Age-Related Changes in Extracellular Matrix.

Extracellular matrix (ECM) is an extracellular tissue structure that, in addition to mechanical support to the cell, is involved in regulation of many cellular processes, including chemical transport, growth, migration, differentiation, and cell senescence. Age-related changes in the structure and composition of the matrix and increase of ECM stiffness with age affect functioning of many tissues and contribute to the development of various pathological conditions. This review considers age-related changes of ECM in various tissues and organs, in particular, effect of ECM changes on aging is discussed.

A new method to measure oxygenator oxygen transfer performance during cardiopulmonary bypass: clinical testing using the Medtronic Fusion oxygenator.

BACKGROUND: There is no acceptable method of testing oxygen transfer performance in membrane oxygenators quickly and easily during cardiopulmonary bypass. Pre-clinical testing of oxygenators is performed under controlled situations in the laboratory, correlating oxygen transfer to blood flow using 100% oxygen. This laboratory method cannot be used clinically as oxygen transfer values vary significantly at each blood flow and the FiO2 is not kept at 1. Therefore, a formula was developed which corrects the existing FiO2 to attain a PaO2 of 150 mmHg: the corrected FiO2 at 150 mmHg. In graph form, this corrected FiO2 (x-axis) is correlated to the patient's oxygen consumption levels (y-axis), which determines the membrane oxygenator oxygen transfer performance. METHODS: Blood gas and hemodynamic parameters taken during cardiopulmonary bypass using the Medtronic Fusion were used to calculate the oxygen consumption (inlet conditions to the oxygenator) and the corrected FiO2 for a PaO2 of 150 mmHg. Validation of the formula "FiO2-PaO2/(Pb-pH2O)+0.21" was carried out by plotting the calculated values on a graph using PaO2 values between 145 to 155 mmHg and then, using the corrected FiO2 for PaO2s outside of this range. RESULTS: All trend-lines correlated significantly to confirm that the Medtronic Fusion had an extrapolated oxygen transfer of 419 milliliters O2/min at an FiO2 of 1 to achieve a PaO2 of 150 mmHg. CONCLUSIONS: Use of the corrected FiO2 correlated to the oxygen transfer conditions of the membrane oxygenator can easily be used on a routine basis, providing valuable information clinically. When used by the manufacturer under laboratory conditions, further clinically relevant data is provided in terms of FiO2 and resultant PaO2s instead of the present limitations using blood flow. In this way, a clinically justifiable method has been developed to finally establish a standard in testing membrane oxygenator performance.

Antiferromagnetic Spin Seebeck Effect.

We report on the observation of the spin Seebeck effect in antiferromagnetic MnF_{2}. A device scale on-chip heater is deposited on a bilayer of MnF_{2} (110) (30 nm)/Pt (4 nm) grown by molecular beam epitaxy on a MgF_{2} (110) substrate. Using Pt as a spin detector layer, it is possible to measure the thermally generated spin current from MnF_{2} through the inverse spin Hall effect. The low temperature (2-80 K) and high magnetic field (up to 140 kOe) regime is explored. A clear spin-flop transition corresponding to the sudden rotation of antiferromagnetic spins out of the easy axis is observed in the spin Seebeck signal when large magnetic fields (>9 T) are applied parallel to the easy axis of the MnF_{2} thin film. When the magnetic field is applied perpendicular to the easy axis, the spin-flop transition is absent, as expected.

Phase diagram of a three-dimensional antiferromagnet with random magnetic anisotropy.

Three-dimensional antiferromagnets with random magnetic anisotropy (RMA) that have been experimentally studied to date have competing two-dimensional and three-dimensional exchange interactions which can obscure the authentic effects of RMA. The magnetic phase diagram of Fe_{x}Ni_{1-x}F_{2} epitaxial thin films with true random single-ion anisotropy was deduced from magnetometry and neutron scattering measurements and analyzed using mean-field theory. Regions with uniaxial, oblique, and easy-plane anisotropies were identified. A RMA-induced glass region was discovered where a Griffiths-like breakdown of long-range spin order occurs.

3D Printing Soft Magnet: Binder Study for Vat Photopolymerization of Ferrosilicon Magnetic Composites.

