The Enigmatic Nature of the TCR-pMHC Interaction: Implications for CAR-T and TCR-T Engineering.

The interaction of the T-cell receptor (TCR) with a peptide in the major histocompatibility complex (pMHC) plays a central role in the adaptive immunity of higher chordates. Due to the high specificity and sensitivity of this process, the immune system quickly recognizes and efficiently responds to the appearance of foreign and altered self-antigens. This is important for ensuring anti-infectious and antitumor immunity, in addition to maintaining self-tolerance. The most common parameter used for assessing the specificity of TCR-pMHC interaction is affinity. This thermodynamic characteristic is widely used not only in various theoretical aspects, but also in practice, for example, in the engineering of various T-cell products with a chimeric (CAR-T) or artificial (TCR-engineered T-cell) antigen receptor. However, increasing data reveal the fact that, in addition to the thermodynamic component, the specificity of antigen recognition is based on the kinetics and mechanics of the process, having even greater influence on the selectivity of the process and T lymphocyte activation than affinity. Therefore, the kinetic and mechanical aspects of antigen recognition should be taken into account when designing artificial antigen receptors, especially those that recognize antigens in the MHC complex. This review describes the current understanding of the nature of the TCR-pMHC interaction, in addition to the thermodynamic, kinetic, and mechanical principles underlying the specificity and high sensitivity of this interaction.

[Quantitative analysis of seasonal dynamics of the species structure in a component parasite community of the minnow Phoxinus phoxinus (L.) of the Pechora River].

Earlier analysis of a seasonal succession of fish parasites assemblage was, as a rule, performed in May-October. At the same time, winter season can be important in seasonal dynamics of the assemblage. In the present work, quantitative analysis of complete seasonal dynamics of species structure of fish assemblage parasites with an example of the adult minnow of the river Pechora was performed. The new stable state of parasites assemblage of the minnow, corresponding to winter season of its existence, is revealed. Irrespective of population density or a biomass of parasitic assemblages of the minnow, obtained dynamic phase portraits well reflect their seasonal succession.

[Food allergy].

Food allergy (FA)--a condition of high sensitivity to food products--is widely spread allergic disease treated by allergologists, gastroenterologists, dermatologists, physicians, pulmonologists. FA pathogenesis involves immunological mechanisms with participation of immunocompetent cells and production of IgE and IgG. Treatment aims at elimination of causative antigen. Proteins of cow milk, hen's eggs, cereals, fish, citrus fruit, nuts, tomatos are most common such antigens. It is especially important for infants. FA manifests with anaphylactic shock, oral allergic syndrome, respiratory symptoms, abdominal impairments. The digestive system is both a target and a course of FA formation. FA arises mostly because of defects of gastrointestinal immune system, inability to synthetize IgA in adequate quantity while IgA has protective properties. Therefore, FA treatment should include probiotics, cytoprotectors, enzymes, sorbents. Atopic dermatitis, one of FA manifestations, is treated with non-hormonal drugs containing lipids, urea, topic inhibitors of calcinevrin. On demand, topic glucocorticosteroids, sometimes in combination with antimicrobial and antifungal drugs are added. Multidisciplinary approach to FA problem gives positive results.

[Application of the dynamic phase portrait method for the analysis of structural transformations in the component parasite communities of the minnow Phoxinus phoxinus (L.)].

The present study aimed to investigate structural changes in communities of fish parasites by the method of dynamic phase portrait. This method allows revealing equilibrium states of communities and analyzing a response of community near and far from these states. Seasonal succession of the parasite communities in Phoxinus phoxinus of different age from the rivers Ulcheksha and Chovju is considered as an example. The obtained phase portrait were found to reflect the seasonal succession of the parasite communities whether the rate of different parasite species abundance was analyzed by the number or biomass. The process of forming was recorded in the studied parasite communities in May, while in June these communities come to the equilibrium state with maximum species diversity, minimum speed of the diversity's change, and considerable quantity of parasites. However, this equilibrium state is unstable. Interpopulation connections lead to further structural transformations, and at the end of July-the beginning of August, when the above parameters have minimal values, the community comes to a new equilibrium state. Later on, in August-September, when the host fish is invading by a new generation of parasites, the community comes out the equilibrium state. Unlike the parasite communities in the host of age 1+-3+, the community in Phoxinus phoxinus 0+ begins to form in July. Diversity index of such community is lesser.

