Czochralski-grown (Na0.5Gd0.5)MoO4 single crystals doped with different concentrations of Yb3+ ions have been investigated by X-ray diffraction. The type and concentration of point defects (different ...Na:Gd ratios, vacancies in Mo and O sites), and, consequently, the real compositions of the investigated crystals have been determined. The presence of additional reflections (50%) for the (Na0.5Gd0.5)MoO4_10%Yb crystal was revealed, indicating the symmetry reduction from space group I41 /a to without any change in the unit cell parameters. Crystal refinement within the framework of space group I41/a revealed an increase in the unit cell parameters for both (Na0.5Gd0.5)MoO4_3%Yb and (Na0.5Gd0.5)MoO4_10%Yb crystals; it can be explained by the kinetic phase transition of order-disorder type caused by the cation ordering at the dodecahedral sites in the local regions of the crystals. The reasons for the possible symmetry reduction in scheelite family crystals are discussed.
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The emergence of a new class of drugs – inhibitors of cyclin-dependent kinases 4/6 (CDK4/6) – has changed the paradigm of treatment of patients with luminal HER2 negative metastatic breast cancer. ...Their effectiveness is confirmed not only by randomized, but also observational studies on a wide heterogeneous population of patients from daily clinical practice; the use of these drugs in the 1st line is significantly expanding in the world. On the territory of the Russian Federation, an observational study of Prometheus was carried out, the purpose of which was to assess the frequency of prescribing CDK4/6 inhibitors, as well as other types of treatment in 1–2nd lines in real clinical practice in Russia, as well as factors and preferences of doctors influencing the choice of therapy. A survey of the target audience, whose answers can be considered reliable and reflecting today’s Russian clinical practice in the treatment of breast cancer, showed that, despite the fact that the overwhelming majority of doctors (78 %) believe that the maximum benefit from the appointment of CDK4/6 inhibitors is expected for the 1st line therapy, in real clinical practice, only 35 % of doctors practice 1 st line prescription. In the 2nd line of therapy, CDK4/6 inhibitors are prescribed by 45 % of experts, in the 3rd (or more) line – 20 %. According to the respondents, the main obstacle to the appointment of CDK4/6 inhibitors is the unresolved issues of the availability of therapy (44 %) and its cost (34 %). Among all the proposed clinical criteria, only the criterion “visceral metastases with impaired function of internal organs” influences the decision not to prescribe a combination of hormonal therapy and a CDK4/6 inhibitor in 1–2nd lines of therapy. Criteria such as ECOG status, menopause status, tumor subtype preceding chemotherapy, timing of progression do not determine the choice when deciding not to prescribe combination therapy.
Introduction
. PARP inhibitors demonstrated high efficacy in BRCA1/2-associated Her2-negative metastatic breast cancer (BC). They were included in the current standard chemotherapy regimen and ...recognized as a priority option for the treatment of such tumours following the results of clinical studies.
Aim
. Review the experience with talazoparib (Talzenna) in the real-world clinical practice of 6 medical centers in Russia.
Materials and methods
. The review included data from 29 patients with HER2-negative metastatic breast cancer associated with a gBRCA mutation, who have been receiving talazoparib therapy in 6 medical centers of Russia since April 2021. Talazoparib was given at the standard dose 1 mg once daily, the dose was reduced, if any adverse event developed.
Results
. The median age of the patients was 50 years. 23 patients had a BRCA1 mutation, 5 patients had a BRCA2 mutation and one of the patients had a PALB2 mutation. Prior to starting talazoparib therapy, patients had received up to 9 lines of therapy for metastatic disease, the median was 1 line. The median follow-up period at that time was only 4.6 months. The median recurrence-free survival (RFS) was not reached. Progression was observed in 10 patients with a treatment period of 1 to 7.5 months, 19 patients continued to receive PARP inhibitor therapy without signs of disease progression, with a treatment period of 2 to 18 months. The objective response rate (ORR) was 57.2%, the clinical efficacy was confirmed in 85.7% of cases. The subgroup analysis showed that the lowest efficacy of therapy was reported in the group of patients, who had received prior therapy with platinum-based drugs, the median progression-free time (mPFT) was 4.5 months. (95% CI: 1.79-9.2). While for patients who had not received the prior platinum drug regimens, the median was not reached. Haematologic toxicities were common adverse events (AEs) for the talazoparib therapy, which were reported in 34.5% of cases. Transfusions of blood components were required in 3 patients, one of them required them repeatedly. All dose modifications were due to hematological toxicities. 7 patients (24.1%) required a dose reduction and 3 patients (10.3%) - repeated dose reduction.
