RESUMO
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.
Assuntos
Quadruplex G , Mieloma Múltiplo , Mutação , Humanos , Mieloma Múltiplo/genética , Polimorfismo de Nucleotídeo Único , Reparo do DNA/genética , Instabilidade GenômicaRESUMO
A total of 263 warfarin naive patients with indications to long-term anticoagulation were included in prospective multicenter study and randomized into Pharmacogenetics and Standard dosing groups. The loading warfarin dose in Pharmacogenetics group was calculated by Gage algorithm and corrected starting on day 5 of treatment according to INR. In Standard dosing group warfarin initial dose was 5 mg and starting on day 3 of treatment it was titrated according to INR. Pharmacogenetics dosing in comparison with prescription of starting dose of 5 mg decreased major bleedings (0 vs. 6, p = 0.031), time to target INR (11 [9-14] vs. 17 [15-24] days, p = 0.046), and frequency of INR fluctuations ≥4.0 (11% vs. 30.9%, p = 0.002). The advantages of the pharmacogenetics dosing were mainly achieved due to the patients with increased warfarin sensitivity.
Assuntos
Anticoagulantes/administração & dosagem , Coagulação Sanguínea/efeitos dos fármacos , Citocromo P-450 CYP2C9/genética , Variantes Farmacogenômicos , Vitamina K Epóxido Redutases/genética , Varfarina/administração & dosagem , Idoso , Anticoagulantes/efeitos adversos , Citocromo P-450 CYP2C9/metabolismo , Cálculos da Dosagem de Medicamento , Monitoramento de Medicamentos , Feminino , Genótipo , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Farmacogenética , Fenótipo , Estudos Prospectivos , Federação Russa , Fatores de Tempo , Resultado do Tratamento , Vitamina K Epóxido Redutases/metabolismo , Varfarina/efeitos adversosRESUMO
Limited comparative data exist regarding the risk of cardiogenic emboli in patients with isolated atrial flutter (AFL). Some studies suggest a lower complication risk in AFL than atrial fibrillation (Afib); however, methodologic limitations and conflicting reports necessitate a comprehensive investigation. Our analysis proposes that isolated AFL carries a lower risk of ischemic events and left atrial thrombus formation than AFib. Importantly, we caution against applying stroke risk assessment approaches designed for AFib to patients with AFL because it may lead to harmful overestimations and unnecessary anticoagulant prescriptions. Furthermore, we highlight the current lack of sufficient data to determine the overall clinical benefit of prolonged anticoagulant therapy in patients with isolated AFL, especially when CHA2DS2-VASc index values are below 4. This review challenges existing perceptions, offering insights into the nuanced risk profiles of the transitional nature of isolated AFL because of the high incidence of AFib development within a year of AFL diagnosis. Tailored risk assessments and further research are essential for precise clinical decision-making in this dynamic landscape.
RESUMO
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.
RESUMO
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.
RESUMO
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.
RESUMO
We present the first experimental results of the study on a novel second harmonic THz-band double-beam gyrotron. The tube has demonstrated a stable single-mode operation with output parameters that are appropriate for the next-generation 1.2 GHz dynamic nuclear polarization-nuclear magnetic resonance spectroscopy. Besides the design mode (TE8,5), a series of other fundamental and second harmonic modes have been excited. This makes the new gyrotron a versatile radiation source, which can be used also in other applications of the high-power science and technologies.