A screening study of thyroid cancer and other thyroid diseases among individuals exposed in utero to iodine-131 from Chernobyl fallout.

BACKGROUND: Like stable iodine, radioiodines concentrate in the thyroid gland, increasing thyroid cancer risk in exposed children. Data on exposure to the embryonic/fetal thyroid are rare, raising questions about use of iodine 131 (I-131) in pregnant women. We present here estimated risks of thyroid disease from exposure in utero to I-131 fallout from the Chernobyl nuclear accident. METHODS: We conducted a cross-sectional thyroid screening study (palpation, ultrasound, thyroid hormones, and, if indicated, fine needle aspiration) from 2003 to 2006. Participants were 2582 mother-child pairs from Ukraine in which the mother had been pregnant at the time of the accident on April 26, 1986, or 2 months after the time during which I-131 fallout was still present (1494 from contaminated areas, 1088 in the comparison group). Individual cumulative in utero thyroid dose estimates were derived from estimated I-131 activity in the mother's thyroid (mean 72 mGy; range 0-3230 mGy). RESULTS: There were seven cases of thyroid carcinoma and one case of Hurthle cell neoplasm identified as a result of the screening. Whereas the estimated excess odds ratio per gray for thyroid carcinoma was elevated (excess odds ratio per gray 11.66), it was not statistically significant (P = 0.12). No radiation risks were identified for other thyroid diseases. CONCLUSION: Our results suggest that in utero exposure to radioiodines may have increased the risk of thyroid carcinoma approximately 20 yr after the Chernobyl accident, supporting a conservative approach to medical uses of I-131 during pregnancy.

Autoimmune thyroiditis and exposure to iodine 131 in the Ukrainian cohort study of thyroid cancer and other thyroid diseases after the Chornobyl accident: results from the first screening cycle (1998-2000).

CONTEXT: Due to the Chornobyl accident, millions were exposed to radioactive isotopes of iodine and some received appreciable iodine 131 (131I) doses. A subsequent increase in thyroid cancer has been largely attributed to this exposure, but evidence concerning autoimmune thyroiditis (AIT) remains inconclusive. OBJECTIVE: The objective of the study was to quantify risk of AIT after 131I exposure. DESIGN/SETTING/PARTICIPANTS: Baseline data were collected from the first screening cycle (1998-2000) of a large cohort of radiation-exposed individuals (n = 12,240), residents of contaminated, iodine-deficient territories of Ukraine. Study individuals were under the age of 18 yr on April 26, 1986, and had thyroid radioactivity measurements made shortly after the accident. OUTCOMES: AIT was defined a priori based on various combinations of elevated antibodies to thyroid peroxidase (ATPO), TSH, and clinical findings; elevated ATPO were considered to be an indicator of thyroid autoimmunity. RESULTS: No significant association was found between 131I thyroid dose estimates and AIT, but prevalence of elevated ATPO demonstrated a modest, significant association with 131I that was well described by several concave models. This relationship was apparent in individuals with moderately elevated ATPO and euthyroid, thyroid disease-free individuals. CONCLUSIONS: Twelve to 14 yr after the Chornobyl accident, no radiation-related increase in prevalence of AIT was found in a large cohort study, the first in which 131I thyroid doses were estimated using individual radioactivity measurements. However, a dose-response relationship with ATPO prevalence raises the possibility that clinically important changes may occur over time. Thus, further follow-up and analysis of prospective data in this cohort are necessary.

[Characteristics of cerebral hemodynamics and psychological adaptation of patients with myocardial infarction during period of rehabilitation and convalescence].

Cerebral circulation and psychological state of 93 myocardial infarction patients aged from 29 to 60 years have been studied. The comparison of data concerning cerebral circulation with psychological profile of these patients enables us to make a conclusion that there is interrelation between the state of cerebral hemodynamics which ensures brain homeostasis and psychological adaptation of patients with myocardial infarction at different stages of the disease

[Surgical treatment of a carbuncle]. / Khirurgicheskoe lechenie karbunkula.

The results of the treatment of 250 patients with a carbuncle of various location were analyzed retrospectively. A differential approach to choice of surgical method with consideration of the degree, phase and localization of inflammation is preferable. Early and radical surgery, antimicrobic drugs, infusion therapy make base of up-to-date and adequate treatment. In the phase of infiltration deep incision often stops the disease or promotes a decrease of the necrotic zone. In suppurations linear incisions were made only on the face for cosmetic reasons. In other areas a few large connected T-, [symbol: see text]-, [symbol: see text]- or cross-formed incisions were preferable. In 30 cases I-formed incision with two rectangular flaps was used.

