Caspases as Putative Biomarkers of Cervical Cancer Development

Resistance to apoptosis is commonly accepted as the principal hallmark of a cancer cell, while caspases are recognized as the key molecular players of the apoptosis regulatory network. Since the level of caspase activity is thought to be directly coupled with aggressive features of cancer cells (such as ability to withstand immune reactions, invasiveness, drug resistance, etc.), these proteases could serve as objective diagnostic markers especially for those types of cancer where early differential diagnosis is needed. Cervical cancer develops through morphologically well-described stages—from intraepithelial lesions of 1/2/3 grade including carcinoma in situ to microinvasive and invasive cancer with precancerous lesions known to be potentially reversible. The percentage of cervical neoplasms diagnosed at early stages is relatively high, providing a basis for the use of cervical cancer as an in vivo model to investigate the mechanisms of apoptosis modulation in malignant cells. The existing diagnostic criteria, despite their usefulness, have substantial limitations with respect to cervical cancer and preneoplastic lesions, so caspases may be helpful in improving them, but there is insufficient data regarding the involvement of these enzymes in cervical cancer development. In this chapter, we report on specific patterns of activity of caspases revealed in tissue biopsies and blood lymphocytes in association with different stages of cervical cancer development. The data indicate that caspases are pivotal components of the in vivo molecular “portrait” of cervical cancer and have the potential of being used as biomarkers

Sequencing-based transcriptome analysis reveals diversification of immune response- and angiogenesis-related expression patterns of early-stage cervical carcinoma as compared with high-grade CIN

BackgroundMolecular diversity of virus-associated cervical cancer remains a relatively underexplored issue, and interrelations of immunologic and angiogenic features during the establishment of a particular landscape of the cervical cancer microenvironment are not well-characterized, especially for its earliest clinical stages, although this may provide insight into the mechanisms behind the differences in tumor aggressiveness, treatment responsiveness and prognosis. In this research, we were aimed at identifying transcriptomic landscapes of early-stage cervical carcinoma that differ substantially in their immune-related characteristics, patterns of signaling pathways and composition of the microenvironment in comparison with immediate precursor (intraepithelial) lesions.MethodsWe performed the Illumina platform-based RNA sequencing using a panel of fresh tissue samples that included human papillomavirus-positive cervical intraepithelial neoplastic lesions (CIN), invasive squamous carcinoma of the cervix of FIGO IA1-IIB stages, and morphologically normal epithelium. The derived transcriptomic profiles were bioinformatically analyzed and compared by patterns of signaling pathway activation, distribution of tumor-infiltrating cell populations, and genomic regions involved.ResultAccording to hierarchical cluster analysis of the whole-transcriptome profiles, tissue samples were distributed between three groups, or gene expression patterns (the one comprising most pre-cancer cases and the other two encompassing mostly early-stage invasive cancer cases). Differentially expressed genes were retrieved in each intergroup pairwise comparison followed by Gene Ontology analysis. Gene set enrichment analysis of the two groups of tumor samples in comparison with the CIN group identified substantial differences in immunological and angiogenic properties between tumorous groups suggesting the development of different molecular phenotypes. Cell composition analysis confirmed the diverse changes in the abundancies of immune and non-immune populations and, accordingly, different impacts of the immune and stromal compartments on the tumor microenvironment in these two groups of tumors compared to CIN. Positional gene expression analysis demonstrated that the identified transcriptomic differences were linked to different chromosomal regions and co-localized with particular gene families implicated in immune regulation, inflammation, cell differentiation, and tumor invasion.ConclusionsOverall, detection of different transcriptomic patterns of invasive cervical carcinoma at its earliest stages supports the diverse impacts of immune response- and angiogenesis-related mechanisms on the onset of tumor invasion and progression. This may provide new options for broadening the applicability and increasing the efficiency of target anti-angiogenic and immune-based therapy of virus-associated cervical carcinoma

