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The lower body negative pressure (LBNP) effect has been studied in terms of phase synchronization between spontaneous oscillations of blood pressure (BP) and heart rate (HR). The effect of LBNP (‒30 mmHg) was generated by the Chibis-M complex, which was used for training the cardiovascular system in cosmonauts on-board the International Space Station (ISS) as a countermeasure to the post-flight orthostatic intolerance. According to the measurement procedure protocol, the subjects (seven young men) were in a supine position. It has been shown that LBNP leads to an increase in the strength of phase synchronization between spontaneous BP and HR oscillations in the frequency range of baroreflex waves (about 0.1 Hz).

Strength training remains the most effective way to maintain or increase muscle mass and strength. Strength training is used during rehabilitation after injuries and prolonged hypokinesia, to prevent the development of age-related sarcopenia, metabolic syndrome, type 2 diabetes, and cardiovascular diseases. Also, strength training is widely used by athletes of various specializations. The effectiveness of strength training varies depending on the individual characteristics, diet, and training program used. In recent years, significant progress has been achieved in understanding the mechanisms of skeletal muscle adaptation in response to strength training. The review addresses the most important mechanisms for increasing muscle mass and strength, which correspond to the current understanding of the problem in the modern literature. We consider the role of neural adaptation, as well as signaling processes that increase the muscle protein synthesis rate, in the development of adaptive changes in response to strength training. Based on the knowledge of these mechanisms, we analyze the key variables of strength training, such as training loads, work volume and movement velocities. The knowledge of the mechanisms that determine the effectiveness of the training process provides a better insight into the most important aspects of strength training.

Computational design of high-functioning electrocatalysts is an integral part of catalyst discovery. However, as we approach the limits of performance imposed by scaling relations, finding active c...

Lysenko, EA, Popov, DV, Vepkhvadze, TF, Sharova, AP, and Vinogradova, OL. Moderate-intensity strength exercise to exhaustion results in more pronounced signaling changes in skeletal muscles of strength-trained compared with untrained individuals. J Strength Cond Res 34(4): 1103-1112, 2020-The aim of our investigation was to compare the response pattern of signaling proteins and genes regulating protein synthesis and degradation in skeletal muscle after strength exercise sessions performed to volitional fatigue in strength-trained and untrained males. Eight healthy recreationally active males and 8 power-lifting athletes performed 4 sets of unilateral leg presses to exhaustion (65% 1 repetition maximum). Biopsy samples of m. vastus lateralis were obtained before, 1 and 5 hours after cessation of exercise. Phosphorylation of p70S6k, 4EBP1, and ACC increased, whereas phosphorylation of eEF2 and FOXO1 decreased only in the trained group after exercise. Expression of DDIT4, MURF1, and FOXO1 mRNAs increased and expression of MSTN mRNA decreased also only in the trained group after exercise. In conclusion, moderate-intensity strength exercise performed to volitional fatigue changed the phosphorylation status of mTORC1 downstream signaling molecules and markers of ubiquitin-proteasome system activation in trained individuals, suggesting activation of protein synthesis and degradation. In contrast to the trained group, signaling responses in the untrained group were considerably less pronounced. It can be assumed that the slowdown in muscle mass gain as the athletes increase in qualification cannot be associated with a decrease in the sensitivity of systems regulating protein metabolism, but possibly with inadequate intake or assimilation of nutrients necessary for anabolism. Perhaps, the intake of highly digestible protein or protein-carbohydrate dietary supplements could contribute to the increase in muscle mass in strength athletes.

The goal of the present study was to identify the possible disturbances in the synchronization of spontaneous fluctuations in arterial pressure (AP) and heart rate (HR) at the frequency of baroreflex waves (~0.1 Hz) in patients prone to vasovagal fainting. In healthy volunteers and patients diagnosed with vasovagal syncope, AP (photo-compensation method) and ECG were continuously recorded, first in a horizontal position, and then during a passive orthostatic test (60°) lasting for 40 min. According to the results of the test, all patients were divided into two groups: subjects with a positive (development of the presyncopal or syncopal states) and a negative result of the orthostatic test. These groups of patients did not differ from each other and from the control group in terms of baseline AP and HR. The values of the phase synchronization index (PSI) of AP and HR were calculated in the frequency range from 0.02 to 0.8 Hz within 10-min recording intervals in the horizontal position and at the initial stage of orthostasis (starting from the second minute after the transition to the vertical position). Initially, all three groups had a distinct peak at the frequency of ~0.1 Hz in the PSI spectra. In the control group and in patients with a negative orthostatic result, a transition to the state of orthostasis was accompanied by an increase in the PSI in this frequency domain, in contrast to the patients with a positive orthostatic test, in which the PSI did not increase. Thus, the lack of amplification of phase synchronization of AP and HR at the early stage of orthostatic test is associated with the subsequent decompensation of hemodynamics and the development of syncope.

Reduction in daily activity leads to dramatic metabolic disorders, while regular aerobic exercise training is effective for preventing this problem. The purpose of this study was to identify genes that are directly related to contractile activity in human skeletal muscle, regardless of the level of fitness. Transcriptome changes after the one-legged knee extension exercise in exercised and contralateral nonexercised vastus lateralis muscle of seven men were evaluated by RNA-seq. Transcriptome change at baseline after 2 mo of aerobic training (5/wk, 1 h/day) was evaluated as well. Postexercise changes in the transcriptome of exercised muscle were associated with different factors, including circadian oscillations. To reveal transcriptome response specific for endurance-like contractile activity, differentially expressed genes between exercised and nonexercised muscle were evaluated at 1 and 4 h after the one-legged exercise. The contractile activity-specific transcriptome responses were associated only with an increase in gene expression and were regulated mainly by CREB/ATF/AP1-, MYC/MAX-, and E2F-related transcription factors. Endurance training-induced changes (an increase or decrease) in the transcriptome at baseline were more pronounced than transcriptome responses specific for acute contractile activity. Changes after training were associated with widely different biological processes than those after acute exercise and were regulated by different transcription factors (IRF- and STAT-related factors). In conclusion, adaptation to regular exercise is associated not only with a transient (over several hours) increase in expression of many contractile activity-specific genes, but also with a pronounced change (an increase or decrease) in expression of a large number of genes under baseline conditions.

Profound effects of spaceflight on the physiology of humans and non-human animals are well-documented but incompletely explored. Current goals to undertake interplanetary missions increase the urgency to learn more about adaptation to prolonged spaceflight and readaptation to Earth-normal conditions, especially with the inclusion of radiation exposures greater than those confronted in traditional, orbital flights. The 30-day-long Bion M-1 biosatellite flight was conducted at a relatively high orbit, exposing the mice to greater doses of radiation in addition to microgravity, a combination of factors relevant to Mars missions. Results of the present studies with mice provide insights into the consequences on brain function of long-duration spaceflight. After landing, mice showed profound deficits in vestibular responses during aerial drop tests. Spaceflown mice displayed reduced grip strength, rotarod performance, and voluntary wheel running, each, which improved gradually but incompletely over the 7-days of post-flight testing. Continuous monitoring in the animals’ home cage activity, in combination with open-field and other tests of motor performance, revealed indices of altered affect, expressed as hyperactivity, potentiated thigmotaxis, and avoidance of open areas which, together, presented a syndrome of persistent anxiety-like behavior. A learned, operant response acquired before spaceflight was retained, whereas the acquisition of a new task was impaired after the flight. We integrate these observations with other results from Bion-M1’s program, identifying deficits in musculoskeletal and cardiovascular systems, as well as in the brain and spinal cord, including altered gene expression patterns and the accompanying neurochemical changes that could underlie our behavioral findings.

To estimate time characteristics of baroreflex resetting process, 9 young subjects participated in “dynamic” tilt tests, during which their body position was periodically changed from supine position to 60° orthostasis and back, periods of “swings” were 24, 12, 6, 4 and 2 min. Baroreflex activity was estimated by phase synchronization index (PSI) of arterial pressure and heart rate fluctuations in frequency range of baroreflex waves (~0.1 Hz). A transition to orthostasis was accompanied by an increase in the PSI. Orthostatic change in the PSI was significantly reduced when the “swing” period decreased to 4 min. These results suggest that the resetting of baroreflex HR control takes about several tens of seconds.

