosis. We tested the safety and efficacy of an immunotoxin directed against a surface antigen that is strongly expressed by leukemic hairy cells. METHODS: RFB4(dsFv)-PE38 (BL22), a recombinant immunotoxin containing an anti-CD22 variable domain (Fv) fused to truncated pseudomonas exotoxin, was administered in a dose-escalation trial by intravenous infusion every other day for a total of three doses. RESULTS: Of 16 patients who were resistant to cladribine, 11 had a complete remission and 2 had a partial remission with BL22. The three patients who did not have a response received low doses of BL22 or had preexisting toxin-neutralizing antibodies. Of the 11 patients in complete remission, 2 had minimal residual disease in the bone marrow or blood. During a median follow-up of 16 months (range, 10 to 23), 3 of the 11 patients who had a complete response relapsed and were retreated; all of these patients had a second complete remission. In 2 of the 16 patients, a serious but completely reversible hemolytic-uremic syndrome developed during the second cycle of treatment with BL22. Common toxic effects included transient hypoalbuminemia and elevated aminotransferase levels. CONCLUSIONS: BL22 can induce complete remissions in patients with hairy-cell leukemia that is resistant to treatment with purine analogues.

Adult↗

Gene expression profiling of lymphomas.

The functional phenotype of a cell results from the simultaneous action of many thousands of genes, which until recently could not be assessed using standard molecular biological techniques. Indeed, molecular genetics and cellular biology inadequately explain the molecular physiology of normal and diseased cells and provide a fragmented view of the role of various genes and their products. Recent advances in techniques of large-scale gene expression allow simultaneous study of thousands of genes of interest in a specific tissue/tumor of interest, and the ability to identify expression signatures associated with functional phenotypes. The application of gene expression profiling to lymphomas has already led to identification of distinct expression signatures associated with a germinal center cell and activated B-cell phenotype, and to the differentiation of tumor cells based on these stages of development. The differentiation of two stages of developmental arrest in large B-cell lymphomas suggests that this subtype is comprised of two diseases, albeit of similar histologic and immunophenotypic character, which were shown to have dramatically different outcomes following chemotherapy. Important information will also be obtained through the association of genes of unknown activity with functional cellular phenotypes and expression signatures, possibly leading to identification of new genes involved in lymphomagenesis and new targets for treatment.

Chromosome Aberrations↗

Reactivation of chronic hepatitis B infection following intensive chemotherapy and successful treatment with lamivudine: a case report and review of the literature.

BACKGROUND: Hepatitis B virus reactivation has been reported in cancer patients following administration of chemotherapy or immunosuppressive therapy and may result in liver damage of varying degrees of severity. Although treatment is supportive in nature, lamivudine, a nucleoside analogue has been found to suppress HBV replication as evidenced by reports of 13 cases in the medical literature. PATIENTS AND METHODS: We report a patient who achieved a successful outcome with lamivudine following reactivation of HBV during combination chemotherapy for non-Hodgkin's lymphoma, and provide a brief overview of the literature including the 13 published case reports. RESULTS: Lamivudine therapy resulted in clinical improvement as well as in normalization of liver function tests and coagulation profile. CONCLUSIONS: Lamivudine has been found to suppress HBV replication manifested both by histology and serum HBV-DNA levels in chronic carriers of HBV who developed reactivation of hepatic disease following chemotherapy. Physicians caring for such patients should be able to recognize this clinical challenge, and lamivudine should be considered.

Adult↗

Role of a doxorubicin-containing regimen in relapsed and resistant lymphomas: an 8-year follow-up study of EPOCH.

