Checkpoint inhibitors like anti-PD1/PD-L1 have demonstrated significant therapeutic efficacy in a subset of patients partly through reinvigoration of CD8 T cells. However, their impact on myeloid ...cells remains largely unknown. Here, we report that anti-PD-L1 treatment favorably impacts the phenotype and function of tumor macrophages by polarizing the macrophage compartment toward a more proinflammatory phenotype. This phenotype was characterized by a decrease in Arginase-I (ARG1) expression and an increase in iNOS, MHCII, and CD40 expression. Whole-transcriptome profiling further confirmed extensive polarization of both tumor monocytes and macrophages from a suppressive to a proinflammatory, immunostimulatory phenotype. This polarization was driven mainly through IFNγ and was associated with enhanced T-cell activity. Transfer of monocytes into anti-PD-L1-treated tumor-bearing mice led to macrophage differentiation into a more proinflammatory phenotype, with an increase in CD8 T cells expressing granzyme-B and an increase in the CD8/Treg ratio compared with control-treated mice. Although in responsive tumor models, anti-PD-L1 treatment remodeled the macrophage compartment with beneficial effects on T cells, both macrophage reprogramming and depletion were needed to maximize anti-PD-L1 responses in a tumor immune contexture with high macrophage burden. Our results demonstrate that anti-PD-L1 treatment can favorably remodel the macrophage compartment in responsive tumor models toward a more proinflammatory phenotype, mainly through increased IFNγ levels. They also suggest that directly targeting these cells with reprogramming and depleting agents may further augment the breadth and depth of response to anti-PD-L1 treatment in less responsive or more macrophage-dense tumor microenvironments. SIGNIFICANCE: This work demonstrates that increased IFNγ signaling following anti-PD-L1 treatment can remodel the macrophage compartment to enhance T-cell responses.
http://cancerres.aacrjournals.org/content/canres/79/7/1493/F1.large.jpg.
Fiducial markers are utilized for image guided radiotherapy (IGRT) alignment during the delivery of liver stereotactic body radiosurgery (SBRT). There are limited data demonstrating the impact of ...matching fiducials on the accuracy of liver SBRT. This study quantifies the benefit of fiducial-based alignment and improvements in inter-observer reliability. Nineteen patients with 24 liver lesions were treated with SBRT. Target localization was performed using fiducial markers on cone-beam computed tomography (CBCT). Each CBCT procedure was retrospectively realigned to match both the liver edge and fiducial markers. The shifts were recorded by seven independent observers. Inter-observer variability was analyzed by calculating the mean error and uncertainty for the set-up. The mean absolute Cartesian error observed from fiducial and liver edge-based alignment was 1.5 mm and 5.3 mm, respectively. The mean uncertainty from fiducial and liver edge-based alignment was 1.8 mm and 4.5 mm, respectively. An error of 5 mm or greater was observed 50% of the time when aligning to the liver surface versus 5% of the time when aligning to fiducial markers. Aligning to the liver edge significantly increased the error, resulting in increased shifts when compared to alignment to fiducials. Tumors of 3 cm or farther from the liver dome had higher mean errors when aligned without fiducials (4.8 cm vs. 4.4 cm,
= 0.003). Our data support the use of fiducial markers for safer and more accurate liver SBRT.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK, VSZLJ
BackgroundCancer immunotherapy has evolved from interferon-alpha (IFNα) and interleukin-2 in the 1980s to CTLA-4 and PD-1/PD-L1 checkpoint inhibitors (CPIs), the latter highlighting the importance of ...enhancing T-cell functions. While the search for novel immunomodulatory pathways continues, combination therapies augmenting multiple pathways can also increase efficacy. The association of autoimmune-related adverse events with clinical efficacy following CPI treatment has been inferred and suggests that breaking tolerance thresholds associated with autoimmunity may affect host immune responses for effective cancer immunotherapy.ResultsHere, we show that loss of autoimmune associated PTPN22, a key desensitization node for multiple signaling pathways, including IFNα receptor (IFNAR) and T-cell receptor, can augment tumor responses. Implantation of syngeneic tumors in Ptpn22-/- mice led to expansion and activation of peripheral and intratumoral T cells and, in turn, spontaneous tumor regression as well as enhanced responses in combination with anti-PD-L1 treatment. Using genetically modified mice expressing a catalytically inactive PTPN22 or the autoimmunity-associated human single-nucleotide polymorphism variant, augmentation of antitumor immunity was dependent on PTPN22 phosphatase activity and partially on its adaptor functions. Further, antitumor responses were dependent on both CD4+ and CD8+T cells and, in part, IFNAR function. Finally, we demonstrate that the autoimmune susceptibility Ptpn22(C1858T) variant is associated with lower risk of developing non-melanoma skin cancers, improved overall survival and increased risk for development of hyperthyroidism or hypothyroidism following atezolizumab (anti-PD-L1) treatment.ConclusionsTogether, these data suggest that inhibition of PTPN22 phosphatase activity may provide an effective therapeutic option for cancer immunotherapy and that exploring genetic variants that shift immune tolerance thresholds may serve as a paradigm for finding new cancer immunotherapy targets.
