Nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended follow-up from the phase III randomised CheckMate 9ER trial.

BACKGROUND: Nivolumab plus cabozantinib (NIVO + CABO) was approved for first-line treatment of advanced renal cell carcinoma (aRCC) based on superiority versus sunitinib (SUN) in the phase III CheckMate 9ER trial (18.1 months median survival follow-up per database lock date); efficacy benefit was maintained with an extended 32.9 months of median survival follow-up. We report updated efficacy and safety after 44.0 months of median survival follow-up in intent-to-treat (ITT) patients and additional subgroup analyses, including outcomes by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk score. PATIENTS AND METHODS: Patients with treatment-naïve aRCC received NIVO 240 mg every 2 weeks plus CABO 40 mg once daily or SUN 50 mg for 4 weeks (6-week cycles), until disease progression/unacceptable toxicity (maximum NIVO treatment, 2 years). Primary endpoint was progression-free survival (PFS) per blinded independent central review (BICR). Secondary endpoints were overall survival (OS), objective response rate (ORR) per BICR, and safety and tolerability. RESULTS: Overall, 323 patients were randomised to NIVO + CABO and 328 to SUN. Median PFS was improved with NIVO + CABO versus SUN [16.6 versus 8.4 months; hazard ratio (HR) 0.59; 95% confidence interval (CI) 0.49-0.71]; median OS favoured NIVO + CABO versus SUN (49.5 versus 35.5 months; HR 0.70; 95% CI 0.56-0.87). ORR (95% CI) was higher with NIVO + CABO versus SUN [56% (50% to 62%) versus 28% (23% to 33%)]; 13% versus 5% of patients achieved complete response, and median duration of response was 22.1 months versus 16.1 months, respectively. PFS and OS favoured NIVO + CABO over SUN across intermediate, poor and intermediate/poor IMDC risk subgroups; higher ORR and complete response rates were seen with NIVO + CABO versus SUN regardless of IMDC risk subgroup. Any-grade (grade ≥3) treatment-related adverse events occurred in 97% (67%) versus 93% (55%) of patients treated with NIVO + CABO versus SUN. CONCLUSIONS: After extended follow-up, NIVO + CABO maintained survival and response benefits; safety remained consistent with previous follow-ups. These results continue to support NIVO + CABO as a first-line treatment for aRCC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03141177.

Pharmacological Properties of Sulfonamide Derivatives, New Inhibitors of Carbonic Anhydrase.

Selective blocking of individual isoforms of carbonic anhydrase (CA) is now one of the main directions in the development of its inhibitors. The new 1,2,4-oxadiazole-containing sulfonamides B12 and B13 predominantly block CA II and CA IX. The study of acute toxicity of B12 and B13 showed their safety. Substance B13 caused a relatively short-term, but rapid (within 30 min) decrease in the intraocular pressure in rabbits, which indicates the promise of its use for the emergency decrease in the intraocular pressure in medical practice. Analysis of the effects of sulfonamides on the functions of CNS showed that compound B12 probably exhibit tranquilizing activity; B13 is promising for the creation of drugs that have an antidepressant effect and at the same time increase the mental and physical performance.

350 mJ electro-optically Q-switched 2.79†µm Cr:Er:YSGG MOPA.

We report on developing three flashlamp-pumped electro-optically Q-switched Cr:Er:YSGG lasers with the Q-switch based on a La3Ga5SiO14 crystal. The "short" laser cavity was optimized for high peak power applications. In this cavity, 300 mJ output energy in 15 ns pulses at a 3 Hz repetition rate was demonstrated with pump energy below 52 J. However, several applications, such as Fe:ZnSe pumping in a gain-switched regime, require longer (∼ 100 ns) pump pulse duration. We developed a 2.9 m long laser cavity that delivers 190 mJ of output energy in 85 ns pulses for these applications. We also demonstrated the Cr:Er:YSGG MOPA system producing 350 mJ output energy at 90 ns pulse duration and 47.5 J of pumping, corresponding to an amplification factor of 3.