PURPOSE: Curative up-front regimens for non-Hodgkin's lymphomas contain doxorubicin, vincristine, and cyclophosphamide, whereas salvage regimens generally contain non-cross-resistant agents. We hypothesized that up-front agents may be highly effective for salvage and developed an infusional regimen based on in vitro evidence of increased efficacy. PATIENTS AND METHODS: A prospective phase II study of etoposide, vincristine, and doxorubicin over 96 hours with bolus cyclophosphamide and oral prednisone (EPOCH) was performed in 131 patients with relapsed or resistant lymphoma. RESULTS: Seventy-nine percent of patients had aggressive histologies, 46% were considered high risk by the International Prognostic Index, and 34% had resistant disease. Eighty-eight percent of patients had received at least four of the agents in EPOCH, and 94% had received doxorubicin. In 125 assessable patients, 29 (24%) achieved complete responses and 60 (50%) achieved partial responses. Among 42 patients with resistant disease, 57% responded, and in 28 patients with relapsed aggressive de novo lymphomas, 89% responded with 54% complete responses. With a median follow-up of 76 months, the overall and event-free survivals (EFS) were 17.5 and 7 months, respectively. In 33 patients with sensitive aggressive disease who did not receive stem-cell transplantation, EFS was 19% at 36 months. Toxicity was primarily hematologic, with an 18% incidence of febrile neutropenia. No clinically significant cardiac toxicity was observed, despite no maximum cumulative doxorubicin dose. CONCLUSION: EPOCH is highly effective in patients who had previously received most/all of the same drugs and produces durable remissions in curable subtypes. Salvage regimens need not contain non-cross-resistant agents, and infusional schedules may partially reverse drug resistance and reduce toxicity.

Adult↗

High-speed screening of combinatorial libraries by gradient packed-column supercritical fluid chromatography.

Packed-column supercritical fluid chromatography (pSFC) with a fast composition gradient is used as a rapid screening tool for combinatorial chemistry. The advantages of fast analysis speed and fast recovery to initial conditions are demonstrated. Retention time reproducibility is similar to isocratic analyses by pSFC and ranges from 0.37 to 0.64% relative standard deviation. A mixture of beta-blockers illustrates the 'normal phase' retention mechanism. For these solutes and a range of analytes, the peak width is relatively constant. Such behavior permits the classical peak capacity equation to be reduced to a simple, straightforward form. Using this as a performance metric, pSFC is shown to be 5-10 times faster than reversed phase HPLC for library screening.

Adrenergic beta-Antagonists↗

Denture esophageal impaction refractory to endoscopic removal in a psychiatric patient.

Impaction of dental prostheses is frequently encountered in psychiatric patients. These patients may present an especially challenging problem because the diagnosis may be delayed, resulting in increased morbidity and mortality. Delay in diagnosis in such patients has been attributed to their inability to give a reliable clinical history. In addition, radiolucent dentures cannot be easily detected by radiographic examination. The purpose of this report is to describe a psychiatric patient with an impacted radiopaque dental prosthesis that was refractory to endoscopic intervention. An esophagotomy was needed to successfully remove the foreign body.

Dental Prosthesis↗

Systemic chemotherapy for HIV-associated lymphoma in the era of highly active antiretroviral therapy.

Treatment of AIDS-associated non-Hodgkin lymphoma poses a complex and multifaceted challenge for the physician. Treatment responses to cytotoxic chemotherapy are relatively poor, relapse rates are high, and AIDS progression continues to be a major concern in patients receiving dose-intensive antilymphoma therapy. The recent advances in anti-HIV therapy have not seen a clear counterpart in improved antilymphoma therapy, but trials are underway that may help move this field forward. For patients who achieve a complete and durable response to antilymphoma therapy, potent antiretroviral therapy may help improve the prognosis from AIDS progression. Major questions persist, however, on the role of chemotherapy dose intensity, the best use of antiretroviral therapy during the administration of lymphoma therapy, and the optimal design of studies that can address these questions.

Anti-HIV Agents↗

Phase I trial of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) in patients with hematologic malignancies.

