[Five year experience in ibrutinib therapy for relapsed and refractory mantle cell lymphoma in real world Russian clinical practice].

BACKGROUND: Mantle cell lymphoma (MCL) is a rare and clinically aggressive lymphoma subtype. Current approaches have greatly improved patients outcomes, but relapse is inevitable. In phase IIIII clinical trials, ibrutinib has shown significant activity in patients with relapsed or refractory (R/R) MCL. AIM: To assess efficacy and toxicity of ibrutinib monotherapy in patients with R/R MCL in routine practice outside of clinical trials. MATERIALS AND METHODS: The study enrolled patients with confirmed R/R MCL who had received at least one line of previous chemotherapy. ECOG 24, cytopenia, infectious complications, hemorrhagic syndrome were not exclusion criteria. Patients received daily oral ibrutinib 560 mg until progression or unacceptable toxicity. RESULTS: From May 2015 to September 2020 ibrutinib therapy was started in 106 patients with R/R MCL in 16 regions of Russia. The median age was 66 years; ECOG2 18%, blastoid variant (or Ki6740% or WBC50109/l) 43%. The median number of previous treatment lines was 2 (111). The ORR was 78.4% (CRR 27.4%). The median PFS was 13.6 months and OS 23.2 months. In the blastoid group the median PFS was 4.4 months vs 36.5 months in the alternative group (p0.001), the median OS 9.0 vs 41.0 (p=0.001). The median OS of patients after progression on ibrutinib was 3.2 months. The common complications are hemorrhages (63%), diarrhea (62%), myalgia and muscle cramps (60%), infections (31%), skin and nail toxicity 15%, arrhythmia 8%. None of recipients had to completely discontinue ibrutinib therapy due to complications. CONCLUSION: Ibrutinib is effective and well tolerated in routine practice of R/R MCL treatment and our results are consistent with international clinical trials. The favorable toxicity profile and the high response rate made it possible to prescribe ibrutinib in severe somatic status, cytopenia, and even in the presence of infectious complications.

[Caroli's disease: diagnostic problems and possibilities of treatment].

Caroli's disease is a rare congenital condition characterized by segmental non-obstructive fibrocystic dilation of intrahepatic bile ducts. Dilated ducts may be infected and contain stones. This review of the modern literature describes few known cases of the disease, analyses its clinical features and results of treatment. The principal diagnostic methods include visualization by ultrasound study, CT, MRT, retrograde and transhepatic cholangiography. Surgical intervention is the method of choice for the treatment of the disease including resection of liver, placement of hepatico-jejunal anastomoses and transplantation. The choice depends on the extent of the lesion and anticipated complications. The authors' observation of the patient with Caroli's disease in a 35 year-old woman is presented. It was successfully treated by left-hand bisegmentectomy even though the disease was diagnosed 14 years after the first symptoms. It is recommended that the disease, even if a rare one, should be included in the algorithm of differential diagnostics ofrecurrent abdominal pain with manifestations of cholestasis or fever of an unknown origin.

[Molecular markers of nuclear DNA in the study of evolution and speciation process in an example of "Lacerta agilis complex" (Sauria: Lacertidae)].

In order to elucidate the molecular-genetic relations of some Lacerta s. str. lizard populations, subspecies and species in comparison with some other genera we used methods revealing four types of nuclear DNA markers. Among these were taxonprint, RAPD, Inter-MIR-PCR markers and also satellite DNA monomer sequences. The aim was to compare the phylogeny and systematics of this reptilian group based on morphological and molecular criteria. This problem has a general importance for understanding a speciation process. Our results show a good correlation between both approaches when genera and species levels were studied. Systematic status of five subspecies of L. agilis were supported but not in all cases, some subspecies have no meaningful genetic differences by three types of molecular markers, but all of them were differed by RAPD markers. The data confirm the subdivision of L. agilis populations into west and east clades proposed by other authors earlier on the basis of mitochondrial DNA and morphology. The population structure of one of the subspecies--L. agilis exigua, was studied on a number of populations distributed from Ural region up to Kabardino-Balkaria by IMP method. There were no significant differences among these 14 populations investigated. The data testify the rapid distribution of the species after the end of Pleistocene glaciation.