Extremely high frequency Schottky diodes based on single GaN nanowires.

Gallium nitride (GaN) is one of the most promising materials for high-frequency devices owing to its prominent material properties. We report on the fabrication and study of a series of Schottky diodes in the ground-signal-ground topology based on individual GaN nanowires. The electrical characterization ofI-Vcurves demonstrated relatively high ideality factor value (about 6-9) in comparison to the planar Au/GaN diodes that can be attributed to the nanowire geometry. The effective barrier height in the studied structures was defined in the range of 0.25-0.4 eV. The small-signal frequency analysis was employed to study the dependency of the scattering parameters in the broad range from 0.1 to 40 GHz. The approximation fitting of the experimental data indicated the record high cutoff frequency of about 165.8 GHz.

Formation of wurtzite sections in self-catalyzed GaP nanowires by droplet consumption.

Wurtzite GaP nanowires are interesting for the direct bandgap engineering and can be used as templates for further growth of hexagonal Si shells. Most wurtzite GaP nanowires have previously been obtained with Au catalysts. Here, we show that long (∼500 nm) wurtzite sections are formed in the top parts of self-catalyzed GaP nanowires grown by molecular beam epitaxy on Si(111) substrates in the droplet consumption stage, which is achieved by abruptly increasing the atomic V/III flux ratio from 2 to 3. We investigate the temperature dependence of the length of wurtzite sections and show that the longest sections are obtained at 610 °C. A supporting model explains the observed trends using a phase diagram of GaP nanowires, where the wurtzite phase is formed within a certain range of the droplet contact angles. The optimal growth temperature for growing wurtzite nanowires corresponds to the largest diffusion length of Ga adatoms, which helps to maintain the required contact angle for the longest time.

Fabrication and electrical study of large area free-standing membrane with embedded GaP NWs for flexible devices.

Flexible optoelectronic structures are required in a wide range of applications. Large scale modified silicone-embedded n-GaP nanowire arrays of a record 6 µm thin membranes were studied. A homogeneous silicone encapsulation was enabled by G-coating using a heavy-load centrifuge. The synthesized graft-copolymers of polydimethylsiloxane (PDMS) and polystyrene demonstrated two times lower adhesion to Si compared to standard PDMS, allowing 3 square inch area high quality silicone/nanowire membrane mechanical release, preserving the growth Si substrate for a further re-use after chemical cleaning. The 90% transparent single-walled carbon nanotubes electrical contacts to the embedded n-GaP nanowires demonstrated mechanical and electrical stability. The presented methods can be used for the fabrication of large scale flexible inorganic optoelectronic devices.

Hydrogen passivation of the n-GaN nanowire/p-Si heterointerface.

The influence of hydrogen plasma treatment on the electrical and optical properties of vertical GaN nanowire (NW)/Si heterostructures synthesized via plasma assisted molecular beam epitaxy is studied. The effect of the treatment is thoroughly studied via variation of the passivation duration. Photoluminescence investigation demonstrates that the passivation affects the doping of the GaN NWs. The samples were processed as photodiodes with a top transparent electrode to obtain detailed information about the n-GaN NWs/p-Si heterointerface under illumination. The electron beam induced current measurements demonstrated the absence of potential barriers between the active parts of the diode and the contacts, indicating ohmic behavior of the latter. I-V characteristics obtained in the dark and under illumination show that hydrogen can effectively passivate the recombination centers at the GaN NWs/Si heterointerface. The optimum passivation duration, providing improved electrical properties, is found to be 10 min within the studied passivation regimes. It is demonstrated that longer treatment causes degradation of the electrical properties. The discovered phenomenon is discussed in detail.

Magnetic properties of Co-based and Fe-based tape amorphous alloys.

The description of the magnetic properties of amorphous alloys and comparison of the model evaluation with experimental data have been carried out in terms of the magnetic theory of disordered systems (Biryukov's theory). The hysteresis loops for a number of amorphous metallic glasses have been investigated and it also has been shown that Biryukov's hypothesis about the weak correlation between spin and electrostatic components is true for the amorphous magnetic system that permits to interpret collectively the results of different magnetometric experiments.

