Provision of in-house training in theory and practice in foreign languages delivery for LSP teachers in Tomsk State University

The global trend for internationalisation in higher education has set high standards in teaching foreig

Cervical Screening within HIV Care: Findings from an HIV-Positive Cohort in Ukraine

HIV-positive women have an increased risk of invasive cervical cancer but cytologic screening is effective in reducing incidence. Little is known about cervical screening coverage or the prevalence of abnormal cytology among HIV-positive women in Ukraine, which has the most severe HIV epidemic in Europe

Natural Flt3Lg-Based Chimeric Antigen Receptor (Flt3-CAR) T Cells Successfully Target Flt3 on AML Cell Lines

Relapsed/refractory acute myeloid leukemia (AML) cannot be cured with chemotherapy alone, as the blasts survive the treatment. Chimeric antigen receptor (CAR) approaches for AML are being actively developed. CARs promote immune reactions through recognition of the target molecular epitopes at the surface of cancer cells. The recognition involves the extracellular portion of the CAR protein, which corresponds to either the antibody or the physiological binding partner of the targeted antigen. Here, we design a chimeric receptor with a full-length natural Flt3-ligand recognition module that targets Flt3 tyrosine kinase, known as an adverse marker in AML. We demonstrate specific killing of Flt3-positive THP-1 cells by Flt3-CAR T cells and the lack of cytotoxicity towards Flt3-negative U937 cells. We prove that the inherent cytolytic capacity of T cells is essential for the killing. Finally, we confirm the authenticity of targeting by its competitive dose-dependent inhibition with a soluble Flt3-ligand. The developed system can be viewed as a non-immunogenic functional equivalent of scFv-mediated targeting. The robust in vitro antitumor effects of Flt3-CAR T cells, combined with their low off-target cytotoxicity, hold promise for AML treatment

Natural Flt3Lg-Based Chimeric Antigen Receptor (Flt3-CAR) T Cells Successfully Target Flt3 on AML Cell Lines

Relapsed/refractory acute myeloid leukemia (AML) cannot be cured with chemotherapy alone, as the blasts survive the treatment. Chimeric antigen receptor (CAR) approaches for AML are being actively developed. CARs promote immune reactions through recognition of the target molecular epitopes at the surface of cancer cells. The recognition involves the extracellular portion of the CAR protein, which corresponds to either the antibody or the physiological binding partner of the targeted antigen. Here, we design a chimeric receptor with a full-length natural Flt3-ligand recognition module that targets Flt3 tyrosine kinase, known as an adverse marker in AML. We demonstrate specific killing of Flt3-positive THP-1 cells by Flt3-CAR T cells and the lack of cytotoxicity towards Flt3-negative U937 cells. We prove that the inherent cytolytic capacity of T cells is essential for the killing. Finally, we confirm the authenticity of targeting by its competitive dose-dependent inhibition with a soluble Flt3-ligand. The developed system can be viewed as a non-immunogenic functional equivalent of scFv-mediated targeting. The robust in vitro antitumor effects of Flt3-CAR T cells, combined with their low off-target cytotoxicity, hold promise for AML treatment

Factors associated with an abnormal finding (LSIL or HSIL) on cervical screening, among women with a test reported at study enrolment.

†<p>Limited to 213 women included in the multivariable model.</p>‡<p>Adjusted a priori for age, previous pregnancies, CD4 count, current smoking, oral contraceptive use, HSV-2 and chlamydia and additionally for BV.</p

Factors associated with having a cervical screening test reported at study enrolment.

†<p>Limited to 870 women included in the multivariable model.</p

Cohort characteristics by cervical screening test report.

†<p>Includes non-cohabiting partnerships;</p>‡<p>Previous pregnancies include still births, live births, miscarriages and terminations. OC, oral hormonal contraceptive.</p

Coinfections by cervical screening test report at enrolment.

<p>Coinfections by cervical screening test report at enrolment.</p

Novel hemizygous CORO1A variant leads to combined immunodeficiency with defective platelet calcium signaling and cell mobility

Background: To date, fewer than 20 patients have been identified as having germline biallelic mutations in the coronin-1A gene (CORO1A) and its protein with clinical features of combined immunodeficiency characterized by T-cell lymphopenia ranging from the severe phenotype to the mild phenotype, recurrent infections, and lymphoproliferative disorders. However, the effects of CORO1A protein disruption on actin-dependent functions in primary cells have not been fully delineated. Objective: We sought to characterize the underlying defects of actin-dependent cellular functions in a female patient with combined immunodeficiency caused by a novel missense variant in the CORO1A gene in combination with a de novo heterozygous microdeletion of chromosome 16p11.2 and also to provide evidence of the pathogenicity of this gene mutation. Methods: To identify the genetic defect, next-generation sequencing followed by Sanger confirmation and array comparative genomic hybridization were performed. Western blot and quantitative PCR tests were used to assess the effects on the protein. Flow cytometry and live microscopy were performed to investigate cellular motility and immune cell counts and function. Results: We demonstrated that the CORO1A hemizygous variant c.19C>T, p. A7C induces significant decreases in cellular levels of the CORO1A protein while leaving mRNA concentrations unaffected. The observed mutation resulted in impaired natural killer cell cytotoxicity and platelet calcium signaling. In addition, primary granulocytes and mesenchymal cells showed significant defects in motility. Conclusion: Collectively, we added new data about the CORO1A gene as a key player in actin cytoskeleton dynamics and cell signaling. Our findings expand the clinical spectrum regarding CORO1A protein deficiency and confirm the importance of a personalized therapeutic approach for each patient

Antigen‐Specific Stimulation and Expansion of CAR‐T Cells Using Membrane Vesicles as Target Cell Surrogates

Development of CAR‐T therapy led to immediate success in the treatment of B cell leukemia. Manufacturing of therapy‐competent functional CAR‐T cells needs robust protocols for ex vivo/in vitro expansion of modified T‐cells. This step is challenging, especially if non‐viral low‐efficiency delivery protocols are used to generate CAR‐T cells. Modern protocols for CAR‐T cell expansion are imperfect since non‐specific stimulation results in rapid outgrowth of CAR‐negative T cells, and removal of feeder cells from mixed cultures necessitates additional purification steps. To develop a specific and improved protocol for CAR‐T cell expansion, cell‐derived membrane vesicles are taken advantage of, and the simple structural demands of the CAR‐antigen interaction. This novel approach is to make antigenic microcytospheres from common cell lines stably expressing surface‐bound CAR antigens, and then use them for stimulation and expansion of CAR‐T cells. The data presented in this article clearly demonstrate that this protocol produced antigen‐specific vesicles with the capacity to induce stronger stimulation, proliferation, and functional activity of CAR‐T cells than is possible with existing protocols. It is predicted that this new methodology will significantly advance the ability to obtain improved populations of functional CAR‐T cells for therapy. Antigenic vesicles (AVs) bind specifically to the surface of their cognate CAR‐T cells. The binding of AVs to CAR‐T cells results in the activation and proliferation of CAR‐T cells. AVs induce CAR‐T cells’ functional maturation and increase CAR‐T cells’ cytotoxic activity. Incubation with AVs results in antigen‐specific expansion of functional CAR‐T cells