Systemic Delivery of mLIGHT-Armed Myxoma Virus Is Therapeutic for Later-Stage Syngeneic Murine Lung Metastatic Osteosarcoma.

Cancers that metastasize to the lungs represent a major challenge in both basic and clinical cancer research. Oncolytic viruses are newly emerging options but successful delivery and choice of appropriate therapeutic armings are two critical issues. Using an immunocompetent murine K7M2-luc lung metastases model, the efficacy of MYXV armed with murine LIGHT (TNFSF14/CD258) expressed under virus-specific early/late promoter was tested in an advanced later-stage disease K7M2-luc model. Results in this model show that mLIGHT-armed MYXV, delivered systemically using ex vivo pre-loaded PBMCs as carrier cells, reduced tumor burden and increased median survival time. In vitro, when comparing direct infection of K7M2-luc cancer cells with free MYXV vs. PBMC-loaded virus, vMyx-mLIGHT/PBMCs also demonstrated greater cytotoxic capacity against the K7M2 cancer cell targets. In vivo, systemically delivered vMyx-mLIGHT/PBMCs increased viral reporter transgene expression levels both in the periphery and in lung tumors compared to unarmed MYXV, in a tumor- and transgene-dependent fashion. We conclude that vMyx-mLIGHT, especially when delivered using PBMC carrier cells, represents a new potential therapeutic strategy for solid cancers that metastasize to the lung.

Systemic delivery of TNF-armed myxoma virus plus immune checkpoint inhibitor eliminates lung metastatic mouse osteosarcoma.

Solid cancers that metastasize to the lungs represent a major therapeutic challenge. Current treatment paradigms for lung metastases consist of radiation therapy, chemotherapies, and surgical resection, but there is no single treatment or combination that is effective for all tumor types. To address this, oncolytic myxoma virus (MYXV) engineered to express human tumor necrosis factor (vMyx-hTNF) was tested after systemic administration in an immunocompetent mouse K7M2-Luc lung metastatic osteosarcoma model. Virus therapy efficacy against pre-seeded lung metastases was assessed after systemic infusion of either naked virus or ex vivo-loaded autologous bone marrow leukocytes or peripheral blood mononuclear cells (PBMCs). Results of this study showed that the PBMC pre-loaded strategy was the most effective at reducing tumor burden and increasing median survival time, but sequential intravenous multi-dosing with naked virus was comparably effective to a single infusion of PBMC-loaded virus. PBMC-loaded vMyx-hTNF also potentially synergized very effectively with immune checkpoint inhibitors anti-PD-1, anti-PD-L1, and anti-cytotoxic T lymphocyte associated protein 4 (CTLA-4). Finally, in addition to the pro-immune stimulation caused by unarmed MYXV, the TNF transgene of vMyx-hTNF further induced the unique expression of numerous additional cytokines associated with the innate and adaptive immune responses in this model. We conclude that systemic ex vivo virotherapy with TNF-α-armed MYXV represents a new potential strategy against lung metastatic cancers like osteosarcoma and can potentially act synergistically with established checkpoint immunotherapies.

Emerging parasitic infections.

Parasitic infections are felt by most individuals to have little impact on the health and well being of most inhabitants of Canada, Western Europe, and the United States. As the authors show in this article, parasites are always "emerging" somewhere and have a significant impact on those areas of the world. Moreover, as we are becoming an ever-smaller global village, catastrophes and instability in the Third World affect control of parasitic diseases endemic to those areas, ensuring greater chances of transmission to visitors there. The foundation of successful limitation of parasitic diseases in both developing and developed regions is still accurate and rapid diagnosis.

Reduction in broad-spectrum antimicrobial use associated with no improvement in hospital antibiogram.

