Based on original qualitative data on the mobilization of anti‐Kyiv combatants during the war in eastern Ukraine (started in 2014), this article suggests an approach for understanding the spontaneous ...mobilization of nonstate armed groups during contemporary military conflicts. This approach is based on the notion of career as a collective path of mobilization unfolding over time. It explains how different mobilization factors usually proposed in the literature on contemporary civil wars acquire their mobilization power. The article identifies five combatant careers leading to joining the anti‐Kyiv armed groups: evolving localists, disrupted outcasts, nationalist warriors, adventurous ideologues, and inspired sympathizers. It demonstrates that (1) mobilization requires the combination of factors such as economic incentives, ideological affinity, social connections, and conflict dynamics in a particularly sequenced way, (2) this combination is different for each career path, and (3) these factors acquire their mobilizing capacity only in the context of particular social trajectories.
Based on original qualitative data on the mobilization of anti‐Kyiv combatants during the war in eastern Ukraine (started in 2014), this article suggests an approach for understanding the spontaneous ...mobilization of nonstate armed groups during contemporary military conflicts. This approach is based on the notion of career as a collective path of mobilization unfolding over time. It explains how different mobilization factors usually proposed in the literature on contemporary civil wars acquire their mobilization power. The article identifies five combatant careers leading to joining the anti‐Kyiv armed groups: evolving localists, disrupted outcasts, nationalist warriors, adventurous ideologues, and inspired sympathizers. It demonstrates that (1) mobilization requires the combination of factors such as economic incentives, ideological affinity, social connections, and conflict dynamics in a particularly sequenced way, (2) this combination is different for each career path, and (3) these factors acquire their mobilizing capacity only in the context of particular social trajectories.
Based on original qualitative data on the mobilization of anti‐Kyiv combatants during the war in eastern Ukraine (started in 2014), this article suggests an approach for understanding the spontaneous ...mobilization of nonstate armed groups during contemporary military conflicts. This approach is based on the notion of career as a collective path of mobilization unfolding over time. It explains how different mobilization factors usually proposed in the literature on contemporary civil wars acquire their mobilization power. The article identifies five combatant careers leading to joining the anti‐Kyiv armed groups: evolving localists, disrupted outcasts, nationalist warriors, adventurous ideologues, and inspired sympathizers. It demonstrates that (1) mobilization requires the combination of factors such as economic incentives, ideological affinity, social connections, and conflict dynamics in a particularly sequenced way, (2) this combination is different for each career path, and (3) these factors acquire their mobilizing capacity only in the context of particular social trajectories.
BackgroundCancer is characterized by an accumulation of somatic mutations, of which a significant subset can generate cancer-specific neoepitopes that are recognized by autologous T cells. Such ...neoepitopes are emerging as important targets for cancer immunotherapy, including personalized cancer vaccination strategies.MethodsWe used whole-exome and RNA sequencing analysis to identify potential neoantigens for a patient with non-small cell lung cancer. Thereafter, we assessed the autologous T-cell reactivity to the candidate neoantigens using a long peptide approach in a cultured interferon gamma ELISpot and tracked the neoantigen-specific T-cells in the tumor by T-cell receptor (TCR) sequencing. In parallel, identified gene variants were incorporated into a Modified Vaccinia Ankara-based vaccine, which was evaluated in the human leucocyte antigen A*0201 transgenic mouse model (HHD).ResultsSequencing revealed a tumor with a low mutational burden: 2219 sequence variants were identified from the primary tumor, of which 23 were expressed in the transcriptome, involving 18 gene products. We could demonstrate spontaneous T-cell responses to 5/18 (28%) mutated gene variants, and further analysis of the TCR repertoire of neoantigen-specific CD4+ and CD8+ T cells revealed TCR clonotypes that were expanded in both blood and tumor tissue. Following vaccination of HHD mice, de novo T-cell responses were generated to 4/18 (22%) mutated gene variants; T cells reactive against two variants were also evident in the autologous setting. Subsequently, we determined the major histocompatibility complex restriction of the T-cell responses and used in silico prediction tools to determine the likely neoepitopes.ConclusionsOur study demonstrates the feasibility of efficiently identifying tumor-specific neoantigens that can be targeted by vaccination in tumors with a low mutational burden, promising successful clinical exploitation, with trials currently underway.
BackgroundPatients with oral potentially malignant disorders (OPMD) having moderate or severe oral epithelial dysplasia (OED) have a greater risk of developing oral squamous cell carcinoma (OSCC) ...compared to mild OED with an odds ratio of 2.4.1 The involvement of specific immune cell types associated with malignant transformation have been reported, giving rise to clinical trials in immunoprevention. However, the immune landscape of OPMD remains understudied. In this study, we aimed to elucidate the immune landscape of high-risk OPMD by transcriptomic profiling for the identification of potential immunoprevention strategy.MethodsHistological evaluation was performed on hematoxylin and eosin (H&E)-stained tissues to investigate the differences of lymphocyte infiltration in benign lesions (n=16), high-risk OPMD consisted of moderate and severe OED (n=46) and early-stage OSCC (n=6). Formalin-fixed paraffin-embedded tissue sections of selected cases from each sample type were subjected to RNA sequencing. Weighted-gene-correlation network analysis (WGCNA) was used to identify key gene modules expressed in specific disease type.2 The immune landscape of high-risk OPMD was elucidated by the enrichment of immune signatures using single-sample gene set enrichment analysis.3–5 The response of high-risk OPMD to anti-PD1 treatment was predicted by the detection of T-cell-inflamed condition.6 Validation was performed by multiplex immunofluorescent (mIF) staining.ResultsOur H&E evaluation showed that lymphocyte infiltration into the epithelial was seen in 80% of high-risk OPMD and early-stage OSCC, compared to 9% of benign lesion. Gene modules identified from WGCNA analysis revealed that genes involved in immune-related pathways were overexpressed in high-risk OPMD and in early-stage OSCC when compared to benign lesion, but unchanged between high-risk OPMD and early-stage OSCC. We further demonstrated that immune signatures representing lymphocyte infiltration, MHC-I antigen presentation and cytotoxic immune responses were enriched in high-risk OPMD, indicating the presence of immune surveillance. High-risk OPMD can be grouped into the T-cell-inflamed and non-immune reactive subtypes. The T-cell-inflamed subtype is enriched with T cells, interferon signaling and PD-1/PD-L1 immune checkpoint proteins, suggesting that these lesions may be amenable to anti-PD1 treatment. Meanwhile, the non-immune reactive subtype demonstrated low enrichment in signatures for immune cell infiltration, indicating a need of intervention to induce lymphocyte infiltration. Using mIF staining, we observed an increase of CD45+ immune cell population expressing PD-L1 in high-risk OPMD.ConclusionsImmune surveillance is a prominent feature of high-risk OPMD. However, different subsets of high-risk OPMD exist, suggesting a need of different immunoprevention approaches to prevent disease progression which warrants further investigation.AcknowledgementsThis study was supported and funded by the Global Challenge Research Fund by the Medical Research Council, UK (MR/P024351/1) and Cancer Research Malaysia. We thank the Ong Heng Tiang & Ong Sek Pek Foundation for scholarship sponsorship.ReferencesIocca O, Sollecito TP, Alawi F, et al. Potentially malignant disorders of the oral cavity and oral dysplasia: a systematic review and meta-analysis of malignant transformation rate by subtype. Head Neck 2020;42:539–55.Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 2008;9:559.Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102:15545–50.Chen YP, Wang YQ, Lv JW, et al. Identification and validation of novel microenvironment-based immune molecular subgroups of head and neck squamous cell carcinoma: implications for immunotherapy. Ann Oncol 2019;30:68–75.Thorsson V, Gibbs DL, Brown SD, et al. The immune landscape of cancer. Immunity 2018;48:812–30.Ayers M, Lunceford J, Nebozhyn M, et al. IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest 2017;127:2930–40.Ethics ApprovalThe use of clinical specimens in this study has been approved by the Medical Ethics Committee, Faculty of Dentistry, University of Malaya DF OS1624/0073(L), and The National Medical Research Register, Malaysia NMRR-16-1764-32566 (IIR).
DNA Vaccines to Attack Cancer Stevenson, Freda K.; Ottensmeier, Christian H.; Johnson, Peter ...
Proceedings of the National Academy of Sciences - PNAS,
10/2004, Letnik:
101, Številka:
Suppl 2
Journal Article
Recenzirano
Odprti dostop
Delivery of antigens by injection of the encoding DNA allows access to multiple antigen-presenting pathways. Knowledge of immunological processes can therefore be used to modify construct design to ...induce selected effector functions. Expression can be directed to specific intracellular sites, and additional genes can be fused or codelivered to amplify responses. Therapeutic vaccination against cancer adds a requirement to overcome tolerance and to activate a weakened immune repertoire. Induction of CD4+ T helper cells is critical for both antibody and T cell effector responses. To activate immunity against tumor antigens, we fused the tumor-derived sequences to genes encoding microbial proteins. This strategy engages T helper cells from the large antimicrobial repertoire for linked help for inducing antibody against cell-surface tumor antigens. The principle of linked T cell help also holds for induction of epitope-specific antitumor CD8+ T cells, but the microbial sequence has to be minimized to avoid competition with tumor antigens. Epitope-specific DNA vaccination leads to powerful antitumor attack and can activate immunity from a profoundly tolerized repertoire. Vaccine designs validated in preclinical models are now in clinical trial with immune responses detected against both tumor antigens and fused microbial antigens. DNA priming is highly efficient, but boosting may benefit from increased antigen expression. Physical methods including electroporation provide increased expression without introducing additional competing antigens. A wide range of cancers can be targeted, and objective assays of response will determine efficacy.
Background. The trend towards an increase in the number of caesarean sections (CS) has led to the fact that many women are more likely to plan a second pregnancy with a caesarean scar niche. ...According to current data, planning pregnancy with a niche may be associated with a decrease in the likelihood of successful implantation, which is a consequence of the uterine form of secondary infertility. In the context of studying the effect of stagnant contents in the projection of the niche on fertility, it is important to assess the prevalence of chronic endometritis (CE) and use new knowledge to personalize patient management schemes in achieving reproductive goals.
Aim. To study the prevalence of CE according to various laboratory diagnostic methods in a group of patients with secondary infertility associated with stagnant contents in the niche projection, compared with a group of fertile patients without stagnant contents in the niche projection; to evaluate the possibilities of the cytological and immunocytochemical (ICC) method for studying the endometrium in the diagnosis of CE in comparison with the histological and immunohistochemical (IHC) method.
Materials and methods. The prospective study included 38 patients of reproductive age with a caesarean scar niche, who met the inclusion criteria. After excluding other known factors of secondary infertility, performing ultrasound and/or magnetic resonance imaging of the pelvic organs on the 5th8th day of the menstrual cycle, where the presence/absence of stagnant contents in the projection of the niche was assessed, the patients were divided into 2 groups: group 1 (n=30) patients with secondary infertility in combination with stagnant contents in the niche projection (main group), group 2 (n=8) patients without clinical complaints, without stagnant contents in the projection of a clinically insignificant niche (control group). All patients (n=38) underwent an aspiration pipel biopsy of the endometrium (and, in the presence of stagnant contents in the projection of the niche) under ultrasound control on the 7th10th day of the menstrual cycle. Then a cytological, ICC study (using the CD138 marker), a histological, IHC study of the endometrium (using the CD138 marker) was performed. The statistical study was carried out using the IBM SPSS Statistica v22 program (IBM Corp., USA).
Results. In the 1st group (n=30), the prevalence of CE according to cytological and ICC studies was 90% (n=27/30), a normal cytological picture was recorded in 10% (n=3/30); the prevalence of CE according to histological and IHC studies was 80% (n=24/30), of which 37.5% (n=9/24) were diagnosed with an incomplete morphological picture of CE, and 62.5% (n=15/24) a complete morphological picture of CE was revealed, a normal morphological picture was recorded in 20% (n=6/30) of cases. In the 2nd group (n=8), the prevalence of CE according to cytological and ICC studies was 12.5% (n=1/8), a normal cytological picture was recorded in 87.5% (n=7/8); according to histological and IHC studies, CE was not diagnosed, a normal morphological picture was recorded in 100% (n=8/8) of cases. A high degree of consistency of laboratory data was revealed for 2 groups (n=38), p=0.0001. The sensitivity of the cytological method compared with the histological method was 95.83% (95% CI 79.7699.26%), specificity 64.29% (95% CI 38.7683.66%), positive predictive value 82.14% (95% CI 64.4192.12%), negative predictive value 90% (95% CI 59.5898.21%), the accuracy of the cytological method compared to the histological one was 84, 21% (95% CI 68.0693.03%).
