Cancer immunotherapy by immunosuppression

We have previously suggested that the stimulatory effect of a weak immune reaction on tumor growth may be necessary for the growth of incipient tumors. In the present paper, we enlarge upon and extend that idea by collecting evidence in the literature bearing upon this new hypothesis that a growing cancer, whether in man or mouse, is throughout its lifespan, probably growing and progressing because of continued immune stimulation by a weak immune reaction. We also suggest that prolonged immunosuppression might interfere with progression and thus be an aid to therapy. While most of the considerable evidence that supports the hypothesis comes from observations of experimental mouse tumors, there is suggestive evidence that human tumors may behave in much the same way, and as far as we can ascertain, there is no present evidence that necessarily refutes the hypothesis

On the Action of Methotrexate and 6-Mercaptopurine on M. avium Subspecies paratuberculosis

BACKGROUND: Clinical improvement in inflammatory bowel disease (IBD) treated with methotrexate and 6-mercaptopurine (6-MP) is associated with a decrease in pro-inflammatory cytokines. This has been presumed to indicate the mechanism of action of methotrexate and 6-MP. Although controversial, there are increasingly compelling data that Mycobacterium avium subspecies paratuberculosis (MAP) may be an etiological agent in some or all of IBD. We hypothesized that the clinical efficacy of methotrexate and 6-MP in IBD may be to simply inhibit the growth of MAP. METHODOLOGY: The effect on MAP growth kinetics by methotrexate and 6-MP were evaluated in cell culture of two strains each of MAP and M. avium using a radiometric ((14)CO(2) BACTEC®) detection system that quantifies mycobacterial growth as arbitrary “growth index units” (GI). Efficacy data are presented as “percent decrease in cumulative GI” (% −ΔcGI). PRINCIPAL FINDINGS: The positive control antibiotic (clarithromycin) has ≥85% −ΔcGI at a concentration of 0.5 µg/ml. The negative control (ampicillin) has minimal inhibition at 64 µg/ml. MAP ATCC 19698 shows ≥80% −ΔcGI for both agents by 4 µg/ml. With the other three isolates, although more effective than ampicillin, 6-MP is consistently less effective than methotrexate. CONCLUSIONS: We show that methotrexate and 6-MP inhibit MAP growth in vitro. Each of the four isolates manifests different % −ΔcGI. These data are compatible with the hypothesis that the clinical improvement in patients with IBD treated with methotrexate and 6-MP could be due to treating a MAP infection. The decrease in pro-inflammatory cytokines, thought to be the primary mechanism of action, may simply be a normal, secondary, physiological response. We conclude that henceforth, in clinical studies that evaluate the effect of anti-MAP agents in IBD, the use of methotrexate and 6-MP should be excluded from any control groups

The Combined Influence of Oral Contraceptives and Human Papillomavirus Virus on Cutaneous Squamous Cell Carcinoma

The vast majority of cutaneous squamous cell carcinoma (CSCC) will occur in those with fair complexion, tendency to burn, and high ultraviolet radiation (UVR) exposure. Organ transplant recipients also are an important population at great risk for CSCC. An association has been reported between oral contraceptive (OC) use, human papillomavirus virus (HPV) and cervical cancer, and there could be a similar association for CSCC. The cutaneous HPV β-E6 protein, a close cousin of the transformative E6 protein underlying anogenital cancers, has been shown to inhibit apoptosis in response to UVR damage and stimulate morphologic transformation in rodent fibroblast cell lines. Furthermore, OC use has been shown to enhance HPV transcription and may contribute to CSCC risk through this pathway

There is more than one way to turn a spherical cellular monolayer inside out: type B embryo inversion in Volvox globator

Höhn S, Hallmann A. There is more than one way to turn a spherical cellular monolayer inside out: type B embryo inversion in Volvox globator. BMC Biology. 2011;9(1): 89.Background: Epithelial folding is a common morphogenetic process during the development of multicellular organisms. In metazoans, the biological and biomechanical processes that underlie such three-dimensional (3D) developmental events are usually complex and difficult to investigate. Spheroidal green algae of the genus Volvox are uniquely suited as model systems for studying the basic principles of epithelial folding. Volvox embryos begin life inside out and then must turn their spherical cell monolayer outside in to achieve their adult configuration; this process is called 'inversion.' There are two fundamentally different sequences of inversion processes in Volvocaceae: type A and type B. Type A inversion is well studied, but not much is known about type B inversion. How does the embryo of a typical type B inverter, V. globator, turn itself inside out? Results: In this study, we investigated the type B inversion of V. globator embryos and focused on the major movement patterns of the cellular monolayer, cell shape changes and changes in the localization of cytoplasmic bridges (CBs) connecting the cells. Isolated intact, sectioned and fragmented embryos were analyzed throughout the inversion process using light microscopy, confocal laser scanning microscopy, scanning electron microscopy and transmission electron microscopy techniques. We generated 3D models of the identified cell shapes, including the localizations of CBs. We show how concerted cell-shape changes and concerted changes in the position of cells relative to the CB system cause cell layer movements and turn the spherical cell monolayer inside out. The type B inversion of V. globator is compared to the type A inversion in V. carteri. Conclusions: Concerted, spatially and temporally coordinated changes in cellular shapes in conjunction with concerted migration of cells relative to the CB system are the causes of type B inversion in V. globator. Despite significant similarities between type A and type B inverters, differences exist in almost all details of the inversion process, suggesting analogous inversion processes that arose through parallel evolution. Based on our results and due to the cellular biomechanical implications of the involved tensile and compressive forces, we developed a global mechanistic scenario that predicts epithelial folding during embryonic inversion in V. globator

Data And Numerical Analysis Of Astronomic Tides, Wind-Waves, And Hurricane Storm Surge Along The Northern Gulf Of Mexico

The northern Gulf of Mexico (NGOM) is a unique geophysical setting for complex tropical storm-induced hydrodynamic processes that occur across a variety of spatial and temporal scales. Each hurricane includes its own distinctive characteristics and can cause unique and devastating storm surge when it strikes within the intricate geometric setting of the NGOM. While a number of studies have explored hurricane storm surge in the NGOM, few have attempted to describe storm surge and coastal inundation using observed data in conjunction with a single large-domain high-resolution numerical model. To better understand the oceanic and nearshore response to these tropical cyclones, we provide a detailed assessment, based on field measurements and numerical simulation, of the evolution of wind waves, water levels, and currents for Hurricanes Ivan (2004), Dennis (2005), Katrina (2005), and Isaac (2012), with focus on Mississippi, Alabama, and the Florida Panhandle coasts. The developed NGOM3 computational model describes the hydraulic connectivity among the various inlet and bay systems, Gulf Intracoastal Waterway, coastal rivers and adjacent marsh, and built infrastructure along the coastal floodplain. The outcome is a better understanding of the storm surge generating mechanisms and interactions among hurricane characteristics and the NGOM\u27s geophysical configuration. The numerical analysis and observed data explain the ∼2 m/s hurricane-induced geostrophic currents across the continental shelf, a 6 m/s outflow current during Ivan, the hurricane-induced coastal Kelvin wave along the shelf, and for the first time a wealth of measured data and a detailed numerical simulation was performed and was presented for Isaac

Tidal hydrodynamics under future sea level rise and coastal morphology in the Northern Gulf of Mexico

This study examines the integrated influence of sea level rise (SLR) and future morphology on tidal hydrodynamics along the Northern Gulf of Mexico (NGOM) coast including seven embayments and three ecologically and economically significant estuaries. A large-domain hydrodynamic model was used to simulate astronomic tides for present and future conditions (circa 2050 and 2100). Future conditions were simulated by imposing four SLR scenarios to alter hydrodynamic boundary conditions and updating shoreline position and dune heights using a probabilistic model that is coupled to SLR. Under the highest SLR scenario, tidal amplitudes within the bays increased as much as 67% (10.0 cm) because of increases in the inlet cross-sectional area. Changes in harmonic constituent phases indicated that tidal propagation was faster in the future scenarios within most of the bays. Maximum tidal velocities increased in all of the bays, especially in Grand Bay where velocities doubled under the highest SLR scenario. In addition, the ratio of the maximum flood to maximum ebb velocity decreased in the future scenarios (i.e., currents became more ebb dominant) by as much as 26% and 39% in Weeks Bay and Apalachicola, respectively. In Grand Bay, the flood-ebb ratio increased (i.e., currents became more flood dominant) by 25% under the lower SLR scenarios, but decreased by 16% under the higher SLR as a result of the offshore barrier islands being overtopped, which altered the tidal prism. Results from this study can inform future storm surge and ecological assessments of SLR, and improve monitoring and management decisions within the NGOM