Conclusions
. Testing for BRCA1/2 mutations in Her2-negative mBC should be a mandatory diagnostic procedure. Talazoparib therapy is an effective and safe treatment option for patients with gBRCAmut HER2-mBC.
Introduction
. The standard of 1st line treatment of HER2+ metastatic breast cancer (mBC) is double blockade with trastuzumab and pertuzumab + taxane, 2nd line – Trastuzumab-emtazine. There are no ...standards for further treatment, as well as the optimal drug sequence. Expansion of the arsenal of therapeutic possibilities and the use of new combinations will certainly improve the results of treatment of this category of patients and increase their life expectancy.
Aim
. We sought to describe treatment patterns of eribulin and clinical outcomes of metastatic HER2-positive breast cancer treated with eribulin plus trastuzumab combination in academic institutions and community oncology practices across the Russian Federation.
Materials and methods
. Patients treated with eribulin anytime between Jan, 2014 and Sep, 2019 with a diagnosis of MBC were identified by 23 providers from Russia. Providers retrospectively reviewed the health records and abstracted selected data points into an electronic case report form for each eligible patient.
Results
. 100 HER2-positive pts received eribulin in combination with trastuzumab. Median age was 55 (31–80) yrs and ECOG status 0–3. 67% pts had visceral metastases. Eribulin was administered as 1st and 2nd line to 23 (23%) pts, 3rd line to 31 (31%) pts, 4th line and later to 46 (46%). Median number of cycles was 5 (2–27). ORR was 12%, SD – 72%, SD > 6 months – 23%, PD – 16%. Clinical efficacy rate achieved in 35%. Median PFS was 5.07 months (95% CI 4.021–6.119). According to the ER-status the response to eribulin and trastuzumab was different. ORR was 18.8%, SD 72.9% in pts with ER-positive MBC (n = 48) and 5.8% and 71.2% respectively in ER-negative MBC (n = 52). Median PFS was 6.97 months (95% CI 3.924–10.016) in pts with ER-positive MBC and 4.67 months (95% CI 3.841–5.499) in ER-negative MBC (р = 0.3). The combination was well tolerated: dose reductions were required in 12% pts, withdrawal due to toxicity in 4% pts. The most common type of toxicity was hematological with neutropenia Gr III-IV in 14 (14%) pts. Peripheral neuropathy Gr III was observed in 5 (5%) pts. No cardiotoxicity was detected.
Conclusions
. This is the real-life data of clinical outcomes for patients receiving eribulin plus trastuzumab for HER2-positive MBC throughout the Russian Federation. Our experience with eribulin plus trastuzumab demonstrates that this combination may be a potential effective treatment option for HER-2 positive MBC patients.
Objectives
. The relevance of the study of magnetoelectric (ME) effect in ring ferromagnetic–piezoelectric heterostructures is due to the possibility of creating various ME devices having improved ...characteristics. A detailed investigation of the nonlinear ME effect in a ring composite heterostructure based on lead zirconate titanate (PZT) piezoceramics and Metglas® amorphous ferromagnetic (FM) alloy under circular magnetization is presented.
Methods.
The ME effect was measured by the low-frequency magnetic field modulation method. Excitation alternating- and constant magnetic bias fields were created using toroidal coils wound on a ring heterostructure for circular magnetization of the FM layer.
Results.