OBJECTIVE: To evaluate the effect of an antimicrobial management programme on broad-spectrum antimicrobial use and antimicrobial susceptibilities of common nosocomial pathogens at a tertiary-care teaching hospital. METHODS: Review of hospital charts of patients who had been prescribed broad-spectrum antimicrobials 48 h earlier. Recommendations to streamline or discontinue antimicrobials were made based on results of available microbiology data, radiography studies, as well as the working diagnosis at the time of review. The charts were reviewed again on the following day to assess acceptance or rejection of the recommendations. Antimicrobial use, measured as defined daily dose per 1000 patient days (DDD/1000 PD), was determined before and after the antimicrobial management programme was started and was assessed as the mean quarterly use in the six quarters preceding implementation of the programme compared to the most recent six quarters that the programme has been in existence. Antibiotic susceptibilities were obtained from the clinical microbiology laboratory. RESULTS: Compared to the six quarters before the programme, broad-spectrum antibiotic use decreased by 28% (693 DDD/1000 PD to 502 DDD/1000 PD, P = 0.003). Total antifungal agent use decreased by a similar amount, i.e. 28% (144 DDD/1000 PD to 103 DDD/1000 PD, P = 0.02). Total antimicrobial use decreased by 27% (1461 DDD/1000 PD to 1069 DDD/1000 PD, P = 0.0007). Susceptibilities of common nosocomial Gram-negative organisms to commonly prescribed antibiotics did not change significantly over the 3 years of the programme. The rate of methicillin-resistant Staphylococcus aureus increased significantly in the non-intensive care areas of the hospital (P = 0.02) and decreased significantly in the intensive care areas of the hospital (P = 0.009) over the 4 year period from 2000 to 2003. CONCLUSION: Implementation of an antibiotic management programme resulted in substantial reductions in both broad-spectrum and total antimicrobial consumption without having a significant impact on antibiotic susceptibilities of common Gram-negative microorganisms within the institution. The changes in MRSA rate in the non-ICU and ICU settings may reflect infection control measures that were in place during the study period.

Dispermic chimerism with two abnormal cell lines, 47,XY, +21 and 47,XX, +12.

Chimerism in humans appears to be a rare phenomenon that is usually discovered by accident. Here we describe a stillborn male fetus with multiple congenital anomalies which was found to have two cytogenetically abnormal cell lines, 47,XY, +21 and 47, XX, +12. The difference in sex chromosome constitution between the cell lines indicated that the fetus had dispermic chimerism. To our knowledge, this is the first report of chimerism with two abnormal cell lines.

Leprosy in wild armadillos (Dasypus novemcinctus) of the Texas Gulf Coast: epidemiology and mycobacteriology

A significant prevalence of leprosy has been demonstrated in wild Louisiana armadillos. The Texas Gulf Coast still has endemic human leprosy, and recent mores in Texas have markedly increased armadillo-human contact. Armadillos were screened by physical examination, and by ear-snip and slit-scrape technique. Animals that screened positive were sacrificed and necropsied under aseptic conditions. Liver, spleen, gross lesions, and four groups of lymph nodes were cultured for mycobacteria and were studied histologically. Base ratios and DNA homology with Mycobacterium leprae were determined on mycobacteria from two armadillos (and two tissues from one of these); these studies indicate that the organism found in Texas armadillos is M leprae. Twenty-one of the armadillos were leprous--4.66%. The local prevalence varied from 1.0% to 15.4%. Epidemiologic implications of these findings and the occurrence of other concomitant mycobacterial infections are discussed.

Schistosoma mansoni control in Cul de Sac Valley, Saint Lucia. 1. A two-year focal surveillance-mollusciciding programme for the control of Biomphalaria glabrata