[Treatment of patients with acute pneumonia]. / Lechenie bol'nykh ostroi pnevmoniei.

Efficiency was studied of treatment of acute pneumonia (AP) in 148 patients with a focal croupous form. In the grave course of AP, antibacterial therapy with benzilpenicillin combined with sulphanilamide agents biseptol and nitrofuran was tried, the correcting therapy having been instituted on obtaining findings from assays of the sputum for sensitivity of the microflora to antibiotics. In those cases with Friendländer's bacilli recoverable, methicillin, oxacillin, macrolids, cephalosporins and some other agents were antibiotics of choice. Administered in the atypical course that was related more frequently to mycoplasms or chlamidia, was erythromycin phosphate i.v., lincomycin. In Staphylococcus-associated pneumonia, there have been used antibiotics resistant to penicillinases and endowed with an inhibitory activity toward staphylococci--oxacillin, methicillin, cephalosporins, chlorophenicols or chlorophphyllipt i.v. combined with an antistaphylacoccal plasma, antistaphylococcal gammaglobulin or hyperimmune plasma. The following drugs were prescribed to ensure bronchial patency and liquefaction of the sputum--euphyllin, mucalthin, bromhexin, lasolvan that are known to stimulate production of sulfoctant. The therapeutic complex comprized fibs, aloe, apilac, prodigiosan, solcoseryl, methyluracil known to stimulate bodily reactivity and resolution of inflammatory infiltration, nicotinic acid, heparin that have been shown to improve micorcirculation, tocopherol, unithiol known to regulate lipid oxidation. The data secured suggest to us a sufficient efficacy of the above-outlined therapy of AP.

[Mosaicism of the upper respiratory tract epithelium in liquidators of the Chernobyl accident]. / Mozaichnost' épiteliia verkhnikh dykhatel'nykh putei u likvidatorov posledstvii avarii na ChAES.

On the basis of findings from the structural analysis of 21 nasal mucosa biopsy specimens of patients with chronic rhinitis including 12 participants in liquidation of the consequences of the Chernobyl accident using morphometric methods, signs of morphofunctional insufficiency of the nasal epithelium are verified. Mechanisms of this phenomenon development are discussed.

[Clinical efficacy of using ximedon in surgical practice]. / Klinicheskaia éffektivnost' primeneniia ksimedona v khirurgicheskoi praktike.

Results of clinical trial of the new pyrimidine derivative--ximedone are presented. The drug was administered per os 0.5 g x 4 times a day (0.5 h before meals). Total course dose achieved 60 g. Ximedone implementation for complex treatment of burns, trophic ulcer of lower limbs, different inflammations demonstrated positive results. Prophylaxy administration of the drug in abdominal surgery at acute appendix resulted with lower incidence of postoperative complications. High efficacy and good tolerability of the drug allows to recommend it for wide medical use.

[Invasion of microorganisms in bronchial mucosa of liquidators of the Chernobyl accident consequences]. / Invaziia mikroorganizamov v slizistuiu obolochku bronkhov likvidatorov posle destvii avarii na Chernobyl'skoi AES.

Bronchial bioptates of 97 liquidators of the Chernobyl accident consequences with chronic bronchitis and 23 patients of control nosological group as well as sputum (174 persons) and BAL (22 persons) of liquidators with chronic obstructive lung disease (COLD) were studied to define pathogenic role of automicroflora in the development of lung diseases. Such methods as electron microscopy, immunohistochemistry and microbiology were used. The revealed invasion of microorganisms occurred against the background of pathology of superficial bronchial epithelium with a decrease of HLA-DR and CD23 lymphocytes and increase of CD1c lymphocytes in lamina propria of bronchial mucosa of the liquidators. Verification of microorganisms characteristic of the upper respiratory tracts and atypical presence of Escherichia coli were found in the contents of the lower parts of broncho-pulmonary system of the liquidators. The obtained results testify to the activation of automicroflora and appearance of pathogenic microorganisms were caused by deterioration of specific and non-specific immune protection in liquidators with COLD.