When excited with circular magnetic fields in a non-resonant mode, the ME ring heterostructure generates a nonlinear ME voltage of higher harmonics. The field and amplitude dependencies of the first three ME voltage harmonics were investigated. ME coefficients were obtained for the linear ME effect α(1) = 5.2 mV/(Oe·cm), the nonlinear ME effect α(2) = 6 mV/(Oe2·cm), and α(3) = 0.15 mV/(Oe3·cm) at an excitation magnetic field frequency f = 1 kHz. The maximum amplitudes of the 1st and 3rd harmonics were observed at a constant bias magnetic field H ~ 7 Oe, which is almost two times smaller than in planar PZT–Metglas® heterostructures.
Conclusions.
A nonlinear ME effect was observed and investigated in a ring heterostructure based on PZT piezoceramics and Metglas® amorphous FM alloy. Due to the absence of demagnetization during circular magnetization of the closed FM layer, nonlinear ME effects are detected at significantly lower amplitudes of the exciting alternating and constant bias magnetic fields as compared to planar heterostructures. The investigated ring heterostructures are of potential use in the creation of frequency multipliers.
At present, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors such as palbociclib, ribociclib, and abemaciclib are widely used for the first-line treatment of locally advanced or metastatic breast ...cancer. However, direct comparisons of these treatment options in randomized studies have not been conducted. Aim of the work is to gather and analyze published data on the comparative effectiveness of CDK4/6 inhibitors in combination with aromatase inhibitors in postmenopausal patients with HR+/HER2– locally advanced or metastatic breast cancer. A systematic review of publications presenting results from original studies on the impact of CDK4/6 inhibitor therapy in combination with aromatase inhibitors on the survival of patients was performed. Nineteen studies with original data on progression-free survival and overall survival were identified. None of the studies found significant differences between different CDK4/6 inhibitors and aromatase inhibitors in terms of progression-free survival. A statistically significant superiority of ribociclib over palbociclib in terms of overall survival was observed in a single matching-adjusted indirect comparison, while seven other studies of various types (real-world data studies, matching-adjusted indirect comparisons, and meta-analyses) did not find significant differences between the investigated drugs in terms of overall survival. Currently, there is no compelling evidence of the superiority of one CDK4/6 inhibitor over others. The decision on the preference for a specific drug within the class can only be made after conducting direct randomized comparison trials, or accumulating sufficient real-world data on the use of palbociclib, ribociclib, and abemaciclib.
Accurate low temperature charge transport measurements in combination with high-precision x-ray diffraction experiments have allowed detection of the symmetry lowering in the single domain ...Tm0.19Yb0.81B12 crystals that belong to the family of dodecaborides with metal-insulator transition. Based on the fine structure analysis we discover the formation of dynamic charge stripes within the semiconducting matrix of Tm0.19Yb0.81B12. The charge dynamics in these conducting nano-size channels is characterized by broad-band optical spectroscopy that allowed estimating the frequency (~2.4 × 1011 Hz) of quantum motion of the charge carriers. It is suggested that cooperative Jahn-Teller effect in the boron sublattice is a cause of the large-amplitude rattling modes of the Tm and Yb ions responsible for the 'modulation' of the conduction band along one of the directions through the variation of 5d-2p hybridization of electron states.
Introduction.
The presence of a germinal BRCA mutation occurs in 3–4% of all breast cancer (BC) patients with various biological subtypes, but significantly with a high frequency in patients with a ...triple negative biological subtype (in 10–20% of cases). For the treatment of patients with HER2-negative metastatic breast cancer associated with gBRCA mutation, the effectiveness of biologically targeted drugs from the group of PARP inhibitors (olaparib and talazoparib) has been proven.
P
urpose.
Comparison of the results of our experience with the use of talazoparib in patients with HER2-gBRCA+ + mBC with the data of the EMBRACA registration study.
Mat
erials and
methods.
