Immune checkpoint inhibitors-related encephalitis in melanoma and non-melanoma cancer patients: a single center experience.

BACKGROUND: Treatment with immune checkpoint inhibitors (ICI) has greatly improved survival for patients with a number of malignant diseases in recent years. Neurological immune-related adverse events (n-irAE) of varying severity have been reported in the literature. We aimed to identify the incidence of n-irAE, focusing on immune-related encephalitis (IRE), in patients treated with ICI for multiple non-hematological malignancies in our institution. METHODS: All patients with histologically verified cancer that received treatment with ICI at the Sheba Medical Center between January 2017 and August 2019 were surveyed. Medical records for each patient were reviewed and information regarding n-irAE was recorded. RESULTS: In total, 1993 patients were included. Eleven cases of IRE were recorded, affecting 0.55% of patients overall, eight had non-melanoma cancer. Eight patients had made a full recovery. CONCLUSIONS: IRE is a n-irAE more frequent than previously reported, particularly in non-melanoma patients. The diagnostic criteria and optimal treatment needs to be determined. ICI re-challenge after IRE can be considered for selected patients.

[The experience of application of standards of laboratory diagnostic of rheumatic diseases in clinical practice.]

The article presents the results of two-year analysis of experience of application of standards of laboratory diagnostic of rheumatic diseases according data of clinical diagnostic laboratory and rheumatic department of the N.N. Burdenko Penzenskaia oblast clinical hospital. The sampling included 2363 examined patients. It was implemented 18 737 analyses i.e. in average 7.9 analyses per one patient. Out of them, tests of detection of auto antibodies consisted 42% (7871), proteins of acute phase - 13.2% (2480), intoxication syndrome - 11.2% (2098). other types of immune diagnostic - 33.6% (6288). The information markers of diagnostic, process activity, severity of course, prognosis and effectiveness of applied therapy are singled out. The conclusions about purpose and evaluation of results of laboratory studies are made.

Subclinical mastitis disrupts oocyte cytoplasmic maturation in association with reduced developmental competence and impaired gene expression in preimplantation bovine embryos.

Subclinical chronic mastitis was induced to examine the effects on oocyte developmental competence. Uninfected Holstein cows were intramammary administrated with serial (every 48h for 20 days) low doses of toxin of Staphylococcus aureus origin (Gram-positive; G+), endotoxin of Escherichia coli origin (Gram-negative; G-) or sterile saline (control). Follicular fluid of toxin- and saline-treated cows was aspirated from preovulatory follicles and used as maturation medium. Oocytes harvested from ovaries collected at the abattoir were matured and then fertilised and cultured for 8 days. The percentage of oocytes undergoing nuclear maturation, determined by meiotic nuclear stages, did not differ between groups. Cytoplasmic maturation, determined by cortical granule distribution, was affected by both toxins (PPPPTGS2) mRNA increased, whereas that of growth differentiation factor 9 (GDF9) decreased in matured oocytes. In addition, PTGS2 expression increased and POU class 5 homeobox 1 (POU5F1) expression decreased in 4-cell embryos developed from both G+ and G- oocytes. Thus, regardless of toxin type, subclinical mastitis disrupts oocyte cytoplasmic maturation and alters gene expression in association with reduced developmental competence.

Effects of Escherichia coli- and Staphylococcus aureus-induced mastitis in lactating cows on oocyte developmental competence.

Mastitis is associated with decreased fertility in dairy cows. In the current study, we created an experimental model to simulate short-term mastitis by a single intramammary administration of Gram-negative endotoxin of Escherichia coli origin (G-), or Gram-positive toxin of Staphylococcus aureus origin (G+), to examine the effect of mastitis on oocyte developmental competence. Healthy Holstein cows were synchronized, and follicular fluid (FF) of cows treated with G+ or G- and of uninfected cows (controls) was aspirated from the preovulatory follicles by transvaginal ultrasound procedure. The aspirated FF was used as maturation medium for in vitro embryo production. The distribution of matured oocytes into different cortical granule classes and meiotic stages was affected by G- administration (P<0.05) but not by G+ administration. The proportion of oocytes that cleaved to two- and four-cell stage embryos (44 h postfertilization) was lower in both G+ and G- groups than in controls (P<0.05). Blastocyst formation rate (7-8 days postfertilization) was lower in the G- group (P<0.05) and numerically lower in the G+ group compared with their uninfected counterparts. The total cell number in blastocysts did not differ among groups; however, the apoptotic index was higher in the G+ group (P<0.05), but not in the G- group, relative to controls. Examining mRNA relative abundance in oocytes and early embryos revealed mastitis-induced alterations in PTGS2 (COX2), POU5F1, and HSF1 but not in SLC2A1 (GLUT1) or GDF9. Results indicate a differential disruptive effect of mastitis induced by G- and G+ on oocyte developmental competence in association with alterations in maternal gene expression.

[Monitoring of intracranial pressure and cerebral compliance in patients with hemispheric non-traumatic hemorrhages].