Liquid Crystal Display (LCD) masking is a 3D printing technique that can produce soft magnetic composite parts to high resolution and complexity for robotics and energy electronics applications. This additive manufacturing technique has the potential to produce larger, lighter-weight, more efficient, and more durable parts for automotive and mechanical applications. This study conducted a binder study to create a low-viscosity and stiff binder capable of loading at least 60 v/v% Fe-6.5 wt%Si particles. Percolation Theory was applied to anticipate the magnetic interaction of suspended particles. A series of binders were formulated, with adjustments to diluent ratios. The behavior of the binders was assessed by studying their rheological properties, conversion rates, and mechanical properties. A post-cure study was conducted across various energy settings using UV, thermal, and a combination of both energy sources to find the combination that provided the best mechanical properties. As a result, 64 v/v% Fe-6.5 wt%Si loading was achieved and cured using UV light of 405 nm wavelength. Vibrating Sample Spectroscopy (VSM) was used to characterize the composite's magnetic behavior, and a significant increase in saturation magnetization and negligible change in coercivity was observed when the added load exceeded the percolation threshold.

4D Visualization of a Nonthermal Coherent Magnon in a Laser Heated Lattice by an X-ray Free Electron Laser.

Ultrafast optical manipulation of magnetic phenomena is an exciting achievement of mankind, expanding one's horizon of knowledge toward the functional nonequilibrium states. The dynamics acting on an extremely short timescale push the detection limits that reveal fascinating light-matter interactions for nonthermal creation of effective magnetic fields. While some cases are benchmarked by emergent transient behaviors, otherwise identifying the nonthermal effects remains challenging. Here, a femtosecond time-resolved resonant magnetic X-ray diffraction experiment is introduced, which uses an X-ray free-electron laser (XFEL) to distinguish between the effective field and the photoinduced thermal effect. It is observed that a multiferroic Y-type hexaferrite exhibits magnetic Bragg peak intensity oscillations manifesting entangled antiferromagnetic (AFM) and ferromagnetic (FM) Fourier components of a coherent AFM magnon. The magnon trajectory constructed in 3D space and time domains is decisive to evince ultrafast field formation preceding the lattice thermalization. A remarkable impact of photoexcitation across the electronic bandgap is directly unraveled, amplifying the photomagnetic coupling that is one of the highest among AFM dielectrics. Leveraging the above-bandgap photoexcitation, this energy-efficient optical process further suggests a novel photomagnetic control of ferroelectricity in multiferroics.

Artificial construction of the layered Ruddlesden-Popper manganite La2Sr2Mn3O10 by reflection high energy electron diffraction monitored pulsed laser deposition.

Pulsed laser deposition has been used to artificially construct the n = 3 Ruddlesden-Popper structure La(2)Sr(2)Mn(3)O(10) in epitaxial thin film form by sequentially layering La(1-x)Sr(x)MnO(3) and SrO unit cells aided by in situ reflection high energy electron diffraction monitoring. The interval deposition technique was used to promote two-dimensional SrO growth. X-ray diffraction and cross-sectional transmission electron microscopy indicated that the trilayer structure had been formed. A site ordering was found to differ from that expected thermodynamically, with the smaller Sr(2+) predominantly on the R site due to kinetic trapping of the deposited cation sequence. A dependence of the out-of-plane lattice parameter on growth pressure was interpreted as changing the oxygen content of the films. Magnetic and transport measurements on fully oxygenated films indicated a frustrated magnetic ground state characterized as a spin glass-like magnetic phase with the glass temperature T(g) ≈ 34 K. The magnetic frustration has a clear in-plane (ab) magnetic anisotropy, which is maintained up to temperatures of 150 K. Density functional theory calculations suggest competing antiferromagnetic and ferromagnetic long-range orders, which are proposed as the origin of the low-temperature glassy state.

Testosterone for Managing Treatment-related Fatigue in Patients With Metastatic Renal Cell Carcinoma: A Phase 2 Randomized Study FARETES.

BACKGROUND: Fatigue is one of the most common adverse events of systemic therapy in patients with metastatic renal cell carcinoma (RCC). The aim of multicenter randomized phase 2 study was to determine the efficacy and safety of testosterone in patients with fatigue developed during targeted therapy. PATIENTS AND METHODS: Male patients with metastatic clear-cell RCC, normal prostate-specific antigen level, low testosterone level, and no evidence of hypothyroidism receiving first-line sunitinib or pazopanib with fatigue were randomly assigned (1:1) to either testosterone undecanoate (1000 mg) and targeted therapy or targeted therapy alone. The primary endpoint was the mean change of fatigue from baseline to 28 days according to the Functional Assessment of Chronic Illness Therapy-Fatigue scale. Secondary endpoints were safety, Functional Assessment of Cancer Therapy-Kidney Symptom Index 19, testosterone serum concentrations, red blood cell count, and hemoglobin level. RESULTS: Sixty patients were assigned to receive testosterone and targeted therapy (N=30) or targeted therapy alone (N=30). As of the data cutoff on December 30, 2019, median follow-up was 18.2 months. The study achieved its primary endpoint based on the significant differences at day 28 favoring testosterone over targeted therapy alone regarding the decreased level of fatigue (difference between groups, 22.5 points; 95% confidence interval, 18.4-26.6; P=0.012). Significant changes in scores demonstrating the enhanced quality of life with testosterone compared with targeted therapy were also observed for Functional Assessment of Cancer Therapy-Kidney Symptom Index 19 disease-related symptoms (P=0.01). There were nonsignificant differences in red blood cell count and hemoglobin level between the 2 groups (all P>0.05). CONCLUSION: Male patients with metastatic RCC and hypogonadism receiving testosterone had less fatigue and better symptom control during targeted therapy.

