Epidemiological impact of waning immunization on a vaccinated population

This is an epidemiological SIRV model based study that is de- signed to analyze the impact of vaccination in containing infection spread, in a 4-tiered population compartment comprised of susceptible, infected, recov- ered and vaccinated agents. While many models assume a lifelong protection through vaccination, we focus on the impact of waning immunization due to conversion of vaccinated and recovered agents back to susceptible ones. Two asymptotic states exist, the \disease-free equilibrium" and the \endemic equi- librium" and we express the transitions between these states as function of the vaccination and conversion rates and using the basic reproduction number. We nd that the vaccination of newborns and adults have dierent consequences on controlling an epidemic. Also, a decaying disease protection within the re- covered sub-population is not sucient to trigger an epidemic on the linear level. We perform simulations for a parameter set modelling a disease with waning immunization like pertussis. For a diusively coupled population, a transition to the endemic state can proceed via the propagation of a traveling infection wave, described successfully within a Fisher-Kolmogorov framework

Endothelial cells regulate p53-dependent apoptosis of neural progenitors after irradiation

Endothelial cells represent an important component of the neurogenic niche and may regulate self-renewal and differentiation of neural progenitor cells (NPCs). Whether they have a role in determining the apoptotic fate of NPCs after stress or injury is unclear. NPCs are known to undergo p53-dependent apoptosis after ionizing radiation, whereas endothelial cell apoptosis after irradiation is dependent on membrane acid sphingomyelinase (ASMase) and is abrogated in sphingomyelin phosphodiesterase 1 (smpd1)- (gene that encodes ASMase) deficient mice. Here we found that p53-dependent apoptosis of NPCs in vivo after irradiation was inhibited in smpd1-deficient mice. NPCs cultured from mice, wild type (+/+) or knockout (−/−), of the smpd1 gene, however, demonstrated no difference in apoptosis radiosensitivity. NPCs transplanted into the hippocampus of smpd1−/− mice were protected against apoptosis after irradiation compared with those transplanted into smpd1+/+ mice. Intravenous administration of basic fibroblast growth factor, which does not cross the blood–brain barrier, known to protect endothelial cells against apoptosis after irradiation also attenuated the apoptotic response of NPCs. These findings provide evidence that endothelial cells may regulate p53-dependent apoptosis of NPCs after genotoxic stress and add support to an important role of endothelial cells in regulating apoptosis of NPCs after injury or in disease

Endothelial Membrane Remodeling Is Obligate for Anti-Angiogenic Radiosensitization during Tumor Radiosurgery

While there is significant interest in combining anti-angiogenesis therapy with conventional anti-cancer treatment, clinical trials have as of yet yielded limited therapeutic gain, mainly because mechanisms of anti-angiogenic therapy remain to a large extent unknown. Currently, anti-angiogenic tumor therapy is conceptualized to either "normalize" dysfunctional tumor vasculature, or to prevent recruitment of circulating endothelial precursors into the tumor. An alternative biology, restricted to delivery of anti-angiogenics immediately prior to single dose radiotherapy (radiosurgery), is provided in the present study.Genetic data indicate an acute wave of ceramide-mediated endothelial apoptosis, initiated by acid sphingomyelinase (ASMase), regulates tumor stem cell response to single dose radiotherapy, obligatory for tumor cure. Here we show VEGF prevented radiation-induced ASMase activation in cultured endothelium, occurring within minutes after radiation exposure, consequently repressing apoptosis, an event reversible with exogenous C(16)-ceramide. Anti-VEGFR2 acts conversely, enhancing ceramide generation and apoptosis. In vivo, MCA/129 fibrosarcoma tumors were implanted in asmase(+/+) mice or asmase(-/-) littermates and irradiated in the presence or absence of anti-VEGFR2 DC101 or anti-VEGF G6-31 antibodies. These anti-angiogenic agents, only if delivered immediately prior to single dose radiotherapy, de-repressed radiation-induced ASMase activation, synergistically increasing the endothelial apoptotic component of tumor response and tumor cure. Anti-angiogenic radiosensitization was abrogated in tumors implanted in asmase(-/-) mice that provide apoptosis-resistant vasculature, or in wild-type littermates pre-treated with anti-ceramide antibody, indicating that ceramide is necessary for this effect.These studies show that angiogenic factors fail to suppress apoptosis if ceramide remains elevated while anti-angiogenic therapies fail without ceramide elevation, defining a ceramide rheostat that determines outcome of single dose radiotherapy. Understanding the temporal sequencing of anti-angiogenic drugs and radiation enables optimized radiosensitization and design of innovative radiosurgery clinical trials

Adenoviral Transduction of Human Acid Sphingomyelinase into Neo-Angiogenic Endothelium Radiosensitizes Tumor Cure