Indicators of intracranial pressure (ICP) and cerebral compliance in 48 patients with primary non-traumatic intracerebral hemorrhages who underwent surgery using precise aspiration and local fibrinolysis were studied. Based on clinical and neuroimaging data, ICP indicators and cerebral compliance, we can evaluate the compressive influence of the cerebral hematoma, perform the dynamic control of fibrinolysis efficacy and intracerebral hematoma aspiration as well as of dislocation syndrome's regress and predict outcomes of disease. The restoration of ICP indicators, cerebral compliance and elimination of middle structure dislocation can be used as criteria of surgery effectiveness. At the same time, the residual volume of the hemorrhage (within 20 ml) during the elimination of compression does not exert any significant effect on the course and outcome.

Examination of possible structural constraints of MHC-binding peptides by assessment of their native structure within their source proteins.

Antigenic peptides bind to major histocompatibility complex (MHC) molecules as a prerequisite for their presentation to T cells. In this study, we investigate possible structural preferences of MHC-binding peptides by examining the conformation space defined by the structures of these peptides within their native source proteins. Comparison of the conformation space of the native structures of MHC-binding nonamers and a corresponding conformation space defined by a random set of nonamers showed no significant difference. This suggests that the environment of the MHC binding groove has evolved to bind peptides with essentially any "structural background." A slight tendency for an extended beta-conformation at positions 8 and 9 was observed for the set of native structures. We suggest that such a preference may facilitate the binding of the C-terminal anchor position of processed peptides into the corresponding specificity pocket. MHC-binding peptides represent examples of short subsequences that are present in two different structural environments: within their native protein and within the MHC binding groove. Comparison of the native and of the bound structure of the peptides showed that peptides up to 14 residues long may adopt different conformations within different protein environments. This has direct implications for structure prediction algorithms.

Structure-based prediction of binding peptides to MHC class I molecules: application to a broad range of MHC alleles.

Specific binding of antigenic peptides to major histocompatibility complex (MHC) class I molecules is a prerequisite for their recognition by cytotoxic T-cells. Prediction of MHC-binding peptides must therefore be incorporated in any predictive algorithm attempting to identify immunodominant T-cell epitopes, based on the amino acid sequence of the protein antigen. Development of predictive algorithms based on experimental binding data requires experimental testing of a very large number of peptides. A complementary approach relies on the structural conservation observed in crystallographically solved peptide-MHC complexes. By this approach, the peptide structure in the MHC groove is used as a template upon which peptide candidates are threaded, and their compatibility to bind is evaluated by statistical pairwise potentials. Our original algorithm based on this approach used the pairwise potential table of Miyazawa and Jernigan (Miyazawa S, Jernigan RL, 1996, J Mol Biol 256:623-644) and succeeded to correctly identify good binders only for MHC molecules with hydrophobic binding pockets, probably because of the high emphasis of hydrophobic interactions in this table. A recently developed pairwise potential table by Betancourt and Thirumalai (Betancourt MR, Thirumalai D, 1999, Protein Sci 8:361-369) that is based on the Miyazawa and Jernigan table describes the hydrophilic interactions more appropriately. In this paper, we demonstrate how the use of this table, together with a new definition of MHC contact residues by which only residues that contribute exclusively to sequence specific binding are included, allows the development of an improved algorithm that can be applied to a wide range of MHC class I alleles.

Knowledge-based structure prediction of MHC class I bound peptides: a study of 23 complexes.

BACKGROUND: The binding of T-cell antigenic peptides to MHC molecules is a prerequisite for their immunogenicity. The ability to identify binding peptides based on the protein sequence is of great importance to the rational design of peptide vaccines. As the requirements for peptide binding cannot be fully explained by the peptide sequence per se, structural considerations should be taken into account and are expected to improve predictive algorithms. The first step in such an algorithm requires accurate and fast modeling of the peptide structure in the MHC-binding groove. RESULTS: We have used 23 solved peptide-MHC class I complexes as a source of structural information in the development of a modeling algorithm. The peptide backbones and MHC structures were used as the templates for prediction. Sidechain conformations were built based on a rotamer library, using the 'dead end elimination' approach. A simple energy function selects the favorable combination of rotamers for a given sequence. It further selects the correct backbone structure from a limited library. The influence of different parameters on the prediction quality was assessed. With a specific rotamer library that incorporates information from the peptide sidechains in the solved complexes, the algorithm correctly identifies 85% (92%) of all (buried) sidechains and selects the correct backbones. Under cross-validation, 70% (78%) of all (buried) residues are correctly predicted and most of all backbones. The interaction between peptide sidechains has a negligible effect on the prediction quality. CONCLUSIONS: The structure of the peptide sidechains follows from the interactions with the MHC and the peptide backbone, as the prediction is hardly influenced by sidechain interactions. The proposed methodology was able to select the correct backbone from a limited set. The impairment in performance under cross-validation suggests that, currently, the specific rotamer library is not satisfactorily representative. The predictions might improve with an increase in the data.