[In silico analysis of the restriction fragments length distribution in the human genome]. / Analiz in silico raspredelenie restriktnykh fragmentov genoma cheloveka po dlinam.

The Restriction On Computer (ROC) program (freely available at http://www.mcb.harvard.edu/gilbert/ROC) was developed and used to analyze the restriction fragment length distribution in the human genome. In contrast to other programs searching for restriction sites, ROC simultaneously analyzes several long nucleotide sequences, such as the entire genomes, and in essence simulates electrophoretic analysis of DNA restriction fragments. In addition, this program extracts and analyzes DNA repeats that account for peaks in the restriction fragment length distribution. The ROC analysis data are consistent with the experimental data obtained via in vitro restriction enzyme analysis (taxonomic printing). A difference between the in vitro and in silico results is explained by underrepresentation of tandem DNA repeats in genomic databases. The ROC analysis of individual genome fragments elucidated the nature of several DNA markers, which were earlier revealed by taxonomic printing, and showed that L1 and Alu repeats are nonrandomly distributed in various chromosomes. Another advantage is that the ROC procedure makes it possible to analyze the nonrandom character of a genomic distribution of short DNA sequences. The ROC analysis showed that a low poly(G) frequency is characteristic of the entire human genome, rather than of only coding sequences. The method was proposed for a more complex in silico analysis of the genome. For instance, it is possible to simulate DNA restriction together with blot hybridization and then to analyze the nature of markers revealed.

Variable and invariable DNA repeat characters revealed by taxonprint approach are useful for molecular systematics.

A specially optimized restriction analysis of highly repetitive DNA elements, called DNA taxonprint, was applied for phylogenetic study of primates and lizards. It was shown that electrophoretic bands of DNA repeats revealed by the taxonprint technique have valuable properties for molecular systematics. Approximately half of taxonprint bands (TB) are invariable and do not disappear from the genomes during evolution or change spontaneously. Presumably these invariable bands are restriction fragments of dispersed DNA repeats. Another group represents variable taxonprint bands that differ even between closely related species. These variable bands are probably represented by tandem DNA repeats and could be used as species-specific markers. It was shown that taxonprint bands are independent characters since the appearance of a new taxonprint band does not change the previous band pattern. Phylogenetic reconstruction carried out on taxonprint data demonstrated that this approach could be of general utility for molecular systematics and species identification.

Restriction endonuclease analysis of highly repetitive DNA as a phylogenetic tool.

Multiple band patterns of DNA repeats in the 20-500-nucleotide range can be detected by digesting genomic DNA with short-cutting restriction endonucleases, followed by end labeling of the restriction fragments and fractionation in nondenaturing polyacrylamide gels. We call such band patterns obtained from genomic DNA "taxonprints" (Fedorov et al. 1992). Here we show that taxonprints for the taxonomic groups studied (mammals, reptiles, fish, insects-altogether more than 50 species) have the following properties: (1) All individuals from the same species have identical taxonprints. (2) Taxonprint bands can be subdivided into those specific for a single species and those specific for groups of closely related species, genera, and even families. (3) Each restriction endonuclease produces unique band patterns; thus, five to ten restriction enzymes (about 100 bands) may be sufficient for a statistical treatment of phylogenetic relationships based on polymorphisms of restriction endinuclease sites. We demonstrate that taxonprint analysis allows one to distinguish closely related species and to establish the degree of similarity among species and among genera. These characteristics make taxonprint analysis a valuable tool for taxonomic and phylogenetic studies.

[Comparison of repeat DNA sequences in the Erinaceidae mammal family by restriction analysis]. / Sravnenie povtoriaiushchikhsia posledovatel'nostei DNK mlekopitaiushchikh semeistva Erinaceidae metodom restriktaznogo analiza.

