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Multiple myeloma (MM) is the second most common hematological malignancy, which remains incurable despite recent advances in treatment strategies. Like other forms of cancer, MM is characterized by genomic instability, caused by defects in DNA repair. Along with mutations in DNA repair genes and genotoxic drugs used to treat MM, non-canonical secondary DNA structures (four-stranded G-quadruplex structures) can affect accumulation of somatic mutations and chromosomal abnormalities in the tumor cells of MM patients. Here, we tested the hypothesis that G-quadruplex structures may influence the distribution of somatic mutations in the tumor cells of MM patients. We sequenced exomes of normal and tumor cells of 11 MM patients and analyzed the data for the presence of G4 context around points of somatic mutations. To identify molecular mechanisms that could affect mutational profile of tumors, we also analyzed mutational signatures in tumor cells as well as germline mutations for the presence of specific SNPs in DNA repair genes or in genes regulating G-quadruplex unwinding. In several patients, we found that sites of somatic mutations are frequently located in regions with G4 context. This pattern correlated with specific germline variants found in these patients. We discuss the possible implications of these variants for mutation accumulation and specificity in MM and propose that the extent of G4 context enrichment around somatic mutation sites may be a novel metric characterizing mutational processes in tumors.

We discovered a specific property of the eigenmodes of a cylindrical waveguide, due to which efficient mode excitation at ultrahigh (s=4n+1, n is integer) multiples of the gyrofrequency can be provided by a polyhelical weakly relativistic electron beam, standardly used for gyrotron operation. In the proof-of-principle experiment with a V-band gyrotron driven by a 25-keV, 2-A beam, about 100 mW radiation power at the fifth cyclotron harmonic (0.22 THz) has been detected in the cw regime. Based on the gyrotron theory, we demonstrate in simulations that, using parameters of existing gyrotrons, this method can be applied for producing cw radiation at a power level of up to several watts in the terahertz gap.

In this paper, transmission of a monochromatic wave through a counterpropagating electron beam under the condition of cyclotron resonance absorption is studied by theoretical analysis and numerical simulation. Conditions of the modulation instability (MI) are analyzed. The MI strongly affects the regimes of transmission. We also derive explicit periodic stationary solutions expressed in terms of elliptic Jacobi functions, as well as bright- and dark-soliton solutions. Analysis of these solutions allows obtaining threshold values of the driving power and frequency for the different regimes of transmission, such as cyclotron absorption, multifrequency self-modulation oscillations, and stationary single-frequency propagation. The theoretical predictions are verified by numerical simulation. In this way, we obtain the conditions at which a continuous-wave driving signal disintegrates into a close-to-periodic train of microwave soliton pulses.

Based on numerical simulations of a boundary problem, we study various scenarios of microwave soliton formation in the process of cyclotron resonance interaction of a short electromagnetic pulse with a counter-propagating initially rectilinear electron beam taking into account the relativistic dependence of the cyclotron frequency on the electrons' energy. When a certain threshold in the pulse energy is exceeded, the incident pulse can propagate without damping in the absorbing beam, similar to the effect of self-induced transparency in optics. However, mutual motion of the wave and electrons can lead to some novel effects. For relatively small energy of the incident pulse, the microwave soliton is entrained by the electron beam opposite to the direction of the wave's group velocity. With an increase in the pulse energy, soliton stopping occurs. This regime is characterized by the close-to-zero pulse velocity and can be interpreted as a variety of the "light stopping." High-energy microwave solitons propagate in the direction of the unperturbed group velocity. Their amplitude may exceed the amplitude of the incident pulse, i.e., nonlinear self-compression takes place. A further increase in the incident energy leads to the formation of additional high-order solitons whose behavior is similar to that of the first-order ones. The characteristics of each soliton (its amplitude and duration) correspond to analytical two-parametric soliton solutions that are to be found from consideration of the unbounded problem.

