Cancer-associated fibroblasts constitute a vital subpopulation of the tumor stroma and are present in more than 90% of epithelial carcinomas. The overexpression of the serine protease fibroblast activation protein (FAP) allows a selective targeting of a variety of tumors by inhibitor-based radiopharmaceuticals (FAPIs). Of these compounds, FAPI-04 has been recently introduced as a theranostic radiotracer and demonstrated high uptake into different FAP-positive tumors in cancer patients. To enable the delivery of higher doses, thereby improving the outcome of a therapeutic application, several FAPI variants were designed to further increase tumor uptake and retention of these tracers. Methods: Novel quinoline-based radiotracers were synthesized by organic chemistry and evaluated in radioligand binding assays using FAP-expressing HT-1080 cells. Depending on their in vitro performance, small-animal PET imaging and biodistribution studies were performed on HT-1080-FAP tumor–bearing mice. The most promising compounds were used for clinical PET imaging in 8 cancer patients. Results: Compared with FAPI-04, 11 of 15 FAPI derivatives showed improved FAP binding in vitro. Of these, 7 compounds demonstrated increased tumor uptake in tumor-bearing mice. Moreover, tumor–to–normal-organ ratios were improved for most of the compounds, resulting in images with higher contrast. Notably two of the radiotracers, FAPI-21 and -46, displayed substantially improved ratios of tumor to blood, liver, muscle, and intestinal uptake. A first diagnostic application in cancer patients revealed high intratumoral uptake of both radiotracers already 10 min after administration but a higher uptake in oral mucosa, salivary glands, and thyroid for FAPI-21. Conclusion: Chemical modification of the FAPI framework enabled enhanced FAP binding and improved pharmacokinetics in most of the derivatives, resulting in high-contrast images. Moreover, higher doses of radioactivity can be delivered while minimizing damage to healthy tissue, which may improve therapeutic outcome.
The secretion of interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-4, IL-5, and IL-10 by antigen-stimulated lymph node cells, eosinophil maturation, and the antibody isotypes produced were examined during intraperitoneal infection of susceptible (B10.A) and resistant (A/Sn) mice with Paracoccidioides brasiliensis. Lymph node cells from resistant mice produced early and sustained levels of IFN-gamma and IL-2, whereas susceptible animals secreted low to undetectable amounts of these type 1 cytokines. Both mouse strains presented late and transient production of IL-4, whereas IL-10 was produced constantly throughout the course of disease. Resistant animals produced increasing levels of IL-5 in the chronic phase of the infection (from the eighth week on), whereas susceptible mice showed two peaks of IL-5 production, at the first and twelfth weeks after infection. Only the susceptible strain presented medullary and splenic eosinophilia concomitant with the raised IL-5 production. In resistant mice, the levels of IgG2a antibodies were significantly higher than those observed in susceptible mice, which preferentially secreted IgG2b and IgA isotypes. Taken together, these results demonstrate that a sustained production of IFN-gamma and IL-2 and a predominant secretion of IgG2a antibodies are associated with resistance to P. brasiliensis. In contrast, the production of low levels of IFN-gamma, early secretion of high levels of IL-5 and IL-10, eosinophilia, and a preferential secretion of IgG2b and IgA isotypes characterize the progressive disease in susceptible animals.
Background:New screening technologies and vaccination against human papillomavirus (HPV), the necessary cause of cervical cancer, may impact optimal approaches to prevent cervical cancer. We evaluated the cost-effectiveness of alternative screening strategies to inform cervical cancer prevention guidelines in Norway.Methods:We leveraged the primary epidemiologic and economic data from Norway to contextualise a simulation model of HPV-induced cervical cancer. The current cytology-only screening was compared with strategies involving cytology at younger ages and primary HPV-based screening at older ages (31/34+ years), an option being actively deliberated by the Norwegian government. We varied the switch-age, screening interval, and triage strategies for women with HPV-positive results. Uncertainty was evaluated in sensitivity analysis.Results:Current cytology-only screening was less effective and more costly than strategies that involve switching to primary HPV testing in older ages. For unvaccinated women, switching at age 34 years to primary HPV testing every 4 years was optimal given the Norwegian cost-effectiveness threshold ($83 000 per year of life saved). For vaccinated women, a 6-year screening interval was cost-effective. When we considered a wider range of strategies, we found that an earlier switch to HPV testing (at age 31 years) may be preferred.Conclusions:Strategies involving a switch to HPV testing for primary screening in older women is expected to be cost-effective compared with current recommendations in Norway.
We have developed a murine model of pulmonary infection byParacoccidioides brasiliensis in which resistance was associated with immunological activities governed by gamma interferon (IFN-γ). To better characterize this model, we measured type 1 and type 2 cytokines in the lungs and investigated the effect of endogenous IFN-γ depletion by monoclonal antibodies in the course of infection of susceptible (B10.A) and resistant (A/Sn) mice. At weeks 4 and 8 after infection, lungs from susceptible animals presented levels of IFN-γ, interleukin-4 (IL-4), IL-5, and IL-10 higher than those in resistant mice. In both mouse strains, neutralization of endogenous IFN-γ induced exacerbation of the pulmonary infection, earlier fungal dissemination to the liver and spleen, impairment of the specific cellular immune response resulting in significantly lower delayed-type hypersensitivity reactions, and increased levels of immunoglobulin G1 (IgG1)- and IgG2b-specific antibodies. Histopathological analysis demonstrated that depletion of IFN-γ changes the focal granulomatous lesions found in the lungs of B10.A and A/Sn mice into coalescent granulomata which destroy the pulmonary architecture. These results suggest that irrespective of the mouse strain, IFN-γ plays a protective role and that this cytokine is one major mediator of resistance against P. brasiliensis infection in mice.
We studied the influence of the growth factor (GF) source, concentration and production time on the plating efficiency of Paracoccidioides brasiliensis yeast cells. The highest plating efficiencies were achieved when the GF was derived from a fast growing P. brasiliensis isolate which was not homologous to the plated samples.The colony forming units (c.f.u.) procedure is widely used when quantitation of viable micro-organisms is desired such as in studies concerning killing of bacteria or fungi by specific and non-specific mechanisms or the effect of therapeutic agents. The method entails plating the inoculum onto an appropriate semi-solid culture medium and counting the number of c.f.u, after an adequate incubation period. Plating efficiency is crucial in this method and has been defined as the number of colonies formed divided by hemacytometer counts of viable units, usually expressed as percentages .The application of the c.f.u, method to the dimorphic fungus Paracoccidioides brasiliensis, employing standard mycological media, presents a very low plating efficiency [4,7]. Improved efficiency was obtained by Castaneda et al. using culture media (brain heart infusion agar (BHI), or modified McVeigh-Morton agar) supplemented with 5% culture filtrate from P. brasiliensis, as a source of growth-promoting factor (GF), and 4% horse serum.We have studied the effect of the GF source, concentration and time produced on the plating efficiency of P. brasiliensis samples in their yeast form. These studies were conducted by plating two P brasiliensis isolates, Pbl8AT, derived from a human isolate (Pbl8) which became attenuated by continuous in vitro subculture, and Pbl8R, which was reisolated from mice infected with Pbl8AT and is highly virulent .As GF sources we used broth filtrates from yeast cultures of Pbl8AT, Pbl8R and Pb192. Pb192 is a human isolate obtained from the fungal culture collection of the
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