PURPOSE: To evaluate the toxicity, pharmacokinetics, immunogenicity, and antitumor activity of anti-Tac(Fv)-PE38 (LMB-2), an anti-CD25 recombinant immunotoxin that contains an antibody Fv fragment fused to truncated Pseudomonas exotoxin. PATIENTS AND METHODS: Patients with CD25(+) hematologic malignancies for whom standard and salvage therapies failed were treated with LMB-2 at dose levels that ranged from 2 to 63 microg/kg administered intravenously over 30 minutes on alternate days for three doses (QOD x 3). RESULTS: LMB-2 was administered to 35 patients for a total of 59 cycles. Dose-limiting toxicity at the 63 microg/kg level was reversible and included transaminase elevations in one patient and diarrhea and cardiomyopathy in another. LMB-2 was well tolerated in nine patients at the maximum-tolerated dose (40 microg/kg QOD x 3); toxicity was transient and most commonly included transaminase elevations (eight patients) and fever (seven patients). Only six of 35 patients developed significant neutralizing antibodies after the first cycle. The median half-life was 4 hours. One hairy cell leukemia (HCL) patient achieved a complete remission, which is ongoing at 20 months. Seven partial responses were observed in cutaneous T-cell lymphoma (one patient), HCL (three patients), chronic lymphocytic leukemia (one patient), Hodgkin's disease (one patient), and adult T-cell leukemia (one patient). Responding patients had 2 to 5 log reductions of circulating malignant cells, improvement in skin lesions, and regression of lymphomatous masses and splenomegaly. All four patients with HCL responded to treatment. CONCLUSION: LMB-2 has clinical activity in CD25(+) hematologic malignancies and is relatively nonimmunogenic. It is the first recombinant immunotoxin to induce major responses in cancer. LMB-2 and similar agents that target other cancer antigens merit further clinical development.

Adult↗

Modulation of clinical drug resistance in a B cell lymphoma patient by the protein kinase inhibitor 7-hydroxystaurosporine: presentation of a novel therapeutic paradigm.

Emerging evidence suggests that apoptosis is an important mechanism of tumor cell death from antineoplastic therapy. 7-hydroxystaurosporine (UCN-01) is a novel protein kinase inhibitor that increases chemotherapy-induced apoptosis in vitro and is in early phases of clinical development. In this report, we present a 68-year-old patient with chemotherapy-resistant lymphoma treated with UCN-01 and chemotherapy. He had a stage IV plasmacytoid lymphoma that failed to enter remission with high-dose EPOCH II (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) chemotherapy. Due to disease progression and transformation to large cell lymphoma in the liver and bone marrow, he received UCN-01. Four weeks later, he received "standard-dose" EPOCH because of progression, developed severe neutropenia for 9 days, and expired from Candida sepsis on day 23. At autopsy, there was no histological evidence of residual lymphoma, although PCR for immunoglobulin gene rearrangement analysis revealed a faint clonal band in two of six nodes but none in the liver. Significantly, no B cells were detected by immunohistochemistry in lymph nodes, and a polyclonal ladder pattern associated with the presence of normal B cells was not seen in the immunoglobulin gene rearrangement PCR assay. Profound peripheral lymphopenia (50 cells/microliter) was also observed. Pharmacokinetics showed UCN-01 salivary concentrations, a surrogate for free drug concentrations, to be within an effective range in vitro (45 nmol/L) as a modulator of DNA-damaging agent cytotoxicity. In vitro, UCN-01 is synergistic with multiple cytotoxic agents and increases fludarabine-induced apoptosis in a human breast cell line. These results suggest that UCN-01 sensitized the lymphoma to the cytotoxic effects of EPOCH, possibly by modulating the "threshold" for apoptosis, and may illustrate a new paradigm for reversal of drug resistance.

Aged↗

Chemotherapy sensitization by rituximab: experimental and clinical evidence.

For most lymphomas, chemotherapy is palliative because of an inability to overcome drug resistance within the lymphoma cells and attempts at overcoming specific drug resistance mechanisms, such as multidrug resistance, have had limited success. However, accumulating evidence suggests that the ability to activate apoptotic pathways may be an important determinant of chemotherapy sensitivity and presents a potentially important new therapeutic strategy. Studies have shown that distinct cellular thresholds exist for apoptosis, and it is likely that multiple developmental and environmental factors converge in a dynamic process to regulate this set point. If the threshold for inducing apoptosis is limiting, then strategies to modulate these pathways may profoundly enhance the efficacy of cytotoxic therapy. Monoclonal antibodies against the CD20 receptor have been shown to directly induce apoptosis and may serve to modulate the threshold for chemotherapy-induced apoptosis. Recent clinical studies of the monoclonal antibody, rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA), and combination chemotherapy have produced unexpectedly high rates of response and progression-free survival, suggesting rituximab improves the efficacy of chemotherapy. Taken together, the results from in vitro and clinical studies suggest that rituximab may modulate the sensitivity of B-cell lymphomas to chemotherapy.

Antibodies, Monoclonal↗

Responses in refractory hairy cell leukemia to a recombinant immunotoxin.