Multiple myeloma (MM) is a malignant neoplasm of terminally differentiated immunoglobulin-producing B lymphocytes called plasma cells. MM is the second most common hematologic malignancy, and it poses a heavy economic and social burden because it remains incurable and confers a profound disability to patients. Despite current progress in MM treatment, the disease invariably recurs, even after the transplantation of autologous hematopoietic stem cells (ASCT). Biological processes leading to a pathological myeloma clone and the mechanisms of further evolution of the disease are far from complete understanding. Genetically, MM is a complex disease that demonstrates a high level of heterogeneity. Myeloma genomes carry numerous genetic changes, including structural genome variations and chromosomal gains and losses, and these changes occur in combinations with point mutations affecting various cellular pathways, including genome maintenance. MM genome instability in its extreme is manifested in mutation kataegis and complex genomic rearrangements: chromothripsis, templated insertions, and chromoplexy. Chemotherapeutic agents used to treat MM add another level of complexity because many of them exacerbate genome instability. Genome abnormalities are driver events and deciphering their mechanisms will help understand the causes of MM and play a pivotal role in developing new therapies.

We study the formation of solitons of microwave self-induced transparency (M/W-SIT) which occurs under cyclotron resonance interaction of an electromagnetic pulse with an initially rectilinear magnetized electron beam. Taking into account the relativistic dependence of the gyrofrequency on the particle energy for electromagnetic wave propagating with a phase velocity different from the speed of light (i.e., far from the autoresonance conditions), such a beam can be considered as a medium of nonisochronous unexcited oscillators. Thus, similar to passing light pulses in the two-level medium, for sufficiently large amplitude and duration the incident electromagnetic pulse decomposes into one or several solitons. We find analytically the generalized solution for the M/W-SIT soliton with amplitude and duration determined, besides the soliton velocity, by the frequency self-shift parameter. The feasibility and stability of the obtained solutions are confirmed in numerical simulations of a semibounded problem describing propagation and nonlinear interaction of an incident electromagnetic pulse.

Within the framework of the average approach and direct 3D PIC (particle-in-cell) simulations, we demonstrate that the gyrotrons operating in the regime of developed turbulence can sporadically emit "giant" spikes with intensities a factor of 100-150 greater than the average radiation power and a factor of 6-9 exceeding the power of the driving electron beams. Together with the statistical features such as a long-tail probability distribution, this allows the interpretation of generated spikes as microwave rogue waves. The mechanism of spikes formation is related to the simultaneous cyclotron interaction of a gyrating electron beam with forward and backward waves near the waveguide cutoff frequency as well as with the longitudinal deceleration of electrons.

For the first time, we demonstrate experimentally the possibility of Cherenkov superradiant generation with a phase imposed by an ultrashort seed microwave pulse. The phases of seed and initiated Ka-band microwave pulses were correlated with the accuracy of 0.5-0.7 rad for the power ratio down to -35  dB. Characteristics of such a process were determined in the frame of a basic theoretical model that describes both spontaneous and stimulated emission of an electron beam moving in corrugated waveguides. The obtained results open up opportunities of reaching extremely high radiation power density in phased arrays of short-pulse coherently operating microwave generators.

The first experiments on the observation of short pulsed superradiant (SR) emission with the excitation of a surface wave by a relativistic electron bunch moving in an oversized corrugated waveguide were performed. Subterahertz SR pulses with a central frequency of 0.14 THz, an ultrashort duration of 150 ps, and an extremely high peak power of 50-70 MW were generated. The experiments were based on a theoretical consideration including the quasioptical approach and direct particle-in-cell simulations.

We demonstrate both theoretically and experimentally the possibility of correlating the phase of a Cherenkov superradiance (SR) pulse to the sharp edge of a current pulse, when spontaneous emission of the electron bunch edge serves as the seed for SR processes. By division of the driving voltage pulse across several parallel channels equipped with independent cathodes we can synchronize several SR sources to arrange a two-dimensional array. In the experiments carried out, coherent summation of radiation from four independent 8-mm wavelength band SR generators with peak power 600 MW results in the interference maximum of the directional diagram with an intensity that is equivalent to radiation from a single source with a power of 10 GW.