Tight focusing of electromagnetic fields by large-aperture mirrors.

We derive nonparaxial input conditions for simulations of tightly focused electromagnetic fields by means of unidirectional nonparaxial vectorial propagation equations. The derivation is based on the geometrical optics transfer of the incident electric field from significantly curved reflecting surfaces such as parabolic and conical mirrors to the input plane, with consideration of the finite thickness of the focusing element and large convergence angles, making the propagation vectorial and nonparaxial. We have benchmarked numerical solutions of propagation equations initiated with the nonparaxial input conditions against the solutions of Maxwell equations obtained by vectorial diffraction integrals. Both transverse and longitudinal components of the electric field obtained by these methods are in excellent agreement.

Transformation of ring-Airy beams during efficient harmonic generation.

We theoretically study the evolution of ring-Airy beams during harmonic generation with the focus on the regime of pump energy depletion. We demonstrate that in this regime, ring-Airy beams still preserve their abrupt autofocusing properties, while transforming to a multiple ring-Airy structure. A similar transformation is observed on the beam of the generated harmonic. We suggest a simple analytical model that explains and predicts with precision our numerical findings.

Effects of the surface preparation and buffer layer on the morphology, electronic and optical properties of the GaN nanowires on Si.

The role of Si (111) substrate surface preparation and buffer layer composition in the growth, electronic and optical properties of the GaN nanowires (NWs) synthesized via plasma-assisted molecular beam epitaxy is studied. A comparison study of GaN NWs growth on the bare Si (111) substrate, silicon nitride interlayer, predeposited AlN and GaO x buffer layers, monolayer thick Ga wetting layer and GaN seeding layer prepared by the droplet epitaxy is performed. It is demonstrated that the homogeneity and the morphology of the NW arrays drastically depend on the chosen buffer layer and surface preparation technique. An effect of the buffer and seeding layers on the nucleation and desorption is also discussed. The lowest NWs surface density of 14 µm-2 is obtained on AlN buffer layer and the highest density exceeding the latter value by more than an order of magnitude corresponds to the growth on the 0.3 ML thick Ga wetting layer. It is shown, that the highest NWs mean elongation rate is obtained with AlN buffer layer, while the lowest elongation rate corresponds to the bare Si (111) surface and it is twice as lower as the first case. It is found, that use of AlN buffer layer corresponds to the most homogeneous NWs array with the smallest length dispersion while the least homogeneous array corresponds to the bare Si substrate. Vertically aligned GaN NWs array on the wide bandgap GaO x semiconductor buffer layer grown by plasma-enhanced chemical vapor deposition demonstrates its potential for electronic applications. Photoluminescence (PL) study of the synthesized samples is characterized by an intense optical response related to the excitons bound to neutral donors. The highest PL intensity is obtained in the sample with AlN buffer layer.

Canine and human sinoatrial node: differences and similarities in the structure, function, molecular profiles, and arrhythmia.

The sinoatrial node (SAN) is the primary pacemaker in canine and human hearts. The SAN in both species has a unique three-dimensional heterogeneous structure characterized by small pacemaker myocytes enmeshed within fibrotic strands, which partially insulate the cells from aberrant atrial activation. The SAN pacemaker tissue expresses a unique signature of proteins and receptors that mediate SAN automaticity, ion channel currents, and cell-to-cell communication, which are predominantly similar in both species. Recent intramural optical mapping, integrated with structural and molecular studies, has revealed the existence of up to five specialized SAN conduction pathways that preferentially conduct electrical activation to atrial tissues. The intrinsic heart rate, intranodal leading pacemaker shifts, and changes in conduction in response to physiological and pathophysiological stimuli are similar. Structural and/or functional impairments due to cardiac diseases including heart failure cause SAN dysfunctions (SNDs) in both species. These dysfunctions are usually manifested as severe bradycardia, tachy-brady arrhythmias, and conduction abnormalities including exit block and SAN reentry, which could lead to atrial tachycardia and fibrillation, cardiac arrest, and heart failure. Pharmaceutical drugs and implantable pacemakers are only partially successful in managing SNDs, emphasizing a critical need to develop targeted mechanism-based therapies to treat SNDs. Because several structural and functional characteristics are similar between the canine and human SAN, research in these species may be mutually beneficial for developing novel treatment approaches. This review describes structural, functional, and molecular similarities and differences between the canine and human SAN, with special emphasis on arrhythmias and unique causal mechanisms of SND in diseased hearts.