An area-wide mollusciciding campaign in Cul de Sac valley, St. Lucia reduced incidence of Schistosoma mansoni from 22 percent to 4.3 percent between 1970 and 1975. Following this, a two-year focal surveillance-mollusciciding programme was introduced. Sites of potential transmission of S. mansoni were identified and routinely searched for Biomphalaria glabrata. If found, the site was treated with clonitrralide 25 percent emulsifiable concentrate. Two chemotherapy campaigns supplemented the snail control programme. As a result of the combined measures, incidence of the infection dropped from 4.3 percent to 1.0 percent and from 2.2 percent to 0.6 percent in areas originally of high and low transmission respectively. The cost of protecting the 7,000 population was US $20,362: of these costs, labour absorbed 68 percent, transport 24 percent, equipment 4 percent and molluscicide 4 percent. The cost per person per year protected was US $1.45 which compares favourably with the $3.24 of the previous scheme. Although effective and relatively cheap, this programme was still dependent on a high standard of supervision for maximum benefit. (AU)

Laboratory and field trials of a slow-release copper molluscicide in St. Lucia

Tests of a slow-release molluscicide containing 50 percent copper sulfate were undertaken in laboratory and field situations in St. Lucia. In laboratory trials, a granule form of the molluscicide produced 100 percent mortality of Biomphalaria glabrata down to 4 mg.liter active ingredient (a.i), while the pellet form produced 100 percent mortality down to 8 mg/liter a.i. In field trials, a dose of 100 mg/liter a.i. in granule form caused mortality of B. glabrata in banana drains but had no effect on B. glabrata populations in a marsh habitat. In both habitats, the dose of 100mg/liter produced mortality of other molluscan fauna which caused changes in the molluscan diversity indices. This failure in field trials may have been due to dilution of copper levels caused by flooding and also by uptake of copper by mud and algae (AU)

Further observations from St Lucia on control of Schistosoma mansoni transmission by provision of domestic water supplies

Individual households in five settlements were provided with piped water in a pilot scheme to investigate the effect on transmission of S. mansoni in St Lucia. Nearby comparison settlements, in the same valley, were provided with water through a public standpipe system. The incidence of S. mansoni infection among children decreased in the experimental area, leading to lower prevalence rates and lower intensity of infection in all age groups. Over the study period, indices of infection increased in the comparison settlements, but by the end of the period development was making those settlements less suitable for comparison purposes and some reduction in transmission was occurring. The changes in human infection rates were reflected in the results of studies with sentinel snails. In the experimental area, infection rates gradually fell owing to reduced water contact and consequently less contamination of the river and its banks, and possibly to the intensity of infection. It is suggested that a piped water supply be considered as a method of schistosomiasis control, but that the cost should not be debited only to the control of this disease since clean water supply has other medical and social benefits (AU)

Evaluation of an experimental mollusciciding programme to control Schistosoma mansoni transmission in St Lucia

The size and number of colonies of Biomphalaria glabrata were reduced after four years of a surveillance/treatment snail control programme using an emulsifiable concentrate of niclosamide (25 percent active ingredient). Surveys among the human population showed that the incidence of new Schistosoma mansoni infections in 0-10 year-old children fell from 22 percent to 4.3 percent, while in a comparison area the incidence remained at 20 percent. With the reduced transmission over four years, the prevalence of infection in a cohort of children examined in 1971 and 1975 fell from 34 percent to 23 percent. The fall in prevalence and intensity of infection led to a reduction of 66 percent in the index of potential contamination, which was reflected in a reduced rate of infection among sentinel snails and representative samples of B. glabrata collected during surveillance searchs. The overall annual cost of the programme was US $3.24 per capita (AU)

Control of Schistosoma mansoni transmission by chemotherapy in St. Lucia. II. Biological results

Chemotherapy of all persons infected with Schistosoma mansoni was begun in Marquis Valley, St. Lucia, in March 1974. From January 1972 to the start of chemotherapy, the infection rate in field Biomphalaria glabrata collected in the valley was 1.09 percent (117/10,736) and the rate in sentinel B. glabrata was 1.48 percent (56/3,790). From March 1974 through December 1975, no infections were detected in either field snails (11,742 collected) or sentinel snails (3,230 exposed). The accumulation data suggest that, because of differences in topography and average annual rainfall, S. mansoni transmission occurs in this valley during the rainy season, whereas in other St. Lucian valleys under study it occurs during the dry season (AU)