Introduction: Mechanical forces and sympathetic influences are key determinants of vascular structure and function. This study tested the hypothesis that hindlimb unloading (HU) exerts diverse effects on forelimb and hindlimb small arteries of rats in functionally different regions of the skeletal muscle and skin. Methods: Male Wistar rats were subjected to HU for 2 weeks, then skeletal muscle arteries (deep brachial and sural) and skin arteries (median and saphenous) were examined in vitro using wire myography or isobaric perfusion and glyoxylic acid staining. Results: HU increased lumen diameter of both forelimb arteries but decreased diameter of the sural artery; the saphenous artery diameter was not affected. Following HU, maximal contractile responses to noradrenaline and serotonin increased in the forelimb but decreased in the hindlimb skeletal muscle feed arteries with no change in skin arteries; all region-specific alterations persisted after endothelium removal. HU increased the sensitivity to vasoconstrictors in the saphenous artery but not in the sural artery. In the saphenous artery, initially high sympathetic innervation density was reduced by HU, sparse innervation in the sural artery was not affected. Electrical stimulation of periarterial sympathetic nerves in isobarically perfused segments of the saphenous artery demonstrated a two-fold decrease of the contractile responses in HU rats compared to that of controls. Conclusion: HU induces contrasting structural and functional adaptations in forelimb and hindlimb skeletal muscle arteries. Additionally, HU had diverse effects in two hindlimb vascular regions. Hyper-sensitivity of the saphenous artery to vasoconstrictors appears to result from the shortage of trophic sympathetic influence. Importantly, HU impaired sympathetically induced arterial vasoconstriction, consistent with the decreased sympathetic constrictor response in humans following space flight.

Introduction Dry immersion (DI) is a ground-based experimental model which reproduces the effects of microgravity on the cardiovascular system and, therefore, can be used to study the mechanisms of post-flight orthostatic intolerance in cosmonauts. However, the effects of long-duration DI on cardiovascular system have not been studied yet. The aim of this work was to study the effects of 21-day DI on systemic hemodynamics and its baroreflex control at rest and during head-up tilt test (HUTT). Methods Ten healthy young men were exposed to DI for 21 days. The day before, on the 7th, 14th, and 19th day of DI, as well as on the 1st and 5th days of recovery they were subjected to HUTT: 15 min in supine position and then 15 min of orthostasis (60°). ECG, arterial pressure, stroke volume and respiration rate were continuously recorded during the test. Phase synchronization index (PSI) of beat-to-beat mean arterial pressure (MAP) and heart rate (HR) in the frequency band of baroreflex waves (∼0.1 Hz) was used as a quantitative measure of baroreflex activity. Results During DI, strong tachycardia and the reduction of stroke volume were observed both in supine position and during HUTT, these indicators did not recover on post-immersion day 5. In contrast, systolic arterial pressure and MAP decreased during HUTT on 14th day of DI, but then restored to pre-immersion values. Before DI and on day 5 of recovery, a transition from supine position to orthostasis was accompanied by an increase in PSI at the baroreflex frequency. However, PSI did not change in HUTT performed during DI and on post-immersion day 1. The amplitude of MAP oscillations at this frequency were increased by HUTT at all time points, while an increase of respective HR oscillations was absent during DI. Conclusion 21-day DI drastically changed the hemodynamic response to HUTT, while its effect on blood pressure was reduced between days 14 and 19, which speaks in favor of the adaptation to the conditions of DI. The lack of increase in phase synchronization of baroreflex MAP and HR oscillations during HUTT indicates disorders of baroreflex cardiac control during DI.

The development of new approaches to the assessment of heart rate variability (HRV) is an important problem, since HRV reflects the functioning of cardiovascular control and is affected by various diseases. The purpose of this study was to evaluate the informative value of statistical and spectral HRV parameters calculated from pulse interval (PI) data of blood pressure as compared with those calculated from RR-interval data of electrocardiograms (ECG). We recorded ECG in conscious rats using skin adhesive electrodes simultaneously with blood pressure signal obtained through a catheter in the femoral artery. It has been found that the PI sequence can be used to calculate the statistical HRV indices that describe the HRV at time intervals about 1 min or longer, but statistical indices of the PI and RR intervals may differ in the analysis of beat-tobeat variations. The power spectra of the RR intervals and PI coincide in the low-frequency region, including the band of baroreflex cardiac rhythm oscillation. However, they can differ in the high-frequency region (at respiration frequency and above).

The results of long-term follow-up of patients (pts) with chronic myeloid leukemia (CML) do not lose their importance. Data from routine clinical practice are of particular interest. The use of 1 st (imatinib, IM) and 2nd generation TKI (2G TKI) led to a significant increase in survival, so the probability of death associated with CML could be significantly lower than the probability of death due to common causes of death other than CML. To analyze the overall survival (OS) and causes of mortality in CML pts treated in routine clinical practice in Russian Federation for a long period (>15 years) of time. The long-term follow-up data of the Russian part of the European LeukemiaNet (ELN) OSP EUTOS multicenter observational study were evaluated. The analyzed cohort consisted of 678 Ph/BCR-ABL-positive CML pts from 35 regions of Russia diagnosed in 2002-2006 with IM therapy initiation ≤6 months (mo) after diagnosis. Median (Me) age was 47(range 18-81) years (y), 47% males. Chronic phase, accelerated phase and blast crisis at diagnosis was in 631 (93%), 41(6%) and 6(1%) pts, respectively. The annual number of newly diagnosed pts was as follows: 2002 - 15 pts, 2003 - 38 pts, 2004 - 46 pts, 2005 - 206 pts, 2006 - 302 pts. The last update for 209 pts was done in Jun. 2021; last contact for 100 pts - in 2020, for 39pts - in 2019, for the other - before 2018. The date of the last contact/death could not be established for 14 pts. Statistical analysis included 661 pts, the OS was evaluated by Kaplan-Mayer method using the SAS 9.4 package. In total, 331 (50%) pts of the analyzed cohort were alive with the Me follow-up of 180 (range 2-232) mo or 15 y (range 2 mo-19,3 y). All pts started therapy with IM with 25% switched to 2G TKI in subsequent therapy lines. In total, 218 (66%) pts achieved MR4, 183 (55%) pts got MMR; 46 (21%) of these pts with deep molecular response (DMR) were observed in hematology centers of Moscow. The 15-y OS in the total cohort was 63% (CI 59-70%)(fig.1). The OS by age groups was as follows: 18-40yy-75% (CI 73-82%), 40-60yy- 63% (CI 59-70%), 60-80yy- 37% (CI 30-45%). The most complete information was provided by Moscow centers (2 centers, 113 pts). The 15-y OS of pts receiving treatment in Moscow was significantly higher vs pts from other regions (32 centers, 548 pts): 75% vs 60%, p=0,0030 (fig.2). The mortality in the whole cohort of 661 pts was 35% (233 pts). Of these 233 pts, 112(48%) pts deaths were due to CML progression to AP or BP (including non-compliant cases); 3pts (1,5%) died after allogenic stem cell transplantation (infection complications); the cause of death was unknown in 50 (21,5%) pts. The highest death rate from CML progression was at 4-9 y of follow-up. Deaths caused by concomitant diseases were in 68 (29%) pts: coronary artery disease/myocardial infarction/heart failure in 42 (62%) of 68 pts, acute ischemic stroke in 10 (15%) pts, second malignancies (Cr- cancer) in 10 (15%) pts (lung tumor, metastatic esophageal Cr, stomach Cr, brain tumor, sigmoid colon Cr, rectal colon Cr, melanoma, renal Cr, breast tumor, other hematological malignancies), accidents - 1 pt, liver cirrhosis - 2 pts, in 2 cases - respiratory virus infections complicated with pneumonia, 1 pt died due to Covid-19. Conclusions. The long-term follow-up of the multicenter study EUTOS OSP in 35 regions of Russian Federation allows not only to characterize the 15-y OS in CML pts but also provides the long-term outlook of the routine clinical practice. Probably, better OS of CML patients receiving treatment in Moscow (2 centers) may be related to organizational issues of interaction with the federal center, better monitoring and timely switching to 2G TKI therapy. The organization and support of multicenter studies may improve the situation with the treatment of diseases of the blood system. Figure 1 Figure 1. Disclosures Chelysheva: Novartis Pharma: Speakers Bureau; Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Vinogradova: Pharmstandart: Speakers Bureau; Novartis Pharma: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Lomaia: Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Pharmstandard: Honoraria. Voloshin: Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Astra Zeneca: Consultancy, Speakers Bureau; Pfizer: Consultancy; Biacad: Consultancy, Speakers Bureau. Turkina: Pharmstandart: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Novartis Pharma: Speakers Bureau.