These studies define a new mechanism-based approach to radiosensitize tumor cure by single dose radiotherapy (SDRT). Published evidence indicates that SDRT induces acute microvascular endothelial apoptosis initiated via acid sphingomyelinase (ASMase) translocation to the external plasma membrane. Ensuing microvascular damage regulates radiation lethality of tumor stem cell clonogens to effect tumor cure. Based on this biology, we engineered an ASMase-producing vector consisting of a modified pre-proendothelin-1 promoter, PPE1(3x), and a hypoxia-inducible dual-binding HIF-2α-Ets-1 enhancer element upstream of the asmase gene, inserted into a replication-deficient adenovirus yielding the vector Ad5H2E-PPE1(3x)-ASMase. This vector confers ASMase over-expression in cycling angiogenic endothelium in vitro and within tumors in vivo, with no detectable enhancement in endothelium of normal tissues that exhibit a minute fraction of cycling cells or in non-endothelial tumor or normal tissue cells. Intravenous pretreatment with Ad5H2E-PPE1(3x)-ASMase markedly increases SDRT cure of inherently radiosensitive MCA/129 fibrosarcomas, and converts radiation-incurable B16 melanomas into biopsy-proven tumor cures. In contrast, Ad5H2E-PPE1(3x)-ASMase treatment did not impact radiation damage to small intestinal crypts as non-dividing small intestinal microvessels did not overexpress ASMase and were not radiosensitized. We posit that combination of genetic up-regulation of tumor microvascular ASMase and SDRT provides therapeutic options for currently radiation-incurable human tumors.</p

Adenoviral Transduction of Human Acid Sphingomyelinase into Neo-Angiogenic Endothelium Radiosensitizes Tumor Cure

<div><p>These studies define a new mechanism-based approach to radiosensitize tumor cure by single dose radiotherapy (SDRT). Published evidence indicates that SDRT induces acute microvascular endothelial apoptosis initiated via acid sphingomyelinase (ASMase) translocation to the external plasma membrane. Ensuing microvascular damage regulates radiation lethality of tumor stem cell clonogens to effect tumor cure. Based on this biology, we engineered an ASMase-producing vector consisting of a modified pre-proendothelin-1 promoter, <i>PPE1(3x)</i>, and a hypoxia-inducible dual-binding <i>HIF-2α-Ets-1</i> enhancer element upstream of the <i>asmase</i> gene, inserted into a replication-deficient adenovirus yielding the vector <i>Ad5H2E-PPE1(3x)-ASMase</i>. This vector confers ASMase over-expression in cycling angiogenic endothelium <i>in vitro</i> and within tumors <i>in vivo</i>, with no detectable enhancement in endothelium of normal tissues that exhibit a minute fraction of cycling cells or in non-endothelial tumor or normal tissue cells. Intravenous pretreatment with <i>Ad5H2E-PPE1(3x)-ASMase</i> markedly increases SDRT cure of inherently radiosensitive MCA/129 fibrosarcomas, and converts radiation-incurable B16 melanomas into biopsy-proven tumor cures. In contrast, <i>Ad5H2E-PPE1(3x)-ASMase</i> treatment did not impact radiation damage to small intestinal crypts as non-dividing small intestinal microvessels did not overexpress ASMase and were not radiosensitized. We posit that combination of genetic up-regulation of tumor microvascular ASMase and SDRT provides therapeutic options for currently radiation-incurable human tumors.</p></div

Infection with <i>Ad5H2E-PPE1(3x)-GFP</i> confers GFP expression specific to endothelial cells.

<p>(<b>A</b>) Schematic representation of gene therapy vectors used to overexpress the GFP reporter or human ASMase. (<b>B</b>) Primary cultures of bovine and human endothelial cells (BAEC, HUVEC and HCAEC) and non-endothelial cells (HeLa) were infected with <i>Ad5H2E-PPE1(3x)-GFP</i>. GFP expression was measured in live cells following detachment 72 h post-infection by flow cytometry.</p

ASMase overexpression in tumor endothelium radiosensitizes MCA/129 fibrosarcomas and B16 melanomas.

<p>1×10¹⁰ PFU of <i>Ad5Empty</i> or <i>Ad5H2E-PPE1(3x)-ASMase</i> was administered intravenously to MCA/129 fibrosarcoma- (<b>A,B</b>) and B16 melanoma (<b>C,D</b>)-bearing sv129/BL6^JAX mice, as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0069025#pone-0069025-g005" target="_blank">Figure 5</a>. Five (<b>A</b>,<b>B</b>) or four (<b>C,D</b>) days post virus administration tumors were locally irradiated with 14.5, 17 Gy and 20 Gy (<b>A,B</b>), or 34 and 41 Gy (<b>C,D). (A,C</b>) Response of MCA/129 fibrosarcoma <b>(A)</b> and B16-F1 melanoma <b>(C)</b> to <i>Ad5Empty</i> (gray lines) or <i>Ad5H2E-PPE1(3x)-ASMase</i> (black lines) followed by IR. N = animals/group. Tumors were measured daily up to 40 days and twice weekly thereafter. Tumor cure was confirmed by local biopsy. (<b>B</b>,<b>D</b>) Quantitation of the impact of <i>Ad5H2E-PPE1(3x)-ASMase</i> on radiation-induced endothelial cell apoptosis within MCA/129 fibrosarcomas <b>(B)</b> and B16-F1 melanomas <b>(D)</b> implanted into sv129/BL6^JAX<i>asmase^+/+</i> mice. Data (mean ± SEM) represent TUNEL-positive endothelial cells quantified from 20 (400× magnification) fields/tumor using 2 tumors/group. (<b>E</b>) ASMase overexpression in tumor endothelium using the murine <i>VEGFR2</i> promoter radiosensitizes B16 melanoma. 2×10¹⁰ PFU of <i>Ad5H2E-mVEGFR2-ASMase</i> was administered intravenously to B16 melanoma-bearing sv129/BL6^JAX mice. Five days thereafter tumors were locally irradiated with 41 Gy. B16 melanoma response to <i>Ad5H2E-mVEGFR2-ASMase</i> and irradiation (black lines) or radiation alone (gray lines) are presented as tumor volumes.</p