As part of the multicenter compassionate use program (CUP) with the support of Pfizer, 24 patients with HER2-negative metastatic gBRCA-associated mutation metastatic breast cancer (HER2-gBRCA+ breast cancer) received biologically targeted therapy with the PARP inhibitor talazoparib at a standard oral dose of 1 mg per day for vital indications . The average age of patients with HER2-gBRCAm+ breast cancer was 50 years (29–90 years).
Results.
Objective response (OR) was registered in 29% of cases, disease control (OR+stabilization) – in 71% of cases. The median progression-free survival (PFS) was 6.5 months (95% CI 3–10). Objective response, disease control, and median PFS were evaluated depending on the biological subtype, the number of lines of previous therapy, and the presence of platinum-containing agents in the anamnesis.
Objective response and disease control were evaluated depending on the biological subtype: in patients with ER+HER2-mBC versus patients with triple negative subtype, OR was 33% vs 22%, and disease control was 83% vs 61%, respectively. In the presence of < 3 vs ≥ 3 lines of therapy for metastatic disease in the anamnesis, OR was 31% vs 12.5%, disease control – 75% vs 50% of cases, respectively. In the presence or absence of platinum-containing agents in the anamnesis, OR was observed in 22% vs 33% of cases, and disease control – 67% vs 67%, respectively.
In patients with the luminal subtype versus patients with the triple negative subtype, the PFS was 9 months vs 5 months, respectively (HR = 0.705; 95% CI 0.231–2.147; p = 0.5208). Median PFS in the presence of <3 vs ≥3 lines of therapy for metastatic disease in the anamnesis was 9 months vs 4 months, respectively (HR = 4,216; 95% CI 1,334–13,327; p = 0.0056). In the presence or absence of platinum-containing agents in previous lines of therapy 5 months vs 9.5 months, respectively (HR =1.484; 95% CI 0.48–4.582; p = 0.4750).
During the treatment with talazoparib adverse events of the 3rd-4th grades were observed in 5 patients (20,8%). These include moderate and severe anemia in 3 patients (12.5%), thrombocytopenia in 1 patient (4%), and neutropenia in 1 patient (4%). The majority of patients (79,5%), which received talazoparib, did not require dose adjustment. The need to reduce the dose to 0.75 mg was noted in 3 patients (12.5%), to 0.5 mg – in 2 patients (8%). Hemotransfusion was performed in 3 patients. For effective therapy safety management regular monitoring of blood parameters is necessary.
Conclusion.
Thus, targeted therapy with talazoparib is an effective treatment option for HER2-gBRCA+ mBC.
The article is concerned with analyzing the efficiency of organization of sales of tourism services: a direction which remains a «bottleneck» for the majority of the national travel companies. ...Activity of tourism enterprises is not limited to creation of high-quality tourism product with correct pricing. It is also necessary to bring this product to the final consumer-tourist and ensure its availability in the target market. To ensure the effective implementation of tourism services, a tourism enterprise must effectively organize sales of tourism product. The organization of sales should define the types of intermediaries and their role in the sales chain, the possibilities of wholesale and retail, the post-sale servicing requirements, the rational structure of the methods and sales channels, the price structure for the final buyer. Based on this, we can confidently talk about the exceptional relevance of management and organization of the system of sales in modern tourism.
Activation of store-operated channels (SOCs) and capacitative calcium influx are triggered by depletion of intracellular calcium stores. However, the exact molecular mechanism of such communication ...remains unclear. Recently, we demonstrated that native SOC channels can be activated by calcium influx factor (CIF) that is produced upon depletion of calcium stores, and showed that Ca2+-independent phospholipase A2 (iPLA2) has an important role in the store-operated calcium influx pathway. Here, we identify the key plasma-membrane-delimited events that result in activation of SOC channels. We also propose a novel molecular mechanism in which CIF displaces inhibitory calmodulin (CaM) from iPLA2, resulting in activation of iPLA2 and generation of lysophospholipids that in turn activate soc channels and capacitative calcium influx. Upon refilling of the stores and termination of CIF production, CaM rebinds to iPLA2, inhibits it, and the activity of SOC channels and capacitative calcium influx is terminated.
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