[The immunomodulator ximedon lowers the level of induced DNA damages in bone marrow and peripheral blood cells: the possibilities for immunogenetic correction]. / Immunomoduliator ksimedon snizhaet uroven' indutsirovannykh povrezhdenii DNK v kletkakh kostnogo mozga i perifericheskoi krovi: vozmozhnosti immunogeneticheskoi korrektsii.

It was established in experiments on albino unbred mice and during treatment of patients with osteomyelitis that 30 mg/kg of ximidon suppresses the formation of micronuclear polychromatophilic erythrocytes found in the bone marrow of mice and peripheral blood of patients with chronic osteomyelitis. The interrelationship of the results obtained with the modulating effect of ximidon on the mitochondrial, thiol, and adenylate cyclase-dependent mechanisms of cell regulation is discussed.

[The ultrastructural characteristics of the bronchial mucosa in chronic inflammation in participants in the cleanup of the aftermath of the accident at the Chernobyl Atomic Electric Power Station]. / Ul'trastrukturnaia kharakteristika slizistoi obolochki bronkhov pri khronicheskom vospalenii u uchastnikov likvidatsii posledstvii avarii na ChAES.

Bronchial biopsies from persons exposed to radiation after the Chernobyl accident with clinically verified chronic bronchitis were studied by electron microscopy. The results demonstrate transformed alterative, compensatory-adaptive and inflammatory reactions in bronchial mucosa of contingent. Nevertheless, their integral significance does not alter the nosologic form, and some structural equivalents have dynamic expression.

[The morphogenesis of pathological processes in the gastric mucosa in chronic gastritis in servicemen who worked in the cleanup of the aftermath of the accident at the Chernobyl Atomic Electric Power Station]. / Morfohenez patolohichnykh protsesiv u slyzovii obolontsi shlunka pry khronichnomu hastryti u viis'kovosluzhbovtsiv--likvidatoriv naslidkiv avariï na ChAES.

Results are submitted of a complex structural analysis of 200 gastrobiopsies taken in those subjects with chronic gastritis who took part in the elimination of the aftermath of the Chernobyl accident, as well as in patients of a control nosologic group with no history of a radiation-factor exposure. The liquidators versus control patients demonstrated morphofunctional changes in gastric mucosa as potential manifestations of induced pathomorphosis of the condition. A number of propositions have been stated concerning features of morphogenesis of pathological processes in gastric mucosa under chronic gastritis in liquidators of the effects of the Chernobyl disaster.

[The morphological diagnosis of Helicobacter pylori in the gastric mucosa in chronic gastritis]. / Morfologicheskaia diagnostika Helicobacter pylori v slizistoi obolochke zheludka pri khronicheskom gastrite.

The importance is substantiated of morphologic verification of H. pylori infection in gastric mucosa in chronic gastritis. Based on the material of gastrobiopsies from 111 patients with chronic gastritis, 77 of whom took part in the elimination of the effects of the Chernobyl disaster, informative value was confirmed of different methods of structural analysis in respect of H. pylori. Arguments are advanced for optimization of therapeutic policy in H. pylori-associated gastritis.

[Sternal osteomyelitis]. / Osteomielit grudiny.

The authors present data based on the analysis of diagnosis and treatment of 11 patients with sternal osteomyelitis which in 9 patients was of traumatic origin and in 2 was hematogenous. Early diagnosis is difficult. Clinical manifestations and roentgenography of the sternum are essential for diagnosis. In combined treatment of osteomyelitis preference is given to radical removal of osteomyelitic masses within healthy tissues with tamponade of the residual osteal cavity by local tissues.

[The dynamics of thyroid diseases in the inhabitants of Kiev and Kiev Province after the accident at the Chernobyl Atomic Electric Power Station]. / Dinamika zabolevanii shchitovidnoi zhelezy u zhitelei Kieva i Kievskoi oblasti posle avarii na ChAES.

Autoimmune affections of the thyroid gland were found to be on the increase as were Hashimoto's disease and follicular adenoma, as evidenced by a pathomorphic study in surgically removed thyroid glands of 12684 patients over 1984-1993. Rise in the frequency of malignant tumors was moderate. Increase in the incidence of papillary microcarcinoma against the background of another surgical pathology of the thyroid gland may be an unfavourable prognostic sign of further growth of morbidity of clinically manifest forms of carcinoma in Kiev and the Kiev Province.