Oncolytic herpes simplex virus vector with enhanced MHC class I presentation and tumor cell killing.
Oncolytic herpes simplex virus type 1 (HSV-1) vectors are promising therapeutic agents for cancer. Their efficacy depends on the extent of both intratumoral viral replication and induction of a host antitumor immune response. To enhance these properties while employing ample safeguards, two conditionally replicating HSV-1 vectors, termed G47Delta and R47Delta, have been constructed by deleting the alpha47 gene and the promoter region of US11 from gamma34.5-deficient HSV-1 vectors, G207 and R3616, respectively. Because the alpha47 gene product is responsible for inhibiting the transporter associated with antigen presentation (TAP), its absence led to increased MHC class I expression in infected human cells. Moreover, some G47Delta-infected human melanoma cells exhibited enhanced stimulation of matched antitumor T cell activity. The deletion also places the late US11 gene under control of the immediate-early alpha47 promoter, which suppresses the reduced growth properties of gamma34.5-deficient mutants. G47Delta and R47Delta showed enhanced viral growth in a variety of cell lines, leading to higher virus yields and enhanced cytopathic effect in tumor cells. G47Delta was significantly more efficacious in vivo than its parent G207 at inhibiting tumor growth in both immune-competent and immune-deficient animal models. Yet, when inoculated into the brains of HSV-1-sensitive A/J mice at 2 x 10(6) plaque forming units, G47Delta was as safe as G207. These results suggest that G47Delta may have enhanced antitumor activity in humans. (+info)
Lead-contaminated imported tamarind candy and children's blood lead levels.
In 1999, an investigation implicated tamarind candy as the potential source of lead exposure for a child with a significantly elevated blood lead level (BLL). The Oklahoma City-County Health Department tested two types of tamarind suckers and their packaging for lead content. More than 50% of the tested suckers exceeded the US Food and Drug Administration (FDA) Level of Concern for lead in this type of product. The authors calculated that a child consuming one-quarter to one-half of either of the two types of suckers in a day would exceed the maximum FDA Provis onal Tolerable Intake for lead. High lead concentrations in the two types of wrappers suggested leaching as a potential source of contamination. The authors used the Environmental Protection Agency's Integrated Exposure Uptake Biokinetic (IEUBK) model to predict the effects of consumption of contaminated tamarind suckers on populat on BLLs. The IEUBK model predicted that consumption of either type of sucker at a rate of one per day would result in dramatic increases in mean BLLs for children ages 6-84 months in Oklahoma and in the percentage of children wth elevated BLLs (> or =10 micrograms per deciliter [microg/dL]). The authors conclude that consumption of these products represents a potential public health threat. In addition, a history of lead contamination in imported tamarind products suggests that import control measures may not be completely effective in preventing additional lead exposure. (+info)
Do drug advertisements in Russian medical journals provide essential information for safe prescribing?
OBJECTIVE: To examine pharmaceutical advertisements in medical journals for their adequacy of information. METHODS: We selected a convenience sample of 5 major Russian medical journals covering different fields of medicine and different types of publications. We evaluated all the ads in all the issues of the selected journals published during 1998. We counted the number of appearances of trade, chemical, and generic names; indication and contraindication; pharmacologic group; safety warnings; and references. Counts in all categories were aggregated for each advertiser. RESULTS: There were 397 placements of 207 distinct advertisements. Only 154 placements (40%) mentioned the generic name, 177 (45%) mentioned any indication, 42 (11%) mentioned safety warnings and contraindications, 21 (5%) warned about drug interactions, and 8 (2%) provided references. The 6 companies responsible for the most ads on average provided less information than the other companies. CONCLUSIONS: Almost none of the drug ads published in Russian medical journals provide the basic information required for appropriate prescribing. This is despite the fact that in Russia, ads that omit essential information and that could lead consumers to misunderstandings about an advertised product are illegal. The arrival of drug advertising in Russia has brought little information and has been potentially damaging. (+info)
Whose standard is it, anyway? How the tobacco industry determines the International Organization for Standardization (ISO) standards for tobacco and tobacco products.
OBJECTIVE: To describe the extent of the tobacco industry involvement in establishing international standards for tobacco and tobacco products and the industry influence on the International Organization for Standardization (ISO). METHODS: Analysis of tobacco industry documents made public as part of the settlement of the Minnesota Tobacco Trial and the Master Settlement Agreement. Search words included "ISO", "CORESTA", "Barclay", "compensation and machine smoking", "tar and nicotine deliveries", and the name of key players, in different combinations. RESULTS: It is clear that the tobacco industry, through the Cooperation Centre for Scientific Research Relative to Tobacco (CORESTA), play a major role in determining the scientific evidence and suggesting the standards that are eventually adopted as international standards for tobacco and tobacco products in several areas, including the measurement of cigarette tar and nicotine yield. CONCLUSIONS: ISO's tobacco and tobacco products standards are not adequate to guide tobacco products regulatory policies, and no health claims can be made based on ISO's tobacco products standards. There is an urgent need for tobacco control advocates and groups worldwide to be more involved with the work of the ISO, both directly and through their national standardisation organisations. (+info)
Safety and immunogenicity of a proteosome-Shigella flexneri 2a lipopolysaccharide vaccine administered intranasally to healthy adults.