Unlabelled: It can be suggested that development of atrial fibrillation (AF) in patients with chronic obstructive pulmonary disease (COPD) is directly related to the system of inflammation. Genetic polymorphism of factors of this system can be one of components of mechanism of AF in COPD. Aim: to elucidate polymorphic markers of genes of factors of the system of inflammation associated with AF in patients with COPD. Material and methods. We examined 208 patients with COPD (52 with and 156 without AF). Examination included spirometry, echocardiography, and study of frequencies of polymorphic markers G(-238)A, G(-308)A of tumor necrosis factor (TNF) gene, C(-819)T of interleukin (IL) 10 gene, G(-174)C of IL-6 gene, rs2228145(AC) of IL-6R gene, and rs2069762(A/C) of IL-2 gene. RESULTS. Factors associated with AF were left atrial volume (odds ratio [OR] 1.021, 95% confidence interval [ClI] 1.004-1.043, p = 0,027), right atrial volume (OR 1.02, 95% CI 1.001-1.040, p=0.021), and carriage of C allele of polymorphic marker G(-174)C of IL-6 gene (OR 6.02, 95% Cl 1.87-19.38, p = 0.003)., Conclusion: C allele of polymorphic marker G(-174)C of IL-6 gene can be considered to be independently associated with development of AF in patients with COPD.

The possibility of the conversion of intense continuous microwave radiation into a periodic train of short pulses by means of resonant interaction with a beam of unexcited cyclotron electron oscillators moving backward is shown. In such a system there is a certain range of parameters where the incident stationary signal splits into a train of short pulses and each of them can be interpreted as a soliton. It is proposed to use this effect for amplitude modulation of radiation of short wavelength gyrotrons.

Currently, the pharmaceutical market there are a large number of anticoagulants, each of which has a number of features. An important factor influencing the choice of drug, is whether or not the methodology of fixing its efficacy and safety. The aim of this review is to describe current approaches to the control of the efficacy and safety of anticoagulants.

We consider the superradiance of an extended relativistic electron bunch moving over a periodically corrugated surface for the generation of multimegawatt terahertz pulses. To study the above process we have developed a three-dimensional, self-consistent, quasioptical theory of Cherenkov stimulated emission which includes a description of the formation of an evanescent wave over a corrugated surface and its excitation by rf current induced in the electron bunch.

Thomboembolism is the most threatening complication in patients with atrial fibrillation. Main source of embolism is the left atrial thrombosis. Mechanisms of development of thromboembolic complications in patients with arrhythmias are far from being deciphered. In this review we discuss possible mechanisms of formation of intracardiac thrombus - abnormalities of functioning of the hemostasis system, endothelial dysfunction, inflammatory reactions, fibrosis of the left atrial wall, genetic traits.

To increase the output power of terahertz gyrotrons to several hundred kilowatts, we suggest using a planar geometry of interaction space with a sheet electron beam and transverse energy extraction. An advantage of this scheme in comparison with conventional cylindrical geometry is the possibility to ensure effective mode selection over the open transverse coordinate in combination with radiation outcoupling that leads to a substantial reduction of Ohmic losses. Similar to unstable resonators in optics for further growth of the radiation power it is beneficial to introduce waveguide tapering.

Thromboembolism is the main cause of death and disability of patients with atrial fibrillation. Indirect anticoagulants are effective means of primary and secondary prevention of thromboembolic complications. However in a number of patients risk associated with therapy with indirect anticoagulants might exceed potential benefit. The principle problem requiring solution in a patient with atrial fibrillation is individual comparative assessment of risk of development of thromboembolic and hemorrhagic complications. Modern stratification scales which allow solving this problem are considered in this review.

Based on analogy to the well-known process of the self-induced transparency of an optical pulse propagating through a passive two-level medium we describe similar effects for a microwave pulse interacting with a cold plasma or rectilinear electron beam under cyclotron resonance condition. It is shown that with increasing amplitude and duration of an incident pulse the linear cyclotron absorption is replaced by the self-induced transparency when the pulse propagates without damping. In fact, the initial pulse decomposes to one or several solitons with amplitude and duration defined by its velocity. In a certain parameter range, the single soliton formation is accompanied by significant compression of the initial electromagnetic pulse. We suggest using the effect of self-compression for producing multigigawatt picosecond microwave pulses.