High power single-mode delivery of mid-infrared sources through chalcogenide fiber.

Mechanically robust and low loss single-mode arsenic sulfide fibers are used to deliver high power mid-infrared sources. Anti-reflection coatings were deposited on the fiber facets, enabling 90% transmission through 20 cm length fibers. 10.3 W was transmitted through an anti-reflection coated fiber at 2053 nm, and uncoated fibers sustained 12 MW/cm2 intensities on the facet without failure. A Cr:ZnSe laser transmitted >1 W at 2520 nm, and a Fe:ZnSe laser transmitted 0.5 W at 4102 nm. These results indicate that by improving the anti-reflection coatings and using a high beam quality mid-infrared source, chalcogenide fibers can reliably deliver ≥10 W in a single mode, potentially out to 6.5 µm.

Static and time-resolved mid-infrared spectroscopy of Hg0.95Cd0.05Cr2Se4 spinel.

Static and time-resolved mid-infrared spectroscopy of ferromagnetic single crystal Hg0.95Cd0.05Cr2Se4 was performed below the absorption edge, in order to reveal the origin of the electronic transitions contributing to the magneto-optical properties of this material. The mid-infrared spectroscopy reveals a strong absorption peak around 0.236 eV which formerly was assigned to a transition within the selenide-chromium complexes ([Formula: see text] Se-Cr2+). To reveal the sensitivity of the transition to the magnetic order, we performed the studies in a temperature range across the Curie temperature and magnetic fields across the value at which the saturation of ferromagnetic magnetization occurs. Despite the fact that the Curie temperature of this ferromagnetic semiconductor is around 107 K, the intensity of the mid-infrared transition reduces substantially increasing the temperature, so that already at 70 K the absorption peak is hardly visible. Such a dramatic decrease of the oscillator strength is observed simultaneously with the strong red-shift of the absorption edge in the magnetic semiconductor. Employing a time-resolved pump-and-probe technique enabled us to determine the lifetime of the electrons in the excited state of this optical transition. In the temperature range from 7 K to 80 K, the lifetime changes from 3 ps to 6 ps. This behavior agrees with the phenomenon of giant oscillator strength described earlier for weakly bound excitons in nonmagnetic semiconductors.

[Dynamics of Reaching Imago Stage by F1 Animals after Terahertz Irradiation of Parental Drosophila].

Terahertz radiation (0.1­10 THz) is increasingly becoming a factor of human habitat. The study of the consequences of radiation allows one to estimate its possible biological danger. Our data indicate that the terahertz irradiation of parental Drosophila shortens the period of embryonic development of their first generation descendants. Significant deviations of data from the control were found, when both females and males were experimental parents. The highest portion of animals with accelerated hatching as compared with the control was found in progenies from irradiated females. The shift of maximal hatching peak to an earlier period was found in descendants of both sexes. Thus, it was for the first time found on the model object (Drosophila) that the terahertz irradiation of parents can have positive or negative consequences in the first generation descendants.

[Endoscopic surgery for benign diseases and injuries of the esophagus (with commentary)]. / Endokhirurgiya dobrokachestvennykh zabolevanii i povrezhdenii pishchevoda (s kommentariem).