Genetic testing for homologous recombination repair (HRR) in metastatic castration-resistant prostate cancer (mCRPC): challenges and solutions.

Patients with metastatic castration-resistant prostate cancer (mCRPC) have an average survival of only 13 months. Identification of novel predictive and actionable biomarkers in the homologous recombination repair (HRR) pathway in up to a quarter of patients with mCRPC has led to the approval of targeted therapies like poly-ADP ribose polymerase inhibitors (PARPi), with the potential to improve survival outcomes. The approval of PARPi has led to guideline bodies such as the National Comprehensive Cancer Network (NCCN) to actively recommend germline and or somatic HRR gene panel testing to identify patients who will benefit from PARPi. However, there are several challenges as genetic testing is still at an early stage especially in low- and middle-income countries, with cost and availability being major impediments. In addition, there are issues such as choice of optimal tissue for genetic testing, archival, storage, retrieval of tissue blocks, interpretation and classification of variants in the HRR pathway, and the need for pretest and post-test genetic counseling. This review provides insights into the HRR gene mutations prevalent in mCRPC and the challenges for a more widespread gene testing to identify actionable germline pathogenic variants and somatic mutations in the HRR pathway, and proposes a clinical algorithm to enhance the efficiency of the gene testing process.

Safety and preliminary efficacy of the Gam-COVID-Vac vaccine and outcomes of SARS-CoV-2 infection in Russian patients with genitourinary malignancies.

BACKGROUND: To our knowledge, there is no clinical data pertaining to COVID-19 outcomes and safety of COVID-19 vaccination in Russian patients with genitourinary (GU) malignancies. Aim of our analysis was to describe the characteristics of the COVID-19 infection course as well as preliminary safety and efficacy of Gam-COVID-Vac vaccine in patients with active GU malignancies. METHODS: Patients were retrospectively identified at nine cancer centers in different regions. Patients were included if COVID-19 was diagnosed by a polymerase chain reaction. Data from additional patients with GU cancers who had no positive SARS-CoV-2 RT-PCR test before vaccination and who received two doses of Gam-COVID-Vac (Sputnik V) between 11 February and 31 August 2021 were collected for safety assessment. Anonymized data were collected through an online registry covering demographics, treatments, and outcomes. RESULTS: The Gam-COVID-Vac vaccine was well tolerated; no grade 3-5 toxicities were reported in 112 vaccinated metastatic GU cancer patients. The most common grade 1 adverse events (81%) were injection site reactions (76%), flu-like illness (68%), and asthenia (49%). Five patients experienced grade 2 chills (4.5%) and 3 patients had grade 2 fever (2.7%). With median follow-up of 6.2 months, two COVID-19 cases were confirmed by RT-PCR test in the vaccine group (of 112 participants; 1.8%). Eighty-eight patients with COVID-19 disease were included in the analysis. The average age as of the study enrollment was 66 (range 39-81) and the majority of patients were male with renal cell carcinoma (RCC). Thirty-six patients (41%) had evidence of metastatic disease, of these 22 patients were receiving systemic therapy. More than half of patients required hospitalization. Fifty-four patients (61%) experienced complications. Sixteen patients who developed COVID-19 pneumonia required mechanical ventilator support. Sixteen patients (18%) died in a median of 23.5 days after the date of COVID-19 diagnosis was established. The 3-month survival rate was 82%. Clinical and/or radiographic progression of cancer during COVID-19 infection or the subsequent 3 months was observed in 10 patients (11.4%). CONCLUSION: Patients with GU malignancies are at increased risk of mortality from COVID-19 infection when compared to the general population. Vaccination could be safe in GU cancer patients. TRIAL REGISTRATION: retrospectively registered.

Phase 2 Multicenter Single-Arm Study of Second-Line Axitinib in Favorable Risk Patients with Metastatic Renal Cell Carcinoma: FavorAx.

BACKGROUND: Targeted therapy with axitinib resulted in a greater objective response rate and prolonged progression-free survival (PFS) compared to sorafenib in patients with previously treated metastatic renal cell carcinoma (mRCC) in the phase 3 AXIS study, where 75% of patients had intermediate and poor International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk. OBJECTIVE: In this phase 2 study (FavorAx), we assessed the activity of axitinib in mRCC patients with a favorable risk and history of prior vascular endothelial growth factor receptor (VEGFR)-directed therapy. PATIENTS AND METHODS: Patients were required to have clear-cell mRCC, favorable risk according to IMDC criteria, and to have received first-line treatment with sunitinib or pazopanib. Prior treatment with other agents was not permitted. The primary endpoint of the study was 5 months PFS. Additional endpoints included response rate, safety, PFS, and overall survival (OS). RESULTS: A total of 21 patients were enrolled, 62% of whom were male. The mean age was 60 years. Eleven (52%) patients had two or more metastatic sites. 67% and 33% of patients received first-line sunitinib or pazopanib, respectively, with a median PFS of 17 months [95% confidence interval (CI), 14-20]. After a median follow-up of 25 months, the median PFS was 19 months (95% CI, 15-23). The current study did achieve its primary endpoint based on the 5-month PFS of 100%. The median OS was not yet reached. The 18 months OS rate was 85.7%. The objective response rate was 33% and one patient achieved a complete response. Seven patients had dose escalation of axitinib and four patients had dose reduction. Grade 3 adverse events were observed in 19% of cases. There was no discontinuation of therapy due to toxicity. CONCLUSIONS: The encouraging PFS and favorable safety profile observed in the FavorAx study support the administration of axitinib in mRCC patients with favorable IMDC risk and a history of prior sunitinib or pazopanib.

Room temperature ferroelectricity in fluoroperovskite thin films.

The NaMnF3 fluoride-perovskite has been found, theoretically, to be ferroelectric under epitaxial strain becoming a promising alternative to conventional oxides for multiferroic applications. Nevertheless, this fluoroperovskite has not been experimentally verified to be ferroelectric so far. Here we report signatures of room temperature ferroelectricity observed in perovskite NaMnF3 thin films grown on SrTiO3. Using piezoresponse force microscopy, we studied the evolution of ferroelectric polarization in response to external and built-in electric fields. Density functional theory calculations were also performed to help understand the strong competition between ferroelectric and paraelectric phases as well as the profound influences of strain. These results, together with the magnetic order previously reported in the same material, pave the way to future multiferroic and magnetoelectric investigations in fluoroperovskites.

Five-year Survival of Patients With Metastatic Renal Cell Carcinoma in the Russian Federation: Results From the RENSUR5 Registry.

BACKGROUND: The 5-year overall survival (OS) of patients with metastatic renal cell carcinoma (mRCC) has been rarely reported. The aim of the RENSUR5 registry study was to obtain real-world data on the use of therapy for mRCC and assess the 5-year OS in the Russian population. PATIENT AND METHODS: Patients were retrospectively identified at 11 cancer centers in different regions of Russia (Astrakhan, Barnaul, Ekaterinburg, Kazan, Krasnoyarsk, Obninsk, Omsk, Rostov-on-Don, Samara, St. Petersburg, and Ufa). Patients were included if mRCC had been diagnosed from January 2010 to January 2011. Anonymized data were collected through an online registry covering the demographic data, treatments, and outcomes. RESULTS: A total of 439 adult mRCC patients were included in the present study for analysis. The mean age at diagnosis of mRCC was 60.9 years (range, 33-90 years; with 9% of patients aged ≥ 75 years). The patients were predominantly men (70.2%) and 67.7% had nephrectomy. Clear cell and non-clear cell tumors were detected in 61.1% and 7.7% of patients, respectively. A total of 271 patients (62%) received systemic therapy. The median duration of therapy was 11 months (95% confidence interval, 9.5-12.5 months). Most treatment was with interferon only (n = 145); 105 patients (23.9%) received targeted therapy, and 69 patients (15.7%) received ≥ 2 treatment lines. The 1-, 3-, and 5-year OS rate was 49.4%, 18.9%, and 8.2%, respectively. The median OS from the start of treatment was 12 months (95% confidence interval, 9.7-14.4 months). CONCLUSION: RENSUR5 is a large real-world database assessing the mRCC treatment patterns and 5-year OS in Russia. According to the first results of the present study, we believe that 5-year OS should improve with novel therapies. The limited administration of targeted therapies was reflected by the results of the 5-year survival rate. The treatment of mRCC has changed in the past years with new treatment options significantly improving OS. The 5-year OS of patients treated with immunotherapy and targeted therapy should be analyzed in the real world.