T- and NK-cell populations with regulatory phenotype and markers of apoptosis in circulating lymphocytes of patients with CIN3 or microcarcinoma of the cervix: evidence for potential mechanisms of immune suppression

Abstract Background Processes and mechanisms responsible for systemic immune suppression in early-stage cervical cancer remain substantially underinvestigated. In this work, we focused on studying the frequencies of circulating regulatory T (CD4 and CD8 Tregs) and NK (NKregs) cells in parallel with assessment of apoptotic markers expression in T cells from patients with preinvasive and microinvasive cervical cancer, with the aim to determine whether up-regulation of apoptosis-associated markers in Т lymphocytes accompanies cervical cancer development and correlates with the change in percentages of regulatory cell populations at systemic level during the initial stages of invasive cervical cancer progression. Methods Fourty two women with histologically confirmed cervical intraepithelial neoplasia grade 3 (CIN3, including carcinoma in situ) or cervical cancer (stage IA) and 30 healthy women (control) were enrolled in the study. Peripheral blood samples were taken immediately before surgery or any treatment and immediately subjected to multicolor flow cytometry. Results Analysis of a combination of CD4/CD8, CD25, CD127, and FoxP3 markers revealed a statistically significant increase in the frequencies of Tregs within both the CD4 and CD8 subsets of circulating lymphocytes in patients with CIN3 and stage IA cancer. In contrast, lower numbers of NKregs (defined as CD16dim/negCD56bright subpopulation) and increased CD56dim/CD56bright NK ratio were found in patients compared to controls, with the percentage of CD16brightCD56dim cells (major subtype of circulating NKs) showing no difference. Patients also exhibited an increased expression of CD95 in total peripheral blood T lymphocytes, along with increased level of Annexin V binding to CD95-positive cells, suggesting higher susceptibility of T cells to apoptosis and potential involvement of CD95-dependent pathway in early-stage cervical cancer. Differential analysis of CD4 and CD8 T cells revealed different trends in the change of CD95 expression, confirming that this change likely has different functional significance for these two subsets. A search for correlations between the phenotypic parameters analyzed in this study was performed to demonstrate that women with early neoplastic lesions of the cervix, such as carcinoma in situ and microinvasive carcinoma, displayed a coordinated increase in expression of Treg markers in circulating lymphocytes, along with more pronounced cross-relationships between Treg numbers, CD95 expression on T cells, and apoptosis, compared to the control group. Conclusions The results of this study suggest that a diversity of immune regulatory mechanisms that provide support for initial stages of invasive growth in cervical cancer patients includes systemic changes in the ratios between the principal regulatory and effector lymphocyte populations both within adaptive and innate immunity

Some features of Pd(II) and Cu(II) adsorption on bentonites

Copper(II) and palladium(II) adsorption from single-component, Cu(NO 3 ) 2 or K 2 PdCl 4 , and two-component Cu(NO 3 ) 2 -K 2 PdCl 4 aqueous solutions by bentonites provided by two different Ukrainian deposits was investigated in this study. As was found, types of the obtained adsorption isotherms depended on the bentonite origin, the nature of the adsorbed metal ion and the component quantity in the aqueous solutions under study. The most complicated adsorption isotherms were obtained for Pd(II) adsorption from the single-component Pd(II) and two-component Pd(II)-Cu(II) solutions. The adsorption of each metal ion decreased in the presence of the second one being evidence of competitive adsorption and confirming the nonhomogenity of adsorption sites

Magnetic hyperfine interactions of ¹¹⁹Sn probe atoms in the binary perovskite CaCu₃Mn₄O₁₂

The manganite CaCu3Mn4O12 doped by 119Sn atoms (about 1 at % with respect to Mn atoms) is studied by Mössbauer spectroscopy. The introduction of diamagnetic tin atoms is found not to affect the structure of the manganite. Tetravalent tin atoms are shown to substitute for the isovalent manganese atoms that are located in an octahedral oxygen surrounding. The cluster method of molecular orbitals is used to calculate the contributions of Mn4+ and Cu2+ cations that belong to different structural sublattices to the hyperfine magnetic field at 119Sn nuclei (H Sn = 105 kOe at T = 77 K). These partial contributions are analyzed, and the intrasublattice Mn4+-O-Mn4+ exchange interactions are found to play a significant role in the formation of the magnetic structure of the manganite

Hyperfine magnetic fields at the nuclei of probe ¹¹⁹Sn atoms and exchange interactions in the CaCu₃Mn_3.96Sn_0.04O₁₂ manganite

We have investigated the hyperfine magnetic interactions between the nuclei of probe 119Sn atoms in the CaCu3Mn3.96Sn0.04O12 double manganite by Mössbauer spectroscopy using magnetic measurements. A consistent description of the results obtained in terms of the Weiss molecular field model by taking into account the peculiarities of the local environment of tin atoms has allowed the indirect Cu2+-O-Mn4+ (J CuMn ≈ −51 ± 1 K) and Mn4+-O-Mn4+ (J MnMn ≈ −0.6 ± 0.6 K) exchange interaction integrals to be estimated. Based on the Kanamori-Goodenough-Anderson model, we show that the magnitude and sign of the intrasublattice exchange integral J MnMn correspond to both the electronic configuration of the Mn4+ cations and the geometry of their local crystallographic environment in the compound under study

Magnetic exchange interactions and supertransferred hyperfine fields at 119Sn probe atoms in CaCu3Mn4O12

The double manganite CaCu3Mn4O12 doped with 119Sn atoms (∼1 at.% with respect to manganese atoms) was studied by use of Mössbauer spectroscopy. Formally tetravalent Sn4+ ions substitute for isovalent manganese ions in the octahedral (Mn4+O6) polyhedra. The covalency effects on the magnetic interactions like superexchange in Cu2+-O-Mn4+ and Mn4+-O-Mn4+ bonds and supertransferred hyperfine interactions of the 119Sn probe atoms in the manganite structure are discussed. Using a semiquantitative nearest-neighbor cluster model relating the hyperfine magnetic field on the 119Sn nuclei (HSn = 105 kOe at T = 77 K) to covalency parameters and angle characterizing the Sn-O-M (M = Cu, Mn) bonds, it has been shown how such an analysis of supertransferred hyperfine interactions of tin probe ions can get fruitful information about strength and sign of the superexchange interactions between Mn4+ and Cu2+ magnetic ions. A consistent description of the results in the framework of the Weiss molecular field model considering the specific local environment of tin atoms has made it possible to estimate exchange integrals: JCuMn = −51.1 ± 0.3 K and JMnMn = −0.6 ± 0.2 K

Hyperfine interactions and local environment of 57Fe probe atoms in perovskite CaMn7O12

International audienceMössbauer spectroscopy has been applied for studying the local environment of 57Fe probe atoms within iron-doped CaMn7O12 manganite with a perovskite-like structure. The 57Fe spectra recorded in the paramagnetic temperature range 90

VH3-53/66-Class RBD-Specific Human Monoclonal Antibody iB20 Displays Cross-Neutralizing Activity against Emerging SARS-CoV-2 Lineages

Immune evasion of SARS-CoV-2 undermines current strategies tocounteract the pandemic, with the efficacy of therapeutic virus-neutralizing monoclonal antibodies (nAbs) being affected the most. In this work, we asked whether two previously identified human cross-neutralizing nAbs, iB14 (class VH1-58) and iB20 (class VH3-53/66), are capable of neutralizing the recently emerged Omicron (BA.1) variant. Both nAbs were found to bind the Omicron RBD with a nanomolar affinity, yet they displayed contrasting functional features. When tested against Omicron, the neutralizing activity of iB14 was reduced 50-fold, whereas iB20 displayed a surprising increase in activity. Thus, iB20 is a unique representative of the VH3-53/66-class of nAbs in terms of breadth of neutralization, which establishes it as a candidate for COVID-19 therapy and prophylactics