Shedding light on the DICER1 mutational spectrum of uncertain significance in malignant neoplasms.

The Dicer protein is an indispensable player in such fundamental cell pathways as miRNA biogenesis and regulation of protein expression in a cell. Most recently, both germline and somatic mutations in DICER1 have been identified in diverse types of cancers, which suggests Dicer mutations can lead to cancer progression. In addition to well-known hotspot mutations in RNAase III domains, DICER1 is characterized by a wide spectrum of variants in all the functional domains; most are of uncertain significance and unstated clinical effects. Moreover, various new somatic DICER1 mutations continuously appear in cancer genome sequencing. The latest contemporary methods of variant effect prediction utilize machine learning algorithms on bulk data, yielding suboptimal correlation with biological data. Consequently, such analysis should be conducted based on the functional and structural characteristics of each protein, using a well-grounded targeted dataset rather than relying on large amounts of unsupervised data. Domains are the functional and evolutionary units of a protein; the analysis of the whole protein should be based on separate and independent examinations of each domain by their evolutionary reconstruction. Dicer represents a hallmark example of a multidomain protein, and we confirmed the phylogenetic multidomain approach being beneficial for the clinical effect prediction of Dicer variants. Because Dicer was suggested to have a putative role in hematological malignancies, we examined variants of DICER1 occurring outside the well-known hotspots of the RNase III domain in this type of cancer using phylogenetic reconstruction of individual domain history. Examined substitutions might disrupt the Dicer function, which was demonstrated by molecular dynamic simulation, where distinct structural alterations were observed for each mutation. Our approach can be utilized to study other multidomain proteins and to improve clinical effect evaluation.

[Laparoscopic appendectomy for mucinous cystadenoma of the appendix]. / Laparoskopicheskaia appendéktomiia pri mutsinoznoi tsistadenome cherveobraznogo otrostka.

Treatment of acute and chronic appendicitis is still an actual problem. There are some rare courses of the disease besides well-known complications of appendicitis. Mucocele is one of the rarest forms of chronic appendicitis. Mucocele is not accompanied by clinical symptoms and diagnosed accidentally in more than 25% of cases. The most serious complication of mucocele of the appendix is malignization observed in up to 36% of cases. Ultrasound, CT and colonoscopy are the most effective methods of perioperative diagnosis. Unclear symptoms, delayed diagnosis and surgical treatment increase the risk of complications (i.e. cystadenocarcinoma).

[Virus-like particles--a new strategy for production of vaccines against influenza virus].

Numerous studies demonstrated that simultaneous expression of some viral proteins in the cell with the aid of a process of self-assembly might lead to the formation of the virus-like particles (VLP) even in the absence of the viral genome. The morphological and antigenic similarity between VLP and native virions represents a promising approach to the new type of vaccines. In the last decade, the threat of the influenza strains with pandemic potential becomes more important. Therefore, the technology for obtaining a new generation of safe and effective non-embryo culture vaccines was developed on the basis of the influenza VLP produced in various expression systems. This provides great advantages in comparison with existing methods of vaccine production. Such vaccines induced full humoral and cellular immune response in animals and humans. This review is focused on the literature concerning the influenza VLPs obtained in various expression systems including insect, mammalian and plant cells.

[Severe disseminated constrictive polyserositis in a patient with rheumatoid arthritis].

Constrictive polyserositis (pleuritis, pericarditis) is a syndrome within the underlying disease (tuberculosis, periodic disease, rheumatoid arthritis, systemic lupus erythematosus, asbestos, silicosis, uremia, some genetic diseases), a complication due to chest surgery or radiation or drug therapy, is occasionally idiopathic (fibrosing mediastinitis). There are frequently great difficulties in making its nosological diagnosis. The paper describes a patient in whom the onset of disease was exudative pleurisy with the signs of constriction, arthralgias; pleural punctures provided serous exudates with 80% lymphocytes. A year later there was ascitis and shin and foot edemas, which concurrent with hepatomegaly and cholestasis was regarded as cryptogenic liver cirrhosis. The signs of constrictive pericarditis were further revealed. The disease was complicated by the development of pulmonary artery thromboembolism (PATE) (which required the use of warfarin) and hemorrhagic vasculitis. Therapy with metipred in combination with isoniazid yielded a slight effect. The diagnoses of tuberculosis, liver cirrhosis, and autoimmune hepatitis, systemic vasculitis were consecutively rejected; the diagnosis of rheumatoid polyarthritis with systemic manifestations was made, by taking into account persistent arthalgias with the minimum signs of arthritis, noticeably increased C-reactive protein, rheumatoid factor, and cyclic citrullinated peptide antibodies (CCPA); plasmapheresis, therapy with metipred and methotrexate, and subtotal pericardectomy were performed. Constrictive polyserositis concurrent with PATE, hemorrhagic vasculitis (probably, drug-induced one), and hepatic lesion has been first described in a CCPA-positive patient with rheumatoid arthritis in the presence of moderate true arthritis (during steroid therapy).

[Changes in indices of inflammatory activity in patients with rheumatoid arthritis during early stages of basic therapy with leflunomide]. / Dinamika pokazatelei vospalitel'noi aktivnosti u bol'nykh revmatoidnym artritom na rannikh étapakh bazisnoi terapii leflunomidom.

AIM: To assess leflunomide efficacy and tolerance in patients with rheumatoid arthritis (RA) during the first four months of the treatment. MATERIAL AND METHODS: The study included 200 RA patients treated in four Moscow clinical centers. Leflunomide was given in a dose of 100 mg/day for 3 days, then 20 mg/day for 16 weeks. The activity of the disease according to the criterion DAS 28 was assessed before the treatment and 4, 8, 12 and 16 weeks after the treatment start. RESULTS: RA activity diminished considerably after one month of leflunomide treatment. Later, the articular syndrome continued to improve. A significant improvement by DAS 28 was observed after 16 weeks of the treatment in 65% (129 of 200) patients, high RA activity persisted only in 17 of 90 patients. CONCLUSION: Leflunomide reduces articular inflammation and raises RA patients' quality of life at early stages of the treatment. This reduction continued for 4 months of the study. Therefore, adequate assessment of leflunomide efficacy should be made only after 4-6 months of therapy.

[Qualitative and quantitative assessment of exposure to geomagnetic field variations on the functional status of the human brain]. / Kachestvennaia i kolichestvennaia otsenka vozdeistviia variatsii geomagnitnogo polia na funktsional'noe sostoianie mozga cheloveka.

The comparison of functional dynamics of human brain with reference to qualitative and quantitative characteristics of local geomagnetic field (GMF) variations was conducted. It was showed that just local GMF variations can be a principal reason of modulation the human brain's functional state. The steady and unsteady states of human brain can be determined: by geomagnetic disturbances before the observation period; by structure and doses of GMF variations; by different combinations of qualitative and quantitative characteristics of GMF variations. The optimal level of GMF activity, manifested in periodic oscillations in certain amplitude-frequency range is demanded for steady brain's functional state. The decrease of optimal GMF activity level and the appearance of aperiodic disturbances of GMF can be a reason of unsteady brain's state.

[Psychophysiological approaches to assessing patients with painful and painless forms of ischemic heart disease]. / Psikhofiziologicheskie podkhody k otsenke bol'nykh s bolevoi i bezbolevoi formoi IBS.

By the results of bicycle ergometry test 28 coronary heart disease (CHD) patients were divided into 2 groups: with a pronounced anginal syndrome (group 1) and coronary insufficiency evident on ECG (group 2). Vegetative and psychophysiological parameters obtained in the examinees (heart rate, arterial pressure, pain threshold, personality profile) demonstrated that increased pain sensitivity, anxiety, predisposition to neurotic reactions were more typical for patients of group 1. Therapeutic response was achieved after psychophysiological correction by means of creation and activation of artificial stable functional connections of the brain.

[Pathogenesis of anemia in systemic scleroderma]. / K patogenezy anemii pri sistemnoi sklerodermii.

The paper reports a case of anemia with complicated genesis in a male patient with systemic scleroderma (SS). Antianemia therapy was not easy, as after rapid disappearance of iron deficiency vitamin B12 deficiency remained, hemolytic component of the disease persisted. The case demonstrates that multicomponent pathogenesis of anemic conditions is possible. This must be taken into consideration when planning therapeutic policy in SS.

[The preliminary results of using tramal in rheumatoid arthritis patients]. / Predvaritel'nye rezul'taty ispol'zovaniia tramala u bol'nykh revmatoidnym artritom.

Patients suffering from active rheumatoid arthritis (RA) were examined for the analgesic effect of tramal. All the patients were administered basic therapy and nonsteroidal anti-inflammatory drugs. Tramal produced a beneficial effect in 79% of the patients. The stable analgesic effect ensued on days 3-5 since the onset of continuous treatment. Provided the drug was administered for a short period of time (not more than 14 days), addiction to tramal was not recorded. Only 11% of the patients demonstrated tramal-induced side effects (drowsiness, dizziness, skin itch), seen in cases where the daily dose exceeded 300 mg.

[Various problems of the diagnosis and therapeutic tactics in systemic lupus erythematosus]. / Nekotorye voprosy diagnostiki i taktiki vedeniia bol'nykh sistemnoi krasnoi volchankoi.

The authors discuss diagnostic aspects of systemic lupus erythematosus (SLE) with emphasis on its early stages and outpatient policy. Formalized diagnostic criteria of the disease are recommended. Clinical features of the variants of SLE onset are briefly reported. Various aspects of the patients' management and regime, limiting measures are considered for a confirmed and tentetive SLE diagnosis.