Multiferroic BaCoF4 in Thin Film Form: Ferroelectricity, Magnetic Ordering, and Strain.

Multiferroic materials have simultaneous magnetic and ferroelectric long-range orders and can be potentially useful for a wide range of applications. Conventional ferroelectricity in oxide perovskites favors nonmagnetic electronic configurations of transition metal ions, thus limiting the number of intrinsic multiferroic materials. On the other hand, this is not necessarily true for multiferroic fluorides. Using molecular beam epitaxy, we demonstrate for the first time that the multiferroic orthorhombic fluoride BaCoF4 can be synthesized in thin film form. Ferroelectric hysteresis measurements and piezoresponse force microscopy show that the films are indeed ferroelectric. From structural information, magnetic measurements, and first-principles calculations, a modified magnetic ground state is identified which can be represented as a combination of bulk collinear antiferromagnetism with two additional canted spin orders oriented along orthogonal axes of the BaCoF4 unit cell. The calculations indicate that an anisotropic epitaxial strain is responsible for this unusual magnetic ground state.

Magnetic materials. Tilt engineering of spontaneous polarization and magnetization above 300 K in a bulk layered perovskite.

Crystalline materials that combine electrical polarization and magnetization could be advantageous in applications such as information storage, but these properties are usually considered to have incompatible chemical bonding and electronic requirements. Recent theoretical work on perovskite materials suggested a route for combining both properties. We used crystal chemistry to engineer specific atomic displacements in a layered perovskite, (Ca(y)Sr(1- y))(1.15)Tb(1.85)Fe2O7, that change its symmetry and simultaneously generate electrical polarization and magnetization above room temperature. The two resulting properties are magnetoelectrically coupled as they arise from the same displacements.

Electric in-plane polarization in multiferroic CoFe2O4/BaTiO3 nanocomposite tuned by magnetic fields.

Ferrimagnetic CoFe2O4 nanopillars embedded in a ferroelectric BaTiO3 matrix are an example for a two-phase magnetoelectrically coupled system. They operate at room temperature and are free of any resource-critical rare-earth element, which makes them interesting for potential applications. Prior studies succeeded in showing strain-mediated coupling between the two subsystems. In particular, the electric properties can be tuned by magnetic fields and the magnetic properties by electric fields. Here we take the analysis of the coupling to a new level utilizing soft X-ray absorption spectroscopy and its associated linear dichroism. We demonstrate that an in-plane magnetic field breaks the tetragonal symmetry of the (1,3)-type CoFe2O4/BaTiO3 structures and discuss it in terms of off-diagonal magnetostrictive-piezoelectric coupling. This coupling creates staggered in-plane components of the electric polarization, which are stable even at magnetic remanence due to hysteretic behaviour of structural changes in the BaTiO3 matrix. The competing mechanisms of clamping and relaxation effects are discussed in detail.

Multiferroic and magnetoelectric materials--novel developments and perspectives.

Magnetoelectric (ME) materials are of utmost interest in view of both fundamental understanding and novel desirable applications. Despite its smallness, the linear ME effect has been shown to control spintronic devices very efficiently, e.g., by using the classic ME antiferromagnet Cr2O3. Similar nano-engineering concepts exist also for type-I multiferroic single phase materials like BiFeO3 and BiMnO3. Record high ME response has been realized in stress-strain coupled multiphase magnetoelectrics like PZT/FeBSiC composites, enabling applications in sensors. In type-II multiferroics, whose ferroelectricity is due to modulated magnetic ordering, the ME coupling is of fundamental interest. Higher-order ME response characterizes disordered systems, which extend the conventional multiferroic scenario toward ME multiglass (e.g., Sr(1-x)MnxTiO3).

Magnetoelectric switching of exchange bias.

The perpendicular exchange bias field, H(EB), of the magnetoelectric heterostructure Cr2O3(111)/(Co/Pt)(3) changes sign after field cooling to below the Néel temperature of Cr2O3 in either parallel or antiparallel axial magnetic and electric freezing fields. The switching of H(EB) is explained by magnetoelectrically induced antiferromagnetic single domains which extend to the interface, where the direction of their end spins controls the sign of H(EB). Novel applications in magnetoelectronic devices seem possible.