We report major responses in 4 of 4 patients with hairy cell leukemia (HCL) who have recently been treated on a phase I trial with the recombinant immunotoxin LMB-2. The immunotoxin, designed to target CD25(+) malignancies, is composed of the Fv portion of the anti-Tac (anti-CD25) antibody, fused to a 38-kD truncated form of Pseudomonas exotoxin A, and has previously been called anti-Tac(Fv)-PE38. All 4 HCL patients were resistant to standard and salvage therapies for HCL, including 2-chlorodeoxyadenosine (CdA) and interferon alpha, and all patients responded to LMB-2 after a single cycle. One patient treated with 2 cycles had a complete remission (CR), with regression of HCL cells from the blood and marrow and resolution of splenomegaly and pancytopenia. As is typical for patients in CR after treatment with CdA, minimal residual disease was detectable by flow cytometry of the bone marrow aspirate. This patient has not relapsed after 11 months. Three other patients had 98% to 99.8% reductions in malignant circulating cells. These results represent a proof of principal that targeted therapy with recombinant Fv-containing proteins can be clinically useful. LMB-2 may be an effective new therapy for patients with chemotherapy-resistant CD25(+) HCL.

ADP Ribose Transferases↗

Smoking and therapeutic response to clozapine in patients with schizophrenia.

BACKGROUND: Of patients with schizophrenia, 70 to 80% smoke. Nicotine corrects certain information processing and cognitive psychomotor deficits seen in many patients with schizophrenia. Clozapine, but not conventional antipsychotics, has been shown to correct some of these deficits. METHODS: We assessed psychopathology and smoking in 70 patients with treatment refractory schizophrenia (55 smokers and 15 nonsmokers) at baseline when they were receiving conventional antipsychotics and again after they were switched to clozapine. RESULTS: Smokers showed significantly greater therapeutic response to clozapine than nonsmokers. Smokers smoked less when treated with clozapine than when treated with conventional antipsychotics. CONCLUSIONS: Certain patients with schizophrenia have contributing pathophysiologic mechanisms that respond favorably to either nicotine or clozapine.

Adult↗

Regional cerebral blood flow and depersonalization after tetrahydrocannabinol administration.

OBJECTIVE: The aim of this study was to examine the relationship between depersonalization induced by tetrahydrocannabinol (THC), and regional brain activation. METHOD: Cerebral blood flow (CBF) was measured by means of positron emission tomography (PET) in 59 normal right-handed volunteers before and following intravenous infusions of THC. RESULTS: After THC, CBF showed a global increase which was more marked in the right hemisphere, frontal lobes and anterior cingulate. CONCLUSION: Regression analyses showed positive correlations between the right frontal and anterior cingulate and depersonalization.

Adult↗

CNS involvement in primary mediastinal large B-cell lymphoma.

PURPOSE: The risk of CNS involvement by non-Hodgkin's Lymphoma (NHL) has been associated with bone marrow and/or testicular involvement; however, it was recently reported that the number of extranodal sites is a more reliable predictor of CNS disease. Because primary mediastinal thymic large B-cell lymphoma (PMLCL) has a high propensity for involving extranodal sites, we investigated the frequency and pattern of CNS involvement in PMLCL. PATIENTS AND METHODS: The medical records of 219 patients with aggressive NHL, consecutively entered onto protocols at the National Cancer Institute between 1987 and 1998, were retrospectively reviewed. RESULTS: Twenty-three patients (11%) had clinical and pathologic features of PMLCL. These patients were young (median age, 29 years), female (61%), and presented with massive mediastinal adenopathy (70%). Extranodal disease occurred at presentation in 70% and at relapse in 93% of patients and involved contiguous intrathoracic structures and/or distant sites, including the lungs, kidneys, liver, adrenals, ovaries, pancreas, and bone. Six patients (26%) developed CNS involvement, two (9%) at presentation and four (27%) at relapse. All had extranodal disease, but only one had bone marrow involvement. Parenchymal and leptomeningeal CNS disease occurred in four and three patients, respectively. CONCLUSION: CNS involvement in PMLCL is associated with extranodal involvement other than bone marrow and may reflect the unique biology of this disease. The propensity to involve the CNS parenchyma raises the concern that intrathecal prophylaxis may not be effective and suggests that CNS imaging should be considered in patients with extranodal disease.

Adult↗