Background: Not everyone with CML responds optimally to TKI-therapy, especially those with BCR::ABL1T315I. PF-114 is a 4 th-generation oral tyrosine kinase-inhibitor (TKI) active against wild-type and mutated BCR::ABL1 isoforms including BCR::ABL1T315I. We present final results of a phase-1 study (NCT02885766). Methods: 3+3 dose-escalation study to determine maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary objectives included safety and efficacy based on haematological, cytogenetic and molecular response criteria. Adverse events (AEs) were graded using NCI-CTCAE v4.03. Results: 51 subjects (5 with accelerated phase CML, 46 - with chronic CML), 23 males, were studied. Daily doses were 50-600 mg/d given once daily continuously. Median age was 50 y (range, 29-82 y). Median CML duration pre-study was 10 y (range, 0.3-23 y). 16 subjects had BCR::ABL1T315I. 25 subjects received ≥ 3 prior TKIs. Median follow-up was ≥ 31 mo and median exposure, 6 mo (range, 0.4-52). Therapy was ongoing in 7 subjects at study termination. Others discontinued because of progression (n = 20), AEs (n = 2), consent withdrawal (n = 5), entry into another study (n = 3) or other reasons (n = 14). The MTD was 600 mg with the grade-3 psoriasis-like skin AE as the DLT. There were no vascular occlusive events or deviations of ankle-brachial index. Complete haematologic response (CHR) was achieved in 14 of 30 subjects, major cytogenetic response (MCyR) in 15 of 44 subjects, complete cytogenetic response (CCyR) in 11 of 50 subjects and major molecular response (MMR) in 8 of 51 subjects. Median duration of CHR was 12 mo and has not been reached for MCyR, CCyR and MMR. The best safety/efficacy dose was 300 mg/d with 6 of 9 subjects achieving a MCyR, 5, a CCyR and 4, MMR. 5 of 16 subjects with BCR::ABL1T315I responded, including 4 achieving a MCyR, 2, a CCyR and 1, a MMR. 2 of 6 subjects failing ponatinib achieved a CHR. Conclusion: PF-114 was safe and effective in subjects failing ≥ 2 TKIs and those with BCR::ABL1T315I including those failing ponatinib. The PF-114 dose for further study is 300 mg/d. Disclosures Turkina: Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau; Novartis Pharma: Speakers Bureau. Vinogradova: Bristol Myers Squibb: Speakers Bureau; Novartis Pharma: Speakers Bureau; Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau. Lomaia: Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Pharmstandard: Honoraria. Chelysheva: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Pharmstandart: Speakers Bureau. Petrova: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau. Cortes: Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Baccarani: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ottmann: Fusion: Honoraria; Incyte: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Novartis: Honoraria. Mikhailov: Fusion Pharma: Current Employment. Novikov: Fusion Pharma: Current Employment. Shulgina: Fusion Pharma: Current Employment. Chilov: Fusion Pharma: Current Employment.

The goal of treatment of relapsed/refractory multiple myeloma (RRMM) is to control the disease, prolong survival, reduce disease-related symptoms, and improve quality of life (QoL). Comprehensive evaluation of new treatment regimens in RRMM pts is worthwhile. We aimed to evaluate QoL, treatment satisfaction, response to treatment and safety during Ixazomib-Lenalidomide-Dexamethasone (IRd) treatment as ≥ 2nd line in RRMM pts in a real world setting. Adult pts with RRMM who have been assigned IRd as ≥2nd line treatment were enrolled in multicenter observational prospective study. Treatment response was evaluated by IMWG 2011, adverse events (AEs) - by CTCAE v.4.0. Pts filled out RAND SF-36 and ESAS-R at baseline and at 1 and 3 mos, and thereafter every 3 mos till 18 mos after IRd treatment start; Patient Treatment Satisfaction Cheklist (PTSC) - at each time-point after IRd treatment start. For analysis of meaningful QoL changes during IRd treatment the proportion of pts with baseline significant QoL impairment who experienced meaningful QoL improvement during IRd treatment was evaluated as well as the number of pts without baseline QoL impairment who maintained it during IRd treatment. For statistical analysis GLM paired test and GEE were employed with adjustment to age, gender and baseline QoL. In total, 40 pts with RRMM were enrolled into the pilot study: median age - 64 years (range, 33-80), 29% males, Durie-Salmon stage at study entry: I/II/III - 3/41/56%, ECOG status 0/1 - 68.7%, 2/3 - 31.6%. Median time since initial MM diagnosis - 51.4 mos (range, 2.9-100.7), disease status at study entry: relapsed - 26%, refractory - 21%, relapsed and refractory - 53%. Median number of lines of prior therapy is 3 (range, 1-3). At the time of analysis the median number of IRd cycles administered is 5, median follow-up - 4.6 (0.4-13.7) mos. Treatment response was not evaluated in 11 pts: 1 - death (at 3 months), 1- refusal, 9 - too early for evaluation. Out from 29 pts one patient achieved complete response (CR), seven pts achieved partial response (PR) and one patient - very good partial response (VGPR), 12 - minor response (MR). Thus, a clinical benefit rate was 70%. Also, seven pts achieved stable disease (23%), one patient was primary refractory to IRd (3.5%), one patient died (3.5%). At the time of analysis all the pts with CR/PR/VGPR (30%) maintained their response to treatment, 4 pts (13%) maintained stable disease and 9 pts (30%) maintained minor response; 7 pts (23%) experienced disease progression. AEs were revealed in 47% pts: grades 1-2 AEs - 12 pts; grades 3-4 AEs - 4 pts; SAEs - 3 pts (neurological toxicity, gastric bleeding, hypotension), all pts with SAEs discontinued IRd treatment. Baseline QoL was dramatically impaired by the majority of SF-36 scales with significant QoL impairment in 42% pts. The most worsening was revealed for physical functioning, role functioning, general health and vitality (Mean scores varied from 24.6 to 47.0 out from 100 scores). At baseline 88% pts had moderate-to severe symptoms (≥4 scores on the scale from 0 to 10); moderate-to severe worse wellbeing, tiredness, pain and shortness of breath had 72,5%, 67,5%, 61,5% and 45% pts, respectively. At 1 month of IRd treatment QoL meaningfully improved or was stable without significant impairment in 61% pts, at 3 months - in 50% pts. In 1 mos of IRd treatment significant improvement was revealed for physical functioning (GLM, 44.9 vs 54.7, p=.01) and general health (GLM, 47.8 vs 56.3, p.05). At 1 month of treatment, meaningful decrease of shortness of breath (in 42% pts), tiredness (36%), and pain (28%) was revealed; at 3 months of IRd treatment this proportion was 33%, 27%, and 13%, accordingly. Regarding treatment satisfaction pts reported the following: at 1 month after treatment start 94% of pts were satisfied with symptoms decrease due to IRd, 89% pts confirmed that IRd was convenient and 97% pts reported global satisfaction with IRd; at 3 months of treatment all the pts confirmed the convenience of IRd regimen, 84% pts were satisfied with IRd treatment. The results obtained in a real-world setting demonstrate clinical benefits of IRd regimen in RRMM pts, which were achieved without negatively affecting QoL and with satisfactory symptom control in these heavily pretreated patients. IISR funded by Takeda Disclosures Ionova: BMS: Research Funding; Takeda: Research Funding. Vinogradova:Novartis: Honoraria, Research Funding.

e19001 Background: The prognosis of relapsed acute myeloid leukemia (R/R AML) remains poor and the management is challenging. Despite the increasing availability of targeted agents, the lower responses still represent a major obstacle to overcome. Antroquinonol is an isoprenyltransferase inhibitor with antitumor activity in vitro and xenograft models of AML. Our aim is to evaluate hematopoietic recovery with Antroquinonol in this phase IIa study. Here, the results from our phase IIa trial demonstrate the safety, tolerability, and activity of Antroquinonol in patients with relapsed AML. Methods: GHAML-2-001 is a phase IIa, open-label study in adult patients with relapsed acute myeloid leukemia or at initial diagnosis when no intensive treatment is possible. Antroquinonol 200 mg BID was administered in a 28-day cycle (up to six cycles). The primary endpoint is hematologic response rate. Secondary endpoints consist of 4-week survival, 24-week survival, duration of hematologic response and transfusion independence, and the response rates. Therapy was continued for as long as tolerated and there was continuing evidence of therapeutic benefit in the opinion of the investigator. Treatment response was assessed by the International Working Group (IWG) response criteria after each cycle. Results: Twelve eligible patients had a median age of 62.5 years (range, 42-69; 6 males, 6 females) and the whole process was conducted between March 2019 and February 2020. Of the two patients who did not complete the therapy period were due to the patient's decision to withdraw: One patient withdrew on day 7 and the other one withdrew on day 49. Among other ten patients who finished all six cycles (168 days), Antroquinonol showed excellent safety and favorable tolerability. At the end of the treatment, the rate of complete remission (CR/CRi) after 6-completed cycles was 50% (5/10) and the 24-week survival rate was 100%. Transfusion independence was achieved in 8 (80%) of 10 transfusion independence evaluable patients at the end of the 6th cycle treatment. Conclusions: In high-risk relapsed AML patients, orally administered Antroquinonol induced CRs and was well tolerated. This significant result suggests the potential of Antroquinonol for the therapy of this underserved population. Clinical trial information: NCT03823352. Clinical trial information: NCT03823352.

8020 Background: MM patients (pts) often receive several lines of therapy with multiple drug combinations and, as lenalidomide (R)-containing regimens are commonly used as first-line therapy, R-free options for subsequent lines are necessary. Additionally, as pts age and become less tolerant to treatment, more convenient regimens, such as all-oral options, with less toxicity are needed. Dexamethasone (dex)-based doublets are effective and tolerable in this setting. Methods: Proteasome inhibitor (PI)-exposed and/or intolerant and R-refractory pts who had ≥2 prior therapies (N = 122) were randomized 3:2 to receive: ixazomib (ixa) 4 mg (5.5 mg from cycle 2 if tolerated) on day (d) 1, 8, 15, and dex 20 mg (≥75 years [yrs], 10 mg) on d 1, 2, 8, 9, 15, 16, 22, 23; or pomalidomide (pom) 4 mg on d 1–21, and dex 40 mg (≥75 yrs, 20 mg) on d 1, 8, 15, 22, in 28-d cycles until progressive disease (PD) or unacceptable toxicity. Pts were stratified by age ( < 65 vs ≥65 yrs), International Staging System (ISS) disease stage at study entry (I/II vs III), and prior lines of therapy (2 vs ≥3). The study was powered to test the primary endpoint of progression-free survival (PFS). Results: In the ixa-dex (n = 73) vs pom-dex (n = 49) arms, median age was 72 vs 68 yrs (36% vs 18% ≥75 yrs), 25% vs 22% of pts had ISS stage III MM, and 52% vs 53% had received ≥3 prior therapies (per stratification). At data cutoff (5/31/2020), 19% vs 20% of pts were ongoing on treatment with ixa-dex vs pom-dex; primary reasons for discontinuation were PD (47% vs 57%) and adverse events (AEs; 23% vs 12%). With median follow-up of 15.3 vs 17.3 months (mos), median PFS (mPFS) was 7.1 vs 4.8 mos with ixa-dex vs pom-dex (hazard ratio [HR] 0.847; 95% confidence interval [CI] 0.535–1.341; p = 0.477); the Table shows mPFS by prior lines, and secondary endpoints. Pts received a median of 6 cycles with both ixa-dex (range 1–25) and pom-dex (range 1–27); 64% of ixa-dex pts were able to escalate to a 5.5 mg dose of ixa. 69% vs 81% of ixa-dex vs pom-dex pts had grade (G) ≥3 AEs, 51% vs 53% had serious AEs, 39% vs 36% had an AE leading to drug discontinuation, 44% vs 32% had an AE leading to dose reduction, and 13% vs 13% died on study. Health-related quality of life (HRQoL; EORTC QLQ-C30/MY20, and EQ-5D-5L) was maintained, and similar between arms. Conclusions: Ixa-dex prolonged PFS vs pom-dex in these heavily pretreated, PI-exposed and/or intolerant, R-refractory pts, but the difference was not statistically significant. Ixa-dex was well tolerated, with lower G≥3 AE rates vs pom-dex, and comparable HRQoL. Clinical trial information: NCT03170882.

Aerobic exercise training is associated with adaptive changes in skeletal muscles and their vascular bed; such changes in individual muscles may vary depending on their characteristics and recruitment. This study was aimed at comparing the effects of eight-week treadmill training on the locomotor and respiratory muscles in rats. The training course increased the aerobic performance in rats, which was evidenced by an increase in maximum O2 consumption and a decrease in the blood lactate concentration in ramp test. The succinate dehydrogenase activity was increased in the red portion of the gastrocnemius muscle, but not in the diaphragm of trained rats. Arterial segments were isolated from feed arteries and studied by wire myography. The relaxation in response to acetylcholine in gastrocnemius arteries in trained animals was higher as compared with controls (due to higher NO production), while contractile responses to noradrenaline (in the presence of propranolol) were not changed. On the contrary, the endothelial function of diaphragm arteries was not affected by training, but contractile responses to activation of α-adrenoceptors were markedly increased. Thus, aerobic training may increase the blood supply rate to both locomotor and respiratory muscles, but the underlying regulatory mechanisms are different. The results obtained allow us to reveal the physiological mechanisms that determine the physical performance of the body under conditions of compromised functioning of the respiratory system.

Introduction Implantable telemetry enables continuous monitoring of physiological functions in freely moving animals and can greatly complement pharmacological research. Despite its miniaturization, a sensor/transmitter constitutes 5% or more of a mouse's bodyweight. The aim of the present study was to evaluate whether factors related to the presence of a probe/transmitter influence the ambulatory activity, strength, agility, or operant, motivated behaviors of this small rodent. Methods Adult male mice (C57BL/6 N, 22–25 g, 9–10 weeks; implanted n = 26, intact n = 45) were evaluated during week-long tests, conducted three and eight weeks after surgical implantation of the PA-C10 blood pressure probe. An open field test, grip force measurement, Rotarod test were performed, followed by 7-day continuous monitoring of spontaneous wheel running activity and positively reinforced operant conditioning in an automated data collection system. Results An implanted blood pressure transmitter did not affect behavior of mice in the open field test, on the Rotarod or their grip force, compared to unoperated controls. Voluntary wheel running distance was reduced three, but not eight weeks after implantation. Three weeks after the surgery, performance in the positively reinforced operant conditioning in operated mice was slightly decreased compared to intact animals, while retention and acquisition of a 2nd, reversal-learning task eight weeks after the surgery were unaffected. Discussion We conclude that an implantable transmitter may have detectable effects in the first few weeks following implantation on some elements of mouse behavior. With sufficient recovery, mice perform comparably to unoperated controls in tests of strength, endurance, agility and learned operant behavior.

The goal of this study is to compare the dynamics of aerobic and force–velocity characteristics of the shoulder girdle muscles and leg muscles during high-volume aerobic training in junior cross-country skiers in the time interval from the end of the preparatory period to the beginning of the competition period. Eleven junior cross-country skiers were repeatedly tested from December to February. In this period, the volume of aerobic training was 22–23 h per week. During the experimental period, the knee extensors torque in the range of angular velocities of 30–300 degrees/s was observed to decrease, with no changes in the volume of the quadriceps muscle of thigh and knee flexor muscles. The maximal oxygen consumption rate (VO2 max) was observed to decrease by 6% (P < 0.05) in the treadmill test, while the oxygen consumption at anaerobic threshold (VO2 at La = 4 mmol/L) was unchanged. On the contrary, the functional capacity of the shoulder girdle muscles was enhanced. The force-velocity characteristics of the shoulder girdle muscles that were estimated in the maximal anaerobic power test at a double poling ergometer increased by 16% (P < 0.01), and the volume of the triceps muscle of arm increased by 4.6 (P < 0.01). The aerobic capacity of the shoulder girdle muscles that were estimated by the VO2 at La = 4 mmol/L increased by 30% (P < 0.05). The potential for increasing the performance of junior cross-country skiers seems to be associated with the increased functional capacity of the shoulder girdle muscles.

The aim of the study was to investigate the effects of voluntary breath-holding on brain activity and physiological functions. We hypothesised that prolonged apnoea would trigger cerebral hypoxia, resulting in a decrease of brain performance; and the apnoea’s effects would be more pronounced in breath-hold divers. Trained breath-hold divers and non-divers performed maximal dry breath-holdings. Lung volume, alveolar partial pressures of O2 and CO2, attention and anxiety levels were estimated. Heart rate, blood pressure, arterial blood oxygenation, brain tissue oxygenation, EEG, and DC potential were monitored continuously during breath-holding. There were a few significant changes in electrical brain activity caused by prolonged apnoea. Brain tissue oxygenation index and DC potential were relatively stable up to the end of the apnoea in breath-hold divers and non-divers. We also did not observe any decrease of attention level or speed of processing immediately after breath-holding. Interestingly, trained breath-hold divers had some peculiarities in EEG activity at resting state (before any breath-holding): non-spindled, sharpened alpha rhythm; slowed-down alpha with the frequency nearer to the theta band; and untypical spatial pattern of alpha activity. Our findings contradicted the primary hypothesis. Apnoea up to 5 min does not lead to notable cerebral hypoxia or a decrease of brain performance in either breath-hold divers or non-divers. It seems to be the result of the compensatory mechanisms similar to the diving response aimed at centralising blood circulation and reducing peripheral O2 uptake. Adaptive changes during apnoea are much more prominent in trained breath-hold divers.

Reactive oxygen species (ROS) produced by NADPH-oxidase (NOX) participate in vascular tone control, but their effects in the arteries of respiratory muscles is poorly understood. Possible targets of vasoregulatory ROS influence are NO-pathway in the endothelium and Rho-kinase pathway in smooth muscle cells. Therefore, the aim of this study was to evaluate the interaction of NOX-dependent control with NO- and Rho-kinase signaling pathways in rat diaphragm arteries (DA). Methods: The segments of DA were isolated from male Wistar rats and mounted in wire myograph (DMT A/S). We studied the effects of NOX inhibitor VAS2870 (1 μM) on contractile responses to α1-adrenergic agonist methoxamine in the absence and in the presence of NO synthase (L-NNA 100 μM) or Rho-kinase (Y27632, 3 μM) inhibitors as well as in the presence of NO donor DEA/NO. Results: VAS2879 prominently attenuated the contractile responses of DA to methoxamine (30% decrease of the area under the concentration-response curve). L-NNA and Y27632 increased and decreased methoxamine-induced contraction of DA, respectively. L-NNA did not change the effects of VAS2870 and the sensitivity to DEA/NO did not differ in arteries with active and inhibited NOX. Along with that Y27632 eliminated the effects of VAS2879 on DA contractile responses to methoxamine. Conclusions: We showed that NOX-produced ROS potentiate contractile responses of DA. ROS did not affect the activity of NO-pathway in either endothelial or smooth muscle cells of DA. However, ROS modulate the activity of the Rho-kinase pathway in DA smooth muscle cells. Supported by RSF (project No 19-75-00060).

Background: A success of the tyrosine kinase inhibitors (TKI) therapy in patients (pts) with chronic myeloid leukemia (CML) allowed to set a new goal: a treatment-free remission (TFR). A stable and long-lasting deep molecular response (DMR) is required for a successful TKI discontinuation. The number of CML pts with stable DMR increases on late terms of TKI therapy. With the relationship to this new goal it is relevant to evaluate the proportion of the potential candidates for TKI discontinuation in accordance with the country-specific features of the CML pts population in routine clinical practice. Aim :To characterize the cohort of CML pts treated in routine clinical practice in Russian Federation and to evaluate the proportion of CML pts eligible for TFR. Methods: The analyzed cohort consisted of 197 pts from 6 regions of Russia covering the population of 10 million inhabitants. All pts with CML diagnosed from 01.10.2009 to 31.12.2012 were included into the prospective multicenter EUTOS Population Based Study (EUTOS PBS). Median (Me) age was 50 (18-82)years, 49% were males. Chronic phase, accelerated phase and blast crisis was diagnosed in 93,4%, 6% and 0,6% pts respectively. Imatinib as a 1st line was used in 97% pts. The 2nd generation TKIs (TKI2) were used as 1st and 2nd -3rd line in 3% and 12% pts respectively; imatinib failure was the main reason of switch to TKI2. Overall survival (OS) and cumulative (CI) of DMR were evaluated and adjusted to the new ELTS (EUTOS long-term-survival) score. A proportion of pts with sustained DMR eligible for TFR was calculated. DMR was considered as BCR-ABL2 years and TKI therapy >3 years. Results:Me follow-up in Russian CML pts cohort of EUTOS PBS was 77 (0,7 - 107) months (mo). The ELTS score available in 179 pts was low, intermediate and high in 86(48%), 50(28%) and 43(24%) pts accordingly. The 7-year OS was 76% in total cohort (figure 1a). The 7-year OS in low, intermediate and high ELTS group was 87%, 68% and 55% respectively (p=0,001). Me time of DMR achievement was 38mo (11,2 - 89 mo). The 7-year CI of DMR was 62%. The CI of 7-year DMR achievement in ELTS low, intermediate and high group was 62%, 42% and 38% respectively with significant difference between low and non-low score pts (p= 0,001) (figure 1b). The data for the molecular response at data cut-off April 2019 were available in 114/123 pts who were alive and treated by TKIs with Me time 85 (range 65 - 105) mo. DMR, major molecular response (MMR, (BCR-ABL >0,01%- 0,1% IS) and no MMR (BCR-ABL> 0,1% IS) was in 76 (66,7%), 8 (7%) and 30 (26,3%) pts respectively. A sustained DMR was in 38 (50%) of 76 pts or 19% of the total cohort of 197 pts. Conclusion: A significant proportion of CML pts reach a sustained DMR on late terms of TKI therapy. In total 19% of CML pts in Russian part of the EUTOS PBS study can be eligible to treatment-free observation after 7 years of TKI therapy. The low ELTS score predicts better survival and better chance of DMR achievement. The evaluation of the TFR perspective in routine clinical practicein important from diagnosis to late terms of treatment. Disclosures Chelysheva: Novartis: Consultancy, Honoraria; Fusion Pharma: Consultancy. Vinogradova:Novartis: Consultancy; Fusion Pharma: Consultancy. Turkina:Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; fusion pharma: Consultancy; Novartis: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy.

Background: PF-114 is a 4th-generation oral tyrosine kinase-inhibitor (TKI) active against wild-type and mutated BCR-ABL1 isoforms including BCR-ABL1T315I. We present data from a phase-1 study in patients with chronic or accelerated phase chronic myeloid leukaemia (CML) failing ≥2 TKIs or with BCR-ABL1T315I (NCT02885766) with ≥6 months therapy. Methods: 3+3 dose-escalation study to determine maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary objectives included safety and efficacy based on haematological, cytogenetic, and molecular criteria. Adverse events (AEs) were graded using NCI-CTCAE v4.03. Results: 51 patients were enrolled. Daily doses were 50 mg (n=3), 100 mg (n=3), 200 mg (n=9), 300 mg (n=11), 400 mg (n=12), 500 mg (n=3), 600 mg (n=6), 750 mg (n=4) given continuously. Median age was 50 years (range, 29-82 years). Median CML duration pre-study was 10 years (range, 0.3-23 years). All patients had baseline ECOG performance scores 0-1. Twelve patients had BCR-ABL1T315I. Patients were heavily pre-treated: 25 received ≥3 prior TKIs; 5 patients with BCR-ABL1T315I received 1 prior TKI. Interim analysis was conducted at follow-up of ≥6 months (cut-off date January 16th 2019). Therapy was ongoing in 17 patients at doses 200 mg (n=4), 300 mg (n=9), 400 mg (n=3) and 600 mg (n=1) with median duration of exposure of 7,4 (range, 4,6-26), 9,2 (range, 7,4-26), 9,2 (range, 8,3-9,2) and 9,2 months. Other patients discontinued because of progression (n=18), adverse events (n=6), consent withdrawal (n=4), participation in another study (n=3) or other reasons (n=3). The MTD was 600 mg with the grade-3 psoriasis-like skin lesions the DLT, which occurred during the first 28 days of treatment. Reversible grade-3 skin toxicity occurred in 11 patients at doses ≥400 mg. There were no other drug-related non-hematologic grade-3 toxicities except 1 grade-3 toxic hepatitis at 400 mg and there were no detectable effects on ankle-brachial index or vascular occlusive events. The best safety/efficacy dose was 300 mg/d with 6 of 11 patients achieving a major cytogenetic response (MCyR) and 4 of them - a major molecular response (MMR). Higher doses were less effective probably because of toxicity-related therapy interruptions and discontinuations. Five of 12 patients with BCR-ABL1T315I responded, 3 of which achieved a complete hematologic response and 4 achieved MCyR. Conclusion: PF-114 was safe and effective in patients with CML failing ≥2 TKIs or with BCR-ABL1T315I. The most effective dose was 300 mg/d. Five of 12 patients with BCR-ABL1T315I responded. A pivotal study is beginning. Disclosures Turkina: Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; fusion pharma: Consultancy; Novartis: Consultancy, Speakers Bureau. Vinogradova:Novartis: Consultancy; Fusion Pharma: Consultancy. Lomaia:Novartis: Other: Travel Grant;Lecture fee; Pfizer: Other: Travel Grant. Shukhov:Pfizer: Consultancy; Novartis: Consultancy. Chelysheva:Novartis: Consultancy, Honoraria; Fusion Pharma: Consultancy. Shikhbabaeva:Novartis: Consultancy; Fusion Pharma: Consultancy. Shuvaev:Fusion Pharma: Consultancy; Novartis: Consultancy; Pfize: Honoraria; BMS: Consultancy. Cortes:Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Immunogen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; BiolineRx: Consultancy; Sun Pharma: Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding. Baccarani:Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Takeda: Consultancy. Ottmann:Roche: Honoraria; Pfizer: Honoraria; Fusion Pharma: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Mikhailov:Fusion Pharma: Employment. Novikov:Fusion Pharma: Employment. Shulgina:Fusion Pharma: Employment. Chilov:Fusion Pharma: Consultancy.

Background: Awareness of Kawasaki disease (KD) is emerging in Russia but the diagnosis is still often missed. Methods: This is a retrospective study of 303 children with KD who received care at a single center in Moscow over the period from 2004 to 2016. Results: Overall, coronary artery aneurysms were documented in 91 (30,0%) of 303 patients and transient ectasia in 40 (13,2%). Intracoronary thrombi were found in 12 of 15 patients with giant aneurysms and in 3 patients with medium-sized aneurysms. Conclusion: The patients with KD in the Moscow region had typical features of the disease described in the literature but the proportion of patients with coronary artery aneurysms was higher than reported from other countries. We assume that this is due to delayed treatment, which has gradually improved over time. Increased awareness of KD in Russia is critical to ensure timely diagnosis and treatment.

In courses of general English, and in preparation for examination in particular, students need much feedback when they submit written works. Besides tips concerning content, coherence and cohesion, grammatical range and accuracy, all of which are standardly included in instructor’s comments, more efficient advice touches upon directions towards lexical improvements. However, such feedback requires a huge amount of time and effort on the part of the instructor, whose workload is heavy enough to make any extra effort undesirable. Besides, the wealth of student texts in the learner corpus allows researchers to make use of the many samples of student writing by applying certain computer tools. As a result, the authors set themselves a task of developing a system of automated lexical inspection of student works. Initially, we used essays in the corpus to work out which formal parameters in the essays demonstrate in what ways essays that have been evaluated as good by the examination experts can be distinguished, then we applied those parameters in the process of automated inspection, after which we proceeded to checking the correlation between the inspection results and the traditional grading. Finally, after a thorough analysis a system of lexical inspection of student essays was established, which paves way to the development of automated lexical feedback in order to orient students in how to improve the lexical variety in their writing.

To investigate the association between multiple single-nucleotide polymorphisms (SNPs), aerobic performance and elite endurance athlete status in Russians. By using GWAS approach, we examined the association between 1,140,419 SNPs and relative maximal oxygen consumption rate ([Formula: see text]O2max) in 80 international-level Russian endurance athletes (46 males and 34 females). To validate obtained results, we further performed case-control studies by comparing the frequencies of the most significant SNPs (with P < 10(-5)-10(-8)) between 218 endurance athletes and opposite cohorts (192 Russian controls, 1367 European controls, and 230 Russian power athletes). Initially, six 'endurance alleles' were identified showing discrete associations with [Formula: see text]O2max both in males and females. Next, case-control studies resulted in remaining three SNPs (NFIA-AS2 rs1572312, TSHR rs7144481, RBFOX1 rs7191721) associated with endurance athlete status. The C allele of the most significant SNP, rs1572312, was associated with high values of [Formula: see text]O2max (males: P = 0.0051; females: P = 0.0005). Furthermore, the frequency of the rs1572312 C allele was significantly higher in elite endurance athletes (95.5%) in comparison with non-elite endurance athletes (89.8%, P = 0.0257), Russian (88.8%, P = 0.007) and European (90.6%, P = 0.0197) controls and power athletes (86.2%, P = 0.0005). The rs1572312 SNP is located on the nuclear factor I A antisense RNA 2 (NFIA-AS2) gene which is supposed to regulate the expression of the NFIA gene (encodes transcription factor involved in activation of erythropoiesis and repression of the granulopoiesis). Our data show that the NFIA-AS2 rs1572312, TSHR rs7144481 and RBFOX1 rs7191721 polymorphisms are associated with aerobic performance and elite endurance athlete status.

International audience; When tested on the treadmill mice do not display a graded increase of heart rate (HR), but rather a sharp shift of cardiovascular indices to high levels at the onset of locomotion. We hypothesized that under test conditions cardiovascular reaction to physical load in mice is masked with stress-associated HR increase. To test this hypothesis we monitored mean arterial pressure (MAP) and heart rate in C57BL/6 mice after exposure to stressful stimuli, during spontaneous locomotion in the open-field test, treadmill running or running in a wheel installed in the home cage. Mice were treated with beta1-adrenoblocker atenolol (2mg/kg ip, A), cholinolytic ipratropium bromide (2mg/kg ip, I), combination of blockers (A+I), anxiolytic diazepam (5mg/kg ip, D) or saline (control trials, SAL). MAP and HR in mice increased sharply after handling, despite 3weeks of habituation to the procedure. Under stressful conditions of open field test cardiovascular parameters in mice were elevated and did not depend on movement speed. HR values did not differ in I and SAL groups and were reduced with A or A+I. HR was lower at rest in D pretreated mice. In the treadmill test HR increase over speeds of 6, 12 and 18m/min was roughly 1/7-1/10 of HR increase observed after placing the mice on the treadmill. HR could not be increased with cholinolytic (I), but was reduced after sympatholytic (A) or A+I treatment. Anxiolytic (D) reduced heart rate at lower speeds of movement and its overall effect was to unmask the dependency of HR on running speed. During voluntary running in non-stressful conditions of the home cage HR in mice linearly increased with increasing running speeds. We conclude that in test situations cardiovascular reactions in mice are governed predominantly by stress-associated sympathetic activation, rendering efforts to evaluate HR and MAP reactions to workload unreliable.

We examined signaling responses in the skeletal muscle of strength athletes after strength exercises under high and moderate load. Eight trained male powerlifters were recruited. The volunteers performed four sets of leg presses to volitional fatigue using a moderate load (65% 1‐repetition maximum [1RM]) for one leg, and a high load (85% 1RM) for the contralateral leg. The work volume performed by the leg moving a moderate load was higher than that of the contralateral leg moving a high load. Biopsy of the m. vastus lateralis was performed before, and at 1, 5, and 10 h after, cessation of exercise. Phosphorylation of p70S6kThr389, 4E‐BP1Thr37/46, and ACCS er79 increased after moderate load exercises, whereas phosphorylation of ERK1/2Thr202/Tyr204 increased, and that of eEF2Thr56 decreased, after high load exercises. Exercise under a moderate load and a high work volume activated mTORC1‐dependent signaling in trained skeletal muscle, whereas exercise under a high load but lower work volume activated the MEK‐ERK1/2 signaling cascade and eEF2.

The effect of strength training on muscle pressor reflex responses was investigated. Ten young, healthy volunteers and eight arm wrestling athletes performed forearm exercises at 30% of maximal voluntary effort until exhaustion. The exercises were either static or rhythmic, with alternating 20-s periods of muscle contraction and relaxation, followed by postexercise forearm arterial occlusion (PEAO). Heart rate, blood pressure (BP), and sympathetic nerve activity directed to muscle blood vessels (MSNA) were continuously recorded during the exercises. MSNA recordings were obtained from the peroneal nerve using a microneurographic method. During static exercises followed by PEAO, there were no differences in BP or MSNA between athletes and nonathlets. In contrast, a significant decrease in muscle pressor reflex responses was observed in the athletes during rhythmic exercises followed by PEAO. The possible relationship between this effect and changes in muscle energy supply, increased wash-out of metabolites, and reduced sensitivity of the muscle receptors in athletes is discussed.

Background. The treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKI) have diminished death probability and have changed the disease course. Achievement of complete cytogenetic response (CCyR) and major molecular response (MMR) are serve as warranties for freedom of progression and death from CML. There are many of CML patients are needed to change of initial TKI therapy with choice of the most efficient and safe drug for continuous life-long therapy to reach the optimal results of CML treatment. The newest of registered TKI drug in Russia is Bosutinib which has dual BCR-ABL and SRC kinase inhibitory activity and had showed good tolerability and efficacy in case of other TKIs resistance or intolerance. Aim. To analyze of own Bosutinib experience in patients with chronic myeloid leukemia with other TKIs resistance or intolerance and to make comparison with clinical trial results. Materials and methods. Clinical trials results from peer-reviewed journals. Outpatients charts of 51 patients (25 male and 26 females) with CML. Disease phase at the moment of Bosutinib therapy initiation was as follows: chronic - 37; acceleration - 8, blastic - 6. Bosutinib was used in the next lines of TKI therapy: second - 10; third - 18; fourth - 23. The indications for Bosutinib therapy were: intolerance to previous TKI - 21; resistance to previous TKI - 30. Results. Median of therapy duration was 6 months (1-50 months). The adverse events and tolerability of Bosutinib were similar with clinical trials data. The treatment was withdrawn by the adverse event only in 5 (10%) patients. The rates of the responses in the whole group of patients were as follows: CHR - 88%, stable in 76%; CCyR - 39%, stable in 37%, MMR - 31% and was 25% at the last follow-up. The Bosutinib efficacy in real life settings was slightly higher than clinical trials data. The factors influencing treatment responses were: disease phase, cause of switching to Bosutinib, line of therapy and presence and kind of BCR-ABL mutations, Therapy was continued in 22 (43%) patients, most them achieved stable optimal treatment response (CCyR and MMR). Conclusions. Bosutinib is a real alternative to other tyrosine kinase inhibitors and has its own mechanism of action and adverse events profile. The use of Bosutinib in real life clinical practice settings showed its efficacy and tolerability and could serve as base for recommendation to apply Bosutinib in hematology practice in Russia. Disclosures No relevant conflicts of interest to declare.

Background: PF-114 mesylate is a 4th-generation oral tyrosine kinase-inhibitor (TKI) active against wild-type and mutated BCRABL1 isoforms including those with a BCRABL1T315I. We present data from a phase-1 study in subjects with chronic or accelerated phase chronic myeloid leukaemia (CML) failing ≥2 TKIs or who have BCRABL1T315I (NCT02885766). Methods: 3+3 dose-escalation design to determine maximum tolerated dose (MTD) followed by expanded cohorts for doses ≤MTD. The primary objective was to determine the MTD and identify dose-limiting toxicities (DLTs) during cycle 1 (28 days). Secondary objectives included safety and anti-CML activity based on hematological, cytogenetic, and molecular criteria. Adverse events (AEs) were assessed and graded using NCI-CTCAE v4.03. Results: 51 subjects were enrolled as of June 26, 2018. Daily doses were 50 mg (n=3), 100 mg (n=3), 200 mg (n=9), 300 mg (n=11), 400 mg (n=12), 500 mg (n=3), 600 mg (n=6), 750 mg (n=4) given on a continuous QD schedule. Median age was 50 years (range, 29-82 years). Median interval from diagnosis to study-entry was 10 years (range, 0-23 years). Subjects had baseline ECOG performance scores Conclusion: MTD of PF-114 is 600 mg with skin toxicity as the DLT. The best safety/efficacy ratio was seen at doses of 200 and 300 mg which are being studied in expanded cohorts and soon in a phase-2 study. Disclosures Turkina: Novartis: Other: provided consultations; Bristol Myers Squibb: Other: provided consultations; Phizer: Other: provided consultations; Fusion Pharma: Other: provided consultations. Shukhov:Novartis: Other: provided consultations and performed lectures ; Bristol Myers Squibb: Other: provided consultations and performed lectures . Chelysheva:Bristol Myers Squibb: Other: provided consultations and performed lectures; Fusion Pharma: Other: provided consultations ; Novartis: Other: provided consultations and performed lectures. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding. Ottmann:Novartis: Consultancy; Pfizer: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Fusion Pharma: Consultancy, Research Funding. Mikhailov:Fusion Pharma: Employment. Novikov:Fusion Pharma: Employment. Shulgina:Fusion Pharma: Employment. Chilov:Fusion Pharma: Employment.

The hypertrophic effect of strength training is known to be due to mechanical and metabolic stimuli. During exercises with the restricted blood supply of working muscles, i.e., under the conditions of intensified metabolic stress, the training effect may be achieved with much lower external loads (20% of one repetition maximum). The effects of 8 weeks of high-intensity (80–85% of one repetition maximum) strength training were compared to low-intensity (50% of one repetition maximum) training without relaxation. The high-intensity strength training resulted in higher increases in strength and size of the exercised muscles than training without relaxation. During high-intensity training, at the muscle cross section, an increase in the area occupied by type II fibers prevails; while, during training without relaxation, an increase in the area occupied by type I fibers prevails. An exercise session without relaxation leads to a more pronounced increase in the secretion of the growth hormone, insulin-like growth factor-1, and cortisol. The expression of gene regulating myogenesis (Myostatin) is changed in different ways after a high-intensity strength exercise session and after an exercise session without relaxation. Low-intensity strength training (50% of one repetition maximum) without relaxation is an efficient way for inducing increases of the strength and size of the trained muscles. This low-intensive type of training may be used in rehabilitation medicine, sports, and fitness.

The lateral stiffness and electromyogram characteristics of the resting calf flexor and extensor muscles have been studied in 18 subjects during a seven-day immersion with and without mechanical stimulation of the foot support zones. It has been shown that as early as day 1 of support deprivation, the lateral stiffness steadily decreases in the m. soleus and, in contrast, drastically increases in the m. tibialis anterior. A mechanical stimulation of the foot support zones decreases the rate and degree of the changes observed in both muscles. The tight correlation of the changes in the lateral stiffness with the muscle activity suggests a significant dependence of these changes on the electromyogram characteristics at rest.

Animals are an essential component of space exploration and have been used to demonstrate that weightlessness does not disrupt essential physiological functions. They can also contribute to space research as models of weightlessness-induced changes in humans. Animal research was an integral component of the 30-day automated Russian biosatellite Bion-M 1 space mission. The aim of the hemodynamic experiment was to estimate cardiovascular function in mice, a species roughly 3000 times smaller than humans, during prolonged spaceflight and post-flight recovery, particularly, to investigate if mice display signs of cardiovascular deconditioning. For the first time, heart rate (HR) and blood pressure (BP) were continuously monitored using implantable telemetry during spaceflight and recovery. Decreased HR and unchanged BP were observed during launch, whereas both HR and BP dropped dramatically during descent. During spaceflight, BP did not change from pre-flight values. However, HR increased, particularly during periods of activity. HR remained elevated after spaceflight and was accompanied by increased levels of exercise-induced tachycardia. Loss of three of the five mice during the flight as a result of the hardware malfunction (unrelated to the telemetry system) and thus the limited sample number constitute the major limitation of the study. For the first time BP and HR were continuously monitored in mice during the 30-day spaceflight and 7-days of post-flight recovery. Cardiovascular deconditioning in these tiny quadruped mammals was reminiscent of that in humans. Therefore, the loss of hydrostatic pressure in space, which is thought to be the initiating event for human cardiovascular adaptation in microgravity, might be of less importance than other physiological mechanisms. Further experiments with larger number of mice are needed to confirm these findings.

The impedance method of pre-ejection period (PEP) evaluation had been adapted for a small animal study and validated with a Millar-type pressure sensor inserted into aorta near the aortic valve or in the left ventricle. A strong correlation (r=0.95) was found between the PEP values deter- mined by the impedance and micromanometer methods. The difference between the PEP estimates was about 5 ms. A signif- icant correlation (r=0.75-0.78) was also found between the PEP and invasive indices of left ventricular contractility, dP/dt|max and dP/dt|max/P. It was observed for a variety of the baseline states added with those during dopamine or ketamine injec- tions. The contractility changes induced by a number of sub- stances were evaluated by the invasive and impedance methods, which showed very similar time course of the responses. Mean- while, the diastolic filling of the heart or changes in the arterial pressure during the tilt test or caused by a hypotensive agent may also affect PEP. Our findings suggest that impedance method can provide an accurate estimation of PEP changes in animal experiments. So, it can be a useful tool for quantifying potential inotropic effects of pharmacological agents. However, it should be also taken into consideration the dependency of PEP on the preload and afterload conditions, especially, when vaso- dilation effects persist.

Recently there was a tendency to increase usage of double poling during cross country skiing and accordingly to increase loading of the arm muscles. The aim of the study was to compare the aerobic performance of cross country skiers in the incremental double poling and running tests till exhaustion. Eight junior subnational level cross country skiers ( V(O)2max 70 (66-72) ml/min/kg) have participated in the study. The rate of blood lactate increase during double poling test was higher than during running test. Double poling V(O)2peak was 88 (84-93)% from running V(O)2max. Relative anaerobic threshold (% V(O)2max at AT), closely linked to the current aerobic performance, was substantially lower in double poling test compared with running test: 79 (57-83)% and 94 (90-98)% respectively. We suggest that the main reserve for further increase of aerobic performance of cross country skiers lies in an increase of double poling aerobic capacity.

The goal of this study was to approbate a strength training protocol designed to improve motor skills at the maximum voluntary contraction (MVC) without hypertrophy of muscles. The main difference between this protocol and classical strength training was that the number of movements during a training session was increased to improve the motor skill, and the rest periods between the training movements were increased in order to minimize the damage of muscle fibers, which is one of the factors inducing muscle hypertrophy. Eleven subjects trained knee extensors of the right leg four times a week during four weeks. The evaluation of strength and speed characteristics with simultaneous recording the EMG activity was performed in both trained and untrained legs immediately before, during, and several times after the whole training period. Before and after the four-week training period, the size and contractile properties of the trained and contralateral knee extensors were evaluated by MRI and twitch interpolation technique. The maximal strength gains were about 17% in both trained and untrained legs; they did not differ significantly from each other. Noticeable increases in the EMG activity during the training period were observed. These changes were not accompanied by any significant changes in the muscle size, which demonstrates the “neural” nature of the training effects.

The effects of four-day dry immersion on metaboreflex regulation of hemodynamics were evaluated during local static exercise (30% of the maximum voluntary contraction) of the calf plantar flexors. One group of immersed subjects received low-frequency electrostimulation of their leg muscles to decrease the immersion effect on the EMG of exercising muscles. Metaboreflex regulation was evaluated by comparison of cardiovascular responses to physical loads with and without post-exercise circulatory occlusion. Immersion slightly increased the heart rate (HR) and reduced the systolic blood pressure in resting subjects; however, it did not have a distinct effect on blood pressure (BP) and HR during exercise or metaboreflex potentiation of hemodynamic shifts.

A chronic respiratory load was produced in Wistar rats by tracheal binding to produce a twofold increase of pleural pressure oscillation amplitude during respiration. Eight weeks after the surgery, a higher proportion of type-I muscle fibers (MFI) in the costal diaphragm along with a greater MFI cross-section area and a higher succinate dehydrogenase activity in MFII in the lumbar diaphragm were observed. During recording the mechanical activity of ring preparations of diaphragm arteries under isometric conditions, an increase in endothelium-dependent relaxation was found, whereas endothelium-independent relaxation and arterial reactivity to noradrenaline did not change. Tracheal binding did not produce any changes of MF in the gastrocnemius muscle, but endothelium-dependent relaxation of gastrocnemius feed arteries was reduced. We conclude that chronic respiratory load affects the endothelial function in diaphragm arteries in a manner favorable for blood flow control in the diaphragm. Functional alterations in gastrocnemius arteries may be associated with the reduced locomotor activity of operated rats.

Most studies examining the molecular mechanisms underlying adaptation of human skeletal muscles to aerobic exercise focused on the response to acute exercise. Here, we examined the effect of a 2‐month aerobic training program on baseline parameters in human muscle. Ten untrained males performed a one‐legged knee extension exercise for 1 h with the same relative intensity before and after a 2‐month aerobic training program. Biopsy samples were taken from vastus lateralis muscle at rest before and after the 2 month training program (baseline samples). Additionally, biopsy samples were taken from the exercised leg 1 and 4 h after the one‐legged continuous knee extension exercise. Aerobic training decreases baseline phosphorylation of FOXO1Ser256, increases that of CaMKIIT hr286, CREB1Ser133, increases baseline expression of mitochondrial proteins in respiratory complexes I–V, and some regulators of mitochondrial biogenesis (TFAM, NR4A3, and CRTC2). An increase in the baseline content of these proteins was not associated with a change in baseline expression of their genes. The increase in the baseline content of regulators of mitochondrial biogenesis (TFAM and NR4A3) was associated with a transient increase in transcription after acute exercise. Contrariwise, the increase in the baseline content of respiratory proteins does not seem to be regulated at the transcriptional level; rather, it is associated with other mechanisms. Adaptation of human skeletal muscle to regular aerobic exercise is associated not only with transient molecular responses to exercise, but also with changes in baseline phosphorylation and expression of regulatory proteins.

The aim of the study was to check the hypothesis that elite endurance athletes (junior and national team) show the decreased final blood lactate concentration after incremental test till exhaustion with increased aerobic performance level. 20 physical active men and 45 elite middle and long distance endurance athletes (speed skaters, triathletes, cross country skiers) participated in the study. Significant negative correlations (r = -0.59--0.87) were found between final blood lactate concentration after incremental test till exhaustion and aerobic performance (anaerobic threshold (AT)) for athletes groups and not for physically active subjects. Moreover the less final blood lactate concentration and more VO2 at AT have elite speed skates, the higher volume of type I muscle fibers in working muscle they have (r = -0.84 and r = 0.7, accordingly).

The effects of low-intensity strength training without relaxation (LISTR) on the force-velocity properties of hip and knee extensor muscles, the power endurance of the knee extensor muscles, and the aerobic performance of the body were studied. The difference between the LISTR and classical strength training (CST) is that the working muscle groups do not relax at the extreme points of the range of motion. The study was performed in two groups each comprising nine young physically active men who trained three times a week for eight weeks. The study showed that LISTR increased the maximum voluntary force to about the same extent as CST, but this was achieved with lower training loads. Moreover, LISTR did not lead to a decrease in the local muscular work capacity, which is usually observed during CST.

Dynamics of the delayed-onset muscle soreness after the exercise on a bicycle ergometer with floating seat under predominantly concentric and eccentric conditions was evaluated using three different tests. Depending on the used test, the maximum delayed-onset muscle soreness was recorded on days 1 to 3 after the exercise without significant differences between the groups performing concentric and eccentric work. A trend of a slower development of both the delayed onset of muscle soreness and the corresponding recovery was recorded by the test with a passive pressure on the working muscle group (knee joint extensor muscles). A positive correlation between the delayed-onset muscle soreness and the relative work intensity was found; the relative intensity was assessed according to the decrease in strength during the recovery period. No correlation between the delayed-onset muscle soreness and exercise duration was detected.

The results of studies of influence of mechanostimulation of the soles’ support zones on the effects of micro-gravity in the motor system are presented. It was shown that mechanostimulation of the soles’ support zones in the regimen of slow and fast walking, every day during 7 days of dry immersion (DI), eliminates fully or suppresses considerably the effects of micro-gravity. Decrease of the force–velocity properties or atrophic changes in the leg extensors were not developed after exposure to simulated micro-gravity in the subjects who “walked” 20 min of each hour six times a day; the transverse stiffness was only slightly lowered and the amplitude of electromyographic activity at rest stayed unchanged. The level of orthostatic deficiency in this group was also lower than in the group without stimulation. These experimental results being in full agreement with previous studies point out to the leading role of the support deafferentation in gravitational deprivation of the tonic muscle system's activity and thus that adequate mechanostimulation of the soles’ support zones can be proposed as a countermeasure against the negative effects of weightlessness.

Conditions during spaceflight, such as the loss of the head-to-foot gravity vector, are thought to potentially alter cerebral blood flow and vascular resistance. The purpose of the present study was to determine the effects of long-term spaceflight on the functional, mechanical, and structural properties of cerebral arteries. Male C57BL/6N mice were flown 30 days in a Bion-M1 biosatellite. Basilar arteries isolated from spaceflight (SF) ( n = 6), habitat control (HC) ( n = 6), and vivarium control (VC) ( n = 16) mice were used for in vitro functional and mechanical testing and histological structural analysis. The results demonstrate that vasoconstriction elicited through a voltage-gated Ca2+ mechanism (30–80 mM KCl) and thromboxane A2 receptors (10−8 − 3 × 10−5 M U46619) are lower in cerebral arteries from SF mice. Inhibition of Rho-kinase activity (1 μM Y27632) abolished group differences in U46619-evoked contractions. Endothelium-dependent vasodilation elicited by acetylcholine (10 μM, 2 μM U46619 preconstriction) was virtually absent in cerebral arteries from SF mice. The pressure-diameter relation was lower in arteries from SF mice relative to that in HC mice, which was not related to differences in the extracellular matrix protein elastin or collagen content or the elastin/collagen ratio in the basilar arteries. Diameter, medial wall thickness, and medial cross-sectional area of unpressurized basilar arteries were not different among groups. These results suggest that the microgravity-induced attenuation of both vasoconstrictor and vasodilator properties may limit the range of vascular control of cerebral perfusion or impair the distribution of brain blood flow during periods of stress.

This paper deals with the typology of surface texture expressions, such as a slippery road, a smooth wooden board, rough hands, coarse or rough fabric. We discuss both their direct uses and metaphors formed with them, such as a slippery person, a smooth speech, a rugged captain. Our language sample includes 10 Uralic languages (Finnish, Estonian, Mari, Erzya, Moksha, Udmurt, Komi-Zyrjan, Hungarian, Khanty, Nenets), as well as 5 languages from other families (Russian, English, Spanish, Chinese, and Korean). The categorisation of these attributes includes primarily the division into visually perceived surfaces and surfaces perceived through physical contact. We discuss how much and in what ways the antonymic areas under observation are asymmetrical in their semantic features and combinability. One more focus in this research is to evaluate texture lexicon variation in an intragenetic study of a group of related languages in comparison with its variation across a broader sample of languages.