Thrombosis of the left atrial appendage (LAA) is considered to be main cause of thromboembolic complications of atrial fibrillation (AF). Aim of this work was to study parameters of the hemostasis system in patients with AF in dependence on the presence of thrombus in the LAA. We examined 92 patients (58 men and 34 women) who at hospital admission had AF attack which lasted more than 48 hours. In patients with thrombus in the LAA according to data of transesophageal echocardiography differed magnitude of mean pulmonary artery pressure (odds ratio [OR] 1.053 95% confidence interval [CI] 1.007 to 1.102, p=0.024), diameter of left ventricular (LV) outflow tract (OR 7.711 95% CI 1.291 to 46.029, p=0.025), LV ejection fraction less than 40% (OR 0.286 95% CI 0.081 to 1.008, p=0.051), levels of type 1 plasminogen activator inhibitor-PAI-1 (OR 0.641 95% CI 0.422 to 0.974, p=0.037), and D-dimer (OR 1.003, 95% CI 1.000 to 1.006, p=0.046). Factors independently related to the presence of thrombus in LAA turned out only levels of PAI-1 (OR 0.51, 95% CI 0.276 to 0.936, p=0.03) and D-dimer (OR 1.01, 95% CI 1.001 to 1.014, p=0.026). Thus depletion of the system of fibrinolysis can lead to thrombus formation in the LAA and increase risk of development of thromboembolic complications.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Many patients with nonvalvular AF have substantial rates of stroke and thromboembolism. The left atrial appendage (LAA) is a common source of cardiac thrombus formation associated with systemic embolism. Recent findings have suggested a link between inflammatory and haemostatic disturbance and genesis of the LAA thrombus. In this review, we describe the genetic variations probably involved in the pathogenesis of LAA thrombosis, their functional implications, and their association with thromboembolic risk. We consider polymorphisms in coagulation factors and the inflammatory markers.

Transesophageal echocardiography (TEE) is routinely used for visualization of left auricular thrombi in patients with atrial fibrillation (AF). Multispiral computed tomography (MSCT) with the use of contrast preparations is a novel method of visualization of intracardiac structures. Forty three patients (27 men, 16 women aged 46-81 years) with duration of atrial fibrillation > 48 hours and scheduled for sinus rhythm restoration were included in this study. TEE and MSCT were carried out in all patients during first 3 days of hospitalization. If according to both methods there were no thrombi in the left auricle cardioversion was performed. If data of one of the methods were suspicious of left auricular thrombus cardioversion was not performed. In these patients both investigations were repeated after 8 weeks of therapy with warfarin. If initially detected mass decreased or disappeared at the background of indirect anticoagulants, it was considered to be a thrombus. In 1/3 of patients repeat examination allowed to reject initial diagnosis of left auricular thrombosis. Simultaneous application of TEE and MSCT detected more thrombi than the use of either of these methods. Rate of detection of thrombi in left atrial auricle with the use of both methods was 32%.

Theoretical investigation of a short electron beam (extended bunch) interaction with a backward wave propagating in a slow wave structure demonstrates the possibility of producing ultrashort superradiance pulses with a peak power which exceeds the power of the driving beam (conversion factor K>1). It is shown that a nonuniform slow wave structure with optimized profile is beneficial in order to increase the conversion factor. The results of theoretical analysis are confirmed by the experiments. At X band using the SINUS-150 accelerator (4 ns, 330 kV, 2.6 kA) 0.6-0.8 ns superradiance pulses with a peak power of 1.2 GW and a conversion factor of 1.5 were obtained. Similar experiments at Ka-band based on the RADAN-303 accelerator (1 ns, 290 kV, 2.5 kA) demonstrated production of the superradiance (SR) pulse with duration 200 ps and peak power about 1 GW (conversion factor of 1.4).

Atrial fibrillation significantly worsens quality and duration of patient's life because of frequent development of thromboembolic complications. The main cause of these complications is formation of intracardiac thrombosis. Prevalence of left atrial thrombosis in patients with atrial fibrillation varies from 8 to 24%. About 90% of thromboses are localized in left auricle. This paper contains review of different methods of detection of left auricular thrombosis. Main structural and functional predictors of thrombosis and possibilities of modern techniques of their visualization are also described. Different methods of echocardiography first of all transesophageal echocardiography are at present foremost in assessment of structural and functional predictors of thrombosis development. With the help of transesophageal echocardiography it is possible to accomplish functional monitoring of the state of left auricle during treatment with different drugs and/or after cardioversion. Detection of risk factors of left auricular thrombosis is an important clinical task because it allows to select a group of high risk patients in which long-term therapy with anticoagulants is indicated.