AIM: To analyze the results of surgical treatment of patients with benign diseases and injuries of the esophagus. MATERIAL AND METHODS: We summarized the experience of different endoscopic interventions in 159 patients with various benign diseases and perforation of the esophagus. Patients with achalasia (72 cases) underwent videolaparoscopic Geller's esophagomyotomy with anterior hemiesophagofundoplication by Dor. Video-assisted thoracoscopic extirpation of the esophagus with simultaneous or delayed esophagocolo/gastroplasty was performed in 56 patients with post-ambustial cicatricial stenosis of the esophagus. Patients with esophageal perforation (14 cases) underwent videolaparoscopic transhiatal mediastinal drainage. Esophageal leiomyoma has been excised through thoracoscopic (9 cases) or laparoscopic access (4 cases). Removal of esophageal diverticulum was made via VATS-access in 4 patients. RESULTS: Satisfactory early and remote results were achieved in all patients with achalasia. Mortality rate was 5.4% (3 out of 56 patients) and 14.3% (2 out of 14 patients) in groups of cicatricial esophageal stenosis and esophageal perforation respectively. Sutures failure after removal of the diverticulum and leiomyoma occurred in 2 and 1 patient respectively and has been successfully cured. CONCLUSION: Endoscopic technologies allow to perform successfully complex reconstructive interventions for dysphagia in patients with cicatricial esophageal stenosis and achalasia even at late stages, to remove benign tumors and diverticula of thoracic esophagus and provide adequate drainage of posterior mediastinum in case of esophageal perforation.

Accessing Extreme Spatiotemporal Localization of High-Power Laser Radiation through Transformation Optics and Scalar Wave Equations.

Although tightly focused intense ultrashort laser pulses are used in many applications from nano-processing to warm dense matter physics, their nonparaxial propagation implies the use of numerical simulations with vectorial wave equations or exact Maxwell solvers that have serious limitations and thus have hindered progress in this important field up to now. Here we present an elegant and robust solution that allows one to map the problem on one that can be addressed by simple scalar wave equations. The solution is based on a transformation optics approach and its validity is demonstrated in both the linear and the nonlinear regime. Our solution allows accessing challenging problems of extreme spatiotemporal localization of high power laser radiation that remain almost unexplored theoretically until now.

The role of electrostatic interactions in the process of diffusional encounter and docking of electron transport proteins.

Electrostatic interaction of plastocyanin and cytochrome f in the process of protein-protein complex formation was investigated by computer simulation methods. It was shown that long-range electrostatic interaction promotes energetically favorable mutual orientation of protein molecules at distances between their cofactors shorter than 5 nm. At distances shorter than 3 nm, these electrostatic interactions lead to a significantly detectable increase in the rate of convergence of the cofactors.

[Endosurgery of benign diseases and injuries of esophagus].

AIM: To analyze the results of endoscopic interventions for benign diseases and injuries of the esophagus. MATERIAL AND METHODS: 159 patients with benign diseases and perforation of the esophagus were operated. There were 72 (45.3%) cases of achalasia, 56 (35.2%) with post-ambustial stenosis of esophagus, 14 (8.8%) with esophageal perforation, 13 (8.2%) with leuomyoma of esophagus and 4 (2.5%) with diverticulum of thoracic esophagus. RESULTS AND DISCUSSION: In long-term period 56 patients with achalasia were followed-up after laparoscopic Heller cardiomyotomy with Dor fundoplication. Good results were observed in all cases. Three patients died in early postoperative period after thoracoscopic extirpation of esophagus with esophagoplasty via laparotomy at the stage of development of the technique. There were no deaths after thoracoscopic extirpation of esophagus with simultaneous laparoscopic gastroplasty. Postoperative period was significantly less after thoracoscopic extirpation of esophagus with simultaneous laparoscopic esophagogastroplasty using whole stomach compared with esophagogastroplasty and esophagocoloplasty via laparotomy. In long-term postoperative period different complications occurred in 17 cases. Two patients with esophageal perforation died after video-assisted laparotranshiatal drainage of posterior mediastinum. