Acute inflammatory demyelinating polyneuropathy (AIDP) -the main form of Guillain-Barre syndrome-is a rare and severe disorder of the peripheral nervous system with an unknown etiology. One of the hallmarks of the AIDP pathogenesis is a significantly elevated cerebrospinal fluid (CSF) protein level. In this paper CSF peptidome and proteome in AIDP were analyzed and compared with multiple sclerosis and control patients. A total protein concentration increase was shown to be because of even changes in all proteins rather than some specific response, supporting the hypothesis of protein leakage from blood through the blood-nerve barrier. The elevated CSF protein level in AIDP was complemented by activization of protein degradation and much higher peptidome diversity. Because of the studies of the acute motor axonal form, Guillain-Barre syndrome as a whole is thought to be associated with autoimmune response against neurospecific molecules. Thus, in AIDP, autoantibodies against cell adhesion proteins localized at Ranvier's nodes were suggested as possible targets in AIDP. Indeed, AIDP CSF peptidome analysis revealed cell adhesion proteins degradation, however no reliable dependence on the corresponding autoantibodies levels was found. Proteome analysis revealed overrepresentation of Gene Ontology groups related to responses to bacteria and virus infections, which were earlier suggested as possible AIDP triggers. Immunoglobulin blood serum analysis against most common neuronal viruses did not reveal any specific pathogen; however, AIDP patients were more immunopositive in average and often had polyinfections. Cytokine analysis of both AIDP CSF and blood did not show a systemic adaptive immune response or general inflammation, whereas innate immunity cytokines were up-regulated. To supplement the widely-accepted though still unproven autoimmunity-based AIDP mechanism we propose a hypothesis of the primary peripheral nervous system damaging initiated as an innate immunity-associated local inflammation following neurotropic viruses egress, whereas the autoantibody production might be an optional complementary secondary process. Molecular & Cellular

Blood as connective tissue potentially contains evidence of all processes occurring within the organism, at least in trace amounts (Petricoin et al., 2006) [1]. Because of their small size, peptides penetrate cell membranes and epithelial barriers more freely than proteins. Among the peptides found in blood, there are both fragments of proteins secreted by various tissues and performing their function in plasma and receptor ligands: hormones, cytokines and mediators of cellular response (Anderson et al., 2002) [2]. In addition, in minor amounts, there are peptide disease markers (for example, oncomarkers) and even foreign peptides related to pathogenic organisms and infection agents. To propose an approach for detailed peptidome characterization, we carried out an LC–MS/MS analysis of blood serum and plasma samples taken from 20 healthy donors on a TripleTOF 5600+ mass-spectrometer. We prepared samples based on our previously developed method of peptide desorption from the surface of abundant blood plasma proteins followed by standard chromatographic steps (Ziganshin et al., 2011) [3]. The mass-spectrometry peptidomics data presented in this article have been deposited to the ProteomeXchange Consortium (Deutsch et al., 2017) [4] via the PRIDE partner repository with the dataset identifier PXD008141 and 10.6019/PXD008141.

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Differential diagnosis of bacterial and viral meningitis is an urgent problem of the modern clinical medicine. Early and accurate detection of meningitis etiology largely determines the strategy of its treatment and significantly increases the likelihood of a favorable outcome for the patient. In the present work, we analyzed the peptidome and cytokine profiles of cerebrospinal fluid (CSF) of 17 patients with meningitis of bacterial and viral etiology and of 20 neurologically healthy controls. In addition to the identified peptides (potential biomarkers), we found significant differences in the cytokine status of the CSF of the patients. We found that cut-off of 100 pg/ml of IL-1β, TNF, and GM-CSF levels discriminates bacterial and viral meningitis with 100% specificity and selectivity. We demonstrated for the first time the reduction in the level of two cytokines, IL-13 and GM-CSF, in the CSF of patients with viral meningitis in comparison with the controls. The decrease in GM-CSF level in the CSF of patients with viral meningitis can be explained by a disproportionate increase in the levels of cytokines IL-10, IFN-γ, and IL-4, which inhibit the GM-CSF expression, whereas IL-1, IL-6, and TNF activate it. These observations suggest an additional approach for differential diagnosis of bacterial and viral meningitis based on the normalized ratio IL-10/IL-1β and IL-10/TNF > 1, as well as on the ratio IFN-γ/IL-1β and IFN-γ/TNF < 0.1. Our findings extend the panel of promising clinical and diagnostic biomarkers of viral and bacterial meningitis and reveal opposite changes in the cytokine expression in meningitis due to compensatory action of pro- and antiinflammatory factors.

The malignant tumor is a complex heterogeneous set of cells functioning in a no less heterogeneous microenvironment. Like any dynamic system, cancerous tumors evolve and undergo changes in response to external influences, including therapy. Initially, most tumors are susceptible to treatment. However, remaining cancer cells may rapidly reestablish the tumor after a temporary remission. These new populations of malignant cells usually have increased resistance not only to the first-line agent, but also to the second- and third-line drugs, leading to a significant decrease in patient survival. Multiple studies describe the mechanism of acquired therapy resistance. In past decades, it became clear that, in addition to the simple selection of pre-existing resistant clones, therapy induces a highly complicated and tightly regulated molecular response that allows tumors to adapt to current and even subsequent therapeutic interventions. This review summarizes mechanisms of acquired resistance, such as secondary genetic alterations, impaired function of drug transporters, and autophagy. Moreover, we describe less obvious molecular aspects of therapy resistance in cancers, including epithelial-to-mesenchymal transition, cell cycle alterations, and the role of intercellular communication. Understanding these molecular mechanisms will be beneficial in finding novel therapeutic approaches for cancer therapy.

Despite a large number of proteomic studies of biological fluids from ovarian cancer patients, there is a lack of sensitive screening methods in clinical practice (Kim et al., 2016) (DOI:https://doi.org/10.1111/cas.12987[1]). Low molecular weight endogenous peptides more easily diffuse across endothelial barriers than proteins and can be more relevant biomarker candidates (Meo et al., 2016) (DOI:https://doi.org/10.18632/oncotarget.8931[2], (Bery et al., 2014) DOI:https://doi.org/10.1186/1559-0275-11-13[3], (Huang et al., 2018) DOI:https://doi.org/10.1097/IGC.0000000000001166[4]). Detailed peptidomic analysis of 26 ovarian cancer and 15 non-cancer samples of biological fluids (ascites and sera) were performed using TripleTOF 5600+ mass-spectrometer. Prior to LC-MS/MS analysis, peptides were extracted from biological fluids using anion exchange sorbent with subsequent peptide desorption from the surface of highly abundant proteins. In total, we identified 4874 peptides; 3123 peptides were specific for the ovarian cancer samples. The mass-spectrometry peptidomics data presented in this data article have been deposited to the ProteomeXchange Consortium (Deutsch et al., 2017) (DOI:https://doi.org/10.1093/nar/gkw936[5]) via the PRIDE partner repository with the dataset identifier PXD009382 and https://doi.org/10.6019/PXD009382, http://www.ebi.ac.uk/pride/archive/projects/PXD009382.

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