Prognostic value of clinical parameters and polymorphisms of apo-B, apo-E, LPL, , PPARA, PPARG2 genes was studied in 154 patients with acute unstable angina. Duration of follow-up was 2 years. Diabetes (OR 3.29, 1.28-8.50, p=0.014), history of stroke (OR 6.11, 1.21-31.00, p=0.029), changes of terminal part of ventricular complex on ECG, recorded during acute phase of ischemic heart disease (OR 2.19, 1.01-4.57, p=0.046), and genotype II of polymorphic marker ID of apoB gene (OR 2.20, 1.06-4.57, p=0.027) were independent predictors of unfavorable course of ischemic heart disease. Thus genetic factors play a role not only in formation of coronary atherosclerosis but determine the course of ischemic heart disease.

The paper reviews data on the possible role of malfunction of nitric oxide (NO) synthesis in pathogenesis of atherosclerosis. The singularities of NO synthesis, types of enzymes catalyzing this reaction (a set of NO-synthases), and some possible aspects of regulation of their activity are briefly surveyed. Available data concerning effect of derangements of NO synthesis on development of endothelial dysfunction and atherosclerosis are discussed. Possible mechanisms of abnormalities of NO synthesis caused by the influence of atherogenic risk factors (hypercholesterolemia, oxidized LDL, diabetes, inflammation etc.) as well as probable clinical consequences of these abnormalities are presented. Genetic aspects of NO synthesis are considered and probable role of NO-synthase genes in inheritance of predisposition to the majority of cardiovascular diseases is stressed. A conclusion is made that available knowledge is not sufficient for unequivocal formulation of the role of NO in development of atherosclerosis, that further studies are necessary.

One hundred nine patients with essential hypertension were studied (50 male and 59 female, mean age - 62,6-/+1,08 years). Seventy six patients had left ventricular hypertrophy measured by echocardiography. NOS3 polymorphisms (Glu298Asp and ecNOS4a/4b) were studied by PCR. In patients without left ventricular hypertrophy (LVH) genotypes frequencies of NOS3 (Glu298Asp) were: Glu/Glu - 34.4%; Glu/Asp - 62,5%; Asp/Asp - 3,1%. In patients with LVH - Glu/Glu - 55.3%; Glu/Asp - 40.8%; Asp/Asp - 3.9%; p=0,117. Percent of Glu/Glu genotype was significantly higher in LVH group (p=0,047). Genotypes frequencies of ecNOS4a/4b were: in patients without LVH - 4b/4b - 37,5%; 4a/4b - 62,5%; 4a/4a - 0; in patients with LVH - 4b/4b - 21.1%; 4a/4b - 76.3%; 4a/4a - 2,6%;. p=0,151. Patients with 4a allele had higher Amax than 4b/4b patients (76,3+2,11 m/s and 67,9+4,72 m/s; p=0,040). Therefore, we show associations between Glu allele of NOS3 (Glu298Asp) and left ventricular hypertrophy and between 4a allele (ecNOS4a/4b) and diastolic dysfunction in patients with essential hypertension.

Experimental results of the observation of coherent stimulated radiation from subnanosecond electron bunches moving through a periodic waveguide and interacting with a backward propagating wave are presented. The subnanosecond microwave pulses in Ka and W bands were generated with repetition frequencies of up to 25 Hz. The mechanism of microwave pulse generation was associated with self-bunching, and the mutual influence of different parts of the electron pulse due to slippage of the wave with respect to the electrons; this can be interpreted as superradiance. The illumination of a panel of neon bulbs resulted in a finely structured pattern corresponding to the excitation of the TM01 mode. Observation of rf breakdown of ambient air, as well as direct measurements by hot-carrier germanium detectors, leads to an estimate of the absolute peak power as high as 60 MW for the 300-ps pulses at 38 GHz. These results are compared with numerical simulations. The initial observation of 75-GHz, 10-15-MW radiation pulses with a duration of less than 150 ps is also reported.