Conclusion. Secondary infertility in patients with stagnant contents in the projection of caesarean scar niche may be associated with CE. Cytological examination of the endometrium in combination with ICC seems to be a promising method for the laboratory evaluation of CE, given the high correlation with histological and IHC data.
Aim. To compare the vaginal and endometrial microbiome in patients with cesarean scar niche (both in the presence of specific complaints of secondary infertility in combination with a niche with ...stagnant contents, and in the absence of such).
Materials and methods. The prospective study included 67 female patients of reproductive age who had a uterine scar after caesarean section that met the inclusion criteria. Depending on the presence or absence of clinical complaints of secondary infertility, ultrasound and/or magnetic resonance imaging of the pelvic organs to visualize stagnant content in the projection of the niche, the patients were divided into two groups: group 1 (n=40) patients with secondary infertility in combination with stagnant contents in the projection of a niche (main group), group 2 (n=27) patients without clinical complaints, with a formed scar on the uterus, without signs of a niche (control group). All patients underwent a comparative study of the vaginal samples and the endometrial samples. The species and quantitative composition of the microbiome was analyzed using real-time polymerase chain reaction. Statistical research was carried out using the IBM SPSS Statistica v22 software (IBM Corp., USA).
Results. Various microbiological communities were found in the analysis of samples of the vagina and endometrium in patients with stagnant content in the projection of the niche (group 1, main) and without it (group 2, control). Lactobacillus spp. was found most often in vaginal discharge samples (more than 50% of cases) both in group 1 and in group 2, however, their level was statistically significantly higher in group 2 (57.5 and 88.9%, respectively), p=0.005. When comparing endometrial samples from patients of groups 1 and 2, it was revealed that in group 1, in the presence of liquid content in the projection of a niche, opportunistic microorganisms were most often detected (more than 50% of cases): Enterobacteriaceae (65%) p0.0001, Streptococcus spp. (60%) p0.0001, Staphylococcus spp. (52.5%) p0.0001, and Gardnerella spp. (22.5%) p=0.0342 and there was a deficiency of Lactobacillus spp. (25%), on the contrary, in group 2, Lactobacillus spp. prevailed (66.7%) p=0.008. Comparative analysis of vaginal samples and endometrial samples of the niche projection in group 1 revealed the predominance (more than 50% of cases) of Lactobacillus spp. in the vagina (57.5%) p=0.003, on the contrary, in the uterine cavity there is a predominance of opportunistic microbiota, p0.001. Comparative analysis of vaginal samples and endometrial samples of the uterine cavity in group 2 revealed a statistically significant predominance of Lactobacillus spp. both in the vagina (88.9%) and in the uterine cavity (66.7%), p=0.0497. In patients with secondary infertility associated with the presence of stagnant content in the projection of the niche, compared with the control group, there was a higher alpha-diversity both in the samples of vaginal discharge (Shannon's index 2.0170.093 vs 1.0600.044; p=0.0120), and in endometrial samples (Shannon's index 3.4480.267 vs 1.0200.040, р=0.00008; Simpson's index 1.109 vs 0.003; p=0.00006). When analyzing beta-diversity, there were no statistically significant differences between groups.
Conclusion. In the structure of the microbiome of the vagina and uterine cavity in women without scar defect on the uterus Lactobacillus spp. predominate. The presence of stagnant content in the projection of a niche is associated with an increase in the frequency and quantitative content of opportunistic microbiota of the uterine cavity, especially Enterobacteriaceae, Streptococcus spp., Staphylococcus spp., Gardnerella spp. Also, in patients with stagnant contents in the projection of the niche, a higher biodiversity was revealed both in the vaginal discharge samples and in the endometrial samples. These results highlight the importance of assessing the endometrial microbiome in women with cesarean section scar, especially those faced with the problem of secondary infertility.
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