Patients with resected stage II–III cutaneous melanomas remain at high risk for metastasis and death. Biomarker development has been limited by the challenge of isolating high-quality RNA for ...transcriptome-wide profiling from formalin-fixed and paraffin-embedded (FFPE) primary tumor specimens. Using NanoString technology, RNA from 40 stage II–III FFPE primary melanomas was analyzed and a 53-immune-gene panel predictive of non-progression (area under the curve (AUC)=0.920) was defined. The signature predicted disease-specific survival (DSS P<0.001) and recurrence-free survival (RFS P<0.001). CD2, the most differentially expressed gene in the training set, also predicted non-progression (P<0.001). Using publicly available microarray data from 46 primary human melanomas (GSE15605), a coexpression module enriched for the 53-gene panel was then identified using unbiased methods. A Bayesian network of signaling pathways based on this data identified driver genes. Finally, the proposed 53-gene panel was confirmed in an independent test population of 48 patients (AUC=0.787). The gene signature was an independent predictor of non-progression (P<0.001), RFS (P<0.001), and DSS (P=0.024) in the test population. The identified driver genes are potential therapeutic targets, and the 53-gene panel should be tested for clinical application using a larger data set annotated on the basis of prospectively gathered data.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Theoretical and practical development of the problem of students’ adaptation in a foreign language and multicultural society is one of the key problems of the academic mobility development of the ...individual throughout life. The need to solve this problem is determined by the socio-cultural dynamics of education development in the context of its global shifts, transformations, and systemic changes. The purpose of the article is to conduct a theoretical analysis of the problem of students' adaptation in the foreign language and multicultural society of the metropolis. The article deals with the problem of cross-cultural adaptation of foreign students in Russian universities to the foreign language and multicultural social medium of the metropolis. The phenomenon of cross-cultural adaptation is studied on an interdisciplinary basis. The authors consider the theoretical approaches to the study of various aspects of cross-cultural adaptation of a person to a foreign language and multicultural society, as well as analyze the educational opportunities and potential of intercultural interaction based on the dialogue of cultures as a mechanism underlying the process of adaptation of students in the foreign language and multicultural society of the metropolis. According to the authors, the success of foreign students’ education is also determined by their readiness to accept the entire cultural diversity of the foreign-speaking world and foreign language culture, as well as their tolerant attitude toward them. The article highlights and characterizes the main directions and specific content of students’ adaptation to foreign language and multicultural society. The authors conclude that cross-cultural adaptation can be an effective way for foreign students to enter the new socio-cultural conditions of the foreign language and multicultural society of the metropolis.
Digital Teacher for the 21st-century School 4.0 Fedorova, Elena Nikolayevna; Berezina, Tamara Ivanovna; Moskalenko, Marina Sergeyevna ...
SHS Web of Conferences,
01/2021, Volume:
121
Conference Proceeding, Journal Article
Peer reviewed
Open access
The article deals with some pedagogical aspects of the digitalization of education. As it is shown in the article, the problem of digital education has been systematically analyzed and discussed for ...the last two decades by various analysts, researchers, and experts. Most of them consider the transition of education into its digital stage as the greatest turning point in the history of civilization and its culture. At present, teachers are facing quite new educational and pedagogical functions. The idea of a digital teacher as the leader of digital educational activity is in the focus of the analysis presented in the article. Educational platforms, online courses, digital textbooks, etc. influence on the transformation of the educational environment. Education is becoming more personalized. The content of teaching and learning is being changed radically according to its new values, meanings, orientations, as well as educational and pedagogical discourses. It is stressed in the article that teacher’s digital skills and competencies should be identified as the key professional pedagogical skills and competencies for his or her life-long learning, professional development and professional growth due to the challenges of the 21st-century knowledge, information and innovations society and education. To fulfill a system of professional-pedagogical and educational functions more effectively and to guarantee the optimal implementation of information and communication technologies (ICTs), it is quite necessary for teachers to have adequate skills and competencies that characterize his or her digital professional culture of teaching.