Hedgehog (Erinaceidae) DNA was digested with teh Sau 96 I, Bsp 143 I, Csp 6 I, Taq I, Hinf I, Msp I, Eco 130I, Bcn I, BsuR I restriction endonucleases. The obtained products were end-labeled and electrophoretically separated in polyacrylamide gel. DNA fragments consisting of highly repetitive genomic sequences were detected as a set of bands corresponding to fragments between 30 and 500 bp in length. Comparison of DNA restriction patterns of the species analyzed revealed the presence of species-specific bands as well as common bands. Phylogenetic trees were constructed by means of the maximum parsimony method and the bootstrap procedure. Our data suggest that hedgehog species from arid areas are clearly distinguished from forest species.

[Activity of enzymes of xenobiotics metabolism in peripheral blood lymphocytes in man]. / Aktivnost fermentov metabolizma ksenobiotikov v limphotsitakh perifericheskoi krovi cheloveka.

The activity of NADPH-cytochrome c-reductase, benzpyrene hydroxylase, epoxy-hydratase and glutathione-S-transferase in human peripheral blood lymphocytes was studied. In the presence of NADPH, native lymphocytes were unable to reduce cytochrome c. In order to improve the availability of substrates for enzymes, lymphocytes were degraded by single-stage freezing-melting. At the same time, the activities of NADPH-cytochrome c-reductase, epoxide hydratase, and glutathione-S-transferase were 1.7 +/- 0.6, 49.0 +/- 18.0, and 30.0 +/- 6.0 nmol/min per mg protein, respectively. The lymphocytic levels of cytochrome P-450 were approximately 0.1-0.2 nmol per mg microsomal protein, while those of cytochrome b5 were nearly 0.5 nmol/mg microsomal protein in the lymphocytes.

[Taxonoprint DNA analysis of certain lizard species from the Lacertidae family]. / Taksonoprintnyi analiz DNK nekotorykh vidov iashcherits semeistva Lacertidae.

It was earlier shown that electrophoretic patterns of the highly repetitive segments of DNA's of some animal species studied seem to have species specificity ("DNA taxonoprint method") [2]. In this paper the results of investigation of more than 20 lizard species of the Lacerta genus in comparison with representatives of some other genera and family are presented. It was shown that in taxonoprints there are one band, at least, but usually more bands common for all Lacerta species. Specimens of genus Podarcis have more similarity with genus Lacerta than genus Eremias. The representatives of Teiidae familie have no resemblance with family Lacertidae at all. Among Lacerta species there are 10, which form the separate group being very similar by most of the taxonoprints. This fact goes in line with hypothesis that 5 parthenogenetic species of this group evolve due to interspecies hybridization of another 5 bisexual species of this group. The other species studied have specific peculiarities in various taxonoprints permitting to draw some conclusions on their relations.

[Study of the minimum frequency of phase 2 introns]. / Issledovanie minimuma chastoty intronov fazy 2.

A study has been made on the distribution of introns of different groups with respect to phases. It has been established that group II introns and nuclear introns have a similar minimum of relative frequency of phase 2 introns. Since the phase of introns is an extremely conservative index, the observed minimum is a trace of relic evolutionary processes. A sample of all known group I introns proved to be insufficient to obtain a valid characteristic of phase distribution. It has been shown that the picture observed in the phase distribution cannot be explained on the basis of the mobile properties of introns only. One of the probable explanations for the intron phase distribution nonuniformity is the process of exon shuffling. An assumption is made that group II introns originated at the early stages of evolution and were involved in the process of exon shuffling.

[Taxonometric analysis of DNA repeating elements]. / Taksonomicheskii analiz povtoriaiushchikhsia élementov DNK.

The method of analysis of low molecular weight fragments of high copied repeats of DNA hydrolysed by restriction nuclease is presented. The P labeled fragments (by means of DNA polymerase I) are electrophoresed in nondenaturing PAAG and radio-autographed. The specific band patterns are observed in region between approximately 20 and 300 bp. When studying some lizard and fish species DNA's it was shown that the patterns observed have species and genus specificity but not individual. The approach supposed can be applied to investigation of interspecies relationships, some evolutionary problems and to the studying of questions concerning the role of DNA repeats in evolution. The method is simple and comparatively cheap and may be called as "taxonomic DNA fingerprint" or "DNA taxonoprint" method.

[The determination of beta-casein gene expression and the assessment of hormonal homeostasis in gynecomastia patients and in breast cancer in men]. / Opredelenie ékspressii genov beta-kazeina i otsenka gormonal'nogo gomeostaza u bol'nykh s ginekomastiei i rakom molochnoi zhelezy u muzhchin.

beta-Casein genes expression in breast epithelium was studied in male patients with various forms of gynecomastia and cancer. Blood serum levels of pituitary, sex and glucocorticoid hormones were assayed in 29 patients with gynecomastia and 22 cases of breast cancer, and in 25 of them beta-casein genes expression was evaluated additionally. Activation of the above genes was established in the tissues studied. Their level proved to be in a correlation with that of prolactin.

[The function of the hypophysis, adrenal cortex and gonads in men with breast cancer]. / Funktsional'noe sostoianie gipofiza, kory nadpochechnikov i gonad u muzhchin, bol'nykh rakom molochnoi zhelezy.

It was established that male patients with breast cancer showed significant disorders of the functional state of the pituitary, adrenal cortex and gonads. This may be significant for the efficacy of combined treatment.

[Functional state of the hypophysis, adrenal cortex and gonads in patients with gynecomastia]. / Funktsional'noe sostoianie gipofiza, kory nadpochechnikov i gonad u bol'nykh ginekomastiei.

Patients with gynecomastia revealed simultaneous increase in blood levels of estrogens, glucocorticoids and pituitary (first of all, gonadotropic) hormones associated with a decrease in blood-androgen concentration. Such combination of disturbances may account for hyperplasia of the male breast.

[The characteristics of the effect of dipalmitoylphosphatidylcholine and its structural fragments on the lipid peroxidation of biological membranes]. / Ossobennosti vliianiia dipal'mitoilfosfatidilkholina i ego strukturnykh fragmentov na perekisnoe okislenie lipidov biologicheskikh membran.

The effect of dipalmitoyl phosphatidylcholine (DPPC) and its structural fragments--phosphatidic acid (PA) and choline chloride--on the ascorbate-dependent mice liver microsomal lipid peroxidation (LP) has been studied at the different LP rate. At DPPC, PA and choline chloride introduction into the incubation medium before the onset of peroxidation induction DPPC causes the more considerable inhibition of LP than PA each separate fragment. The inhibition effect of DPPC is lower than PA or choline chloride when DPPC, PA and choline chloride added on the background of developing process of peroxidation (e.i. after LP induction). A specific regulatory role of PC in the normal cell membrane LP process and during pathologic development is under discussion.

[Effect of phenformin on fetal mass in rats previously immunized with an extract of homologous thyroid gland]. / Vliianie fenformina na massu plodov u krys, predvaritel'no immunizirovannykh ékstraktom tkani gomologichnoi shchitovidnoi zhelezy.

Rats immunized with homologous thyroid antigen 9-27 weeks before delivery manifest an increase in the mean weight of fetus as compared with normal pregnant rats. Administration of phenformin (7.5 mg/day per os) during immunization and over 30 days after its discontinuance led to a significant weight reduction as compared with immunized animals not given phenformin. The latter's effect became more potent with an increase in the interval between immunization discontinuance and delivery. Prophylaxis and cure of the latent and evident autoimmune lesions of the thyroid gland during childhood and juvenescence are regarded as approaches to the prevention of endocrine and metabolic disorders favouring large fetus delivery.