We studied the safety and immunogenicity of a Shigella flexneri 2a vaccine comprising native S. flexneri 2a lipopolysaccharide (LPS) complexed to meningococcal outer membrane proteins-proteosomes-in normal, healthy adults. A two-dose series of immunizations was given by intranasal spray, and doses of 0.1, 0.4, 1.0, and 1.5 mg (based on protein) were studied in a dose-escalating design. The vaccine was generally well tolerated. The most common reactions included rhinorrhea and nasal stuffiness, which were clearly dose related (P < or = 0.05). These reactions were self-limited and generally mild. The vaccine elicited S. flexneri 2a LPS-specific immunoglobulin A (IgA), IgG, and IgM antibody-secreting cells (ASCs) in a dose-responsive manner. At doses of 1.0 or 1.5 mg, highly significant (P < 0.001) increases in ASCs of all antibody isotypes occurred and 95% of subjects had an ASC response in at least one antibody isotype. Dose-related serum antibody responses were observed, with geometric mean two- to fivefold rises in specific serum IgA and IgG titers and two- to threefold rises in IgM in the 1.0- and 1.5-mg-dose groups (P < 0.0001 for each isotype). Elevated serum antibody levels persisted through day 70. Increases in fecal IgG and IgA and also in urinary IgA specific for S. flexneri 2a LPS were demonstrated. These were most consistent and approached statistical significance (P = 0.02 to 0.12 for various measures) on day 70 after the first dose. The magnitude of immune responses to intranasally administered proteosome-S. flexneri 2a LPS vaccine is similar to those reported for live vaccine candidates associated with protective efficacy in human challenge models, and further evaluation of this product is warranted. (+info)
Summary of the Guidelines for Preventing Opportunistic Infections among Hematopoietic Stem Cell Transplant Recipients.
This article contains highlights of "Guidelines for Preventing Opportunistic Infections among Hematopoietic Stem Cell Transplant Recipients: Recommendations of the CDC, the Infectious Diseases Society of America, and the American Society of Blood and Marrow Transplantation," which was published in the Morbidity and Mortality Weekly Report. There are sections on the prevention of bacterial, viral, fungal, protozoal, and helminth infections and on hospital infection control, strategies for safe living following transplantation, immunizations, and hematopoietic stem cell safety. The guidelines are evidence-based, and prevention strategies are rated by both the strength of the recommendation and the quality of evidence that supports it. Recommendations are given for preventing cytomegalovirus disease with prophylactic or preemptive gancyclovir, herpes simplex virus disease with prophylactic acyclovir, candidiasis with fluconazole, and Pneumocystis carinii pneumonia with trimethoprim-sulfamethoxazole. Hopefully, following the recommendations made in the guidelines will reduce morbidity and mortality from opportunistic infections in hematopoietic stem cell transplant recipients. (+info)
Construction, genotypic and phenotypic characterization, and immunogenicity of attenuated DeltaguaBA Salmonella enterica serovar Typhi strain CVD 915.
A promising live attenuated typhoid vaccine candidate strain for mucosal immunization was developed by introducing a deletion in the guaBA locus of pathogenic Salmonella enterica serovar Typhi strain Ty2. The resultant DeltaguaBA mutant, serovar Typhi CVD 915, has a gene encoding resistance to arsenite replacing the deleted sequence within guaBA, thereby providing a marker to readily identify the vaccine strain. CVD 915 was compared in in vitro and in vivo assays with wild-type strain Ty2, licensed live oral typhoid vaccine strain Ty21a, or attenuated serovar Typhi vaccine strain CVD 908-htrA (harboring mutations in aroC, aroD, and htrA). CVD 915 was less invasive than CVD 908-htrA in tissue culture and was more crippled in its ability to proliferate after invasion. In mice inoculated intraperitoneally with serovar Typhi and hog gastric mucin (to estimate the relative degree of attenuation), the 50% lethal dose of CVD 915 (7.7 x 10(7) CFU) was significantly higher than that of wild-type Ty2 (1.4 x 10(2) CFU) and was only slightly lower than that of Ty21a (1.9 x 10(8) CFU). Strong serum O and H antibody responses were recorded in mice inoculated intranasally with CVD 915, which were higher than those elicited by Ty21a and similar to those stimulated by CVD 908-htrA. CVD 915 also elicited potent proliferative responses in splenocytes from immunized mice stimulated with serovar Typhi antigens. Used as a live vector, CVD 915(pTETlpp) elicited high titers of serum immunoglobulin G anti-fragment C. These encouraging preclinical data pave the way for phase 1 clinical trials with CVD 915. (+info)
Construction and characterization of genetically defined aro omp mutants of enterotoxigenic Escherichia coli and preliminary studies of safety and immunogenicity in humans.
Enterotoxigenic Escherichia coli (ETEC) is a leading cause of diarrhea in travelers to countries where the disease is endemic and causes a major disease burden in the indigenous population, particularly children. We describe here the generation and preclinical characterization of candidate strains of ETEC which are intended to provide the basis of a live attenuated oral vaccine to prevent this disease. It has been shown previously that a spontaneously arising toxin-negative variant ETEC strain, E1392/75-2A, could confer 75% protection against challenge when administered to volunteers. Unfortunately this strain induced mild diarrhea in 15% of recipients. To eliminate the unacceptable reactogenicity of strain E1392/75-2A, it was further attenuated by introducing three different combinations of defined deletion mutations into the chromosome. A mouse intranasal model of immunization was developed and used to show that all of the strains were immunogenic. Immune responses against colonization factor antigens (CFAs) were particularly strong when the bacterial inocula were grown on "CFA agar," which induces strong expression of these antigens. Two of the strains were selected for a phase I dose escalation safety study with healthy adult volunteers. Freshly grown organisms were harvested from CFA agar plates and administered to volunteers as a suspension containing from 5 x 10(7) to 5 x 10(9) CFU. The vaccine was well tolerated at all doses and induced significant immune responses in all recipients at the highest dose of either strain. The results provide the basis for further clinical evaluation of these vaccine candidates. (+info)