Background Accurate assessment of prognosis remains clinically challenging in stage II to III cutaneous melanoma. Studies have implicated CD2 in immune surveillance, T-cell activation, and antitumor ...immunity, but its role in melanoma progression warrants further investigation. Objective We sought to investigate the prognostic role of CD2 in primary cutaneous melanoma. Methods Patients with American Joint Committee on Cancer stage II and III cutaneous melanoma were identified by retrospective review of dermatopathology databases from 2001 to 2010 at Mount Sinai Medical Center and Geisinger Medical Center. Additional patients were provided by New York University Medical Center based on retrospective review and tissue availability. Immunohistochemistry was performed on tumors from 90 patients with known recurrence status and documented follow-up. Results Primary tumors from patients who developed recurrent disease had fewer CD2+ cells ( P = .0003). In multivariable analyses including standard clinicopathologic predictors, CD2 was an independent predictor of disease recurrence ( P = .008) and overall survival ( P = .007). CD2 count correlated with characterization of tumor-infiltrating lymphocytes ( P = .0004). Among the intermediate prognosis group of patients with nonbrisk tumor-infiltrating lymphocytes, CD2 count was predictive of disease recurrence ( P = .0006) and overall survival ( P = .0318). Limitations Our retrospective design may have resulted in incomplete representation of patients lacking documented follow-up. Conclusions CD2 may be an independent predictor of disease recurrence and overall survival among patients with primary cutaneous melanoma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor cell immunotherapies have demonstrated long-lasting, and specific anti-tumor immune responses in animal models. The studies ...reported here specifically evaluate two aspects of the immune response generated by such immunotherapies: the persistence of irradiated tumor cells at the immunization site, and the breadth of the immune response elicited to tumor associated antigens (TAA) derived from the immunotherapy. To further define the mechanism of GM-CSF-secreting cancer immunotherapies, immunohistochemistry studies were performed using the B16F10 melanoma tumor model. In contrast to previous reports, our data revealed that the irradiated tumor cells persisted and secreted high levels of GM-CSF at the injection site for more than 21 days. Furthermore, dense infiltrates of dendritic cells were observed only in mice treated with GM-CSF-secreting B16F10 cells, and not in mice treated with unmodified B16F10 cells with or without concurrent injection of rGM-CSF. In addition, histological studies also revealed enhanced neutrophil and CD4+ T cell infiltration, as well as the presence of apoptotic cells, at the injection site of mice treated with GM-CSF-secreting tumor cells. To evaluate the scope of the immune response generated by GM-CSF-secreting cancer immunotherapies, several related B16 melanoma tumor cell subclones that exist as a result of genetic drift in the original cell line were used to challenge mice previously immunized with GM-CSF-secreting B16F10 cells. These studies revealed that GM-CSF-secreting cancer immunotherapies elicit T cell responses that effectively control growth of related but antigenically distinct tumors. Taken together, these studies provide important new insights into the mechanism of action of this promising novel cancer immunotherapy.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UL, UM, UPUK, VKSCE, ZAGLJ
Speech remains intelligible despite the elimination of canonical acoustic correlates of phonemes from the spectrum. A portion of this perceptual flexibility can be attributed to modulation ...sensitivity in the auditory-to-phonetic projection, although signal-independent properties of lexical neighborhoods also affect intelligibility in utterances composed of words. Three tests were conducted to estimate the effects of exposure to natural and sine-wave samples of speech in this kind of perceptual versatility. First, sine-wave versions of the easy and hard word sets were created, modeled on the speech samples of a single talker. The performance difference in recognition of easy and hard words was used to index the perceptual reliance on signal-independent properties of lexical contrasts. Second, several kinds of exposure produced familiarity with an aspect of sine-wave speech: (a) sine-wave sentences modeled on the same talker; (b) sine-wave sentences modeled on a different talker, to create familiarity with a sine-wave carrier; and (c) natural sentences spoken by the same talker, to create familiarity with the idiolect expressed in the sine-wave words. Recognition performance with both easy and hard sine-wave words improved after exposure only to sine-wave sentences modeled on the same talker. Third, a control test showed that signal-independent uncertainty is a plausible cause of differences in recognition of easy and hard sine-wave words. The conditions of beneficial exposure reveal the specificity of attention underlying versatility in speech perception. (Contains 3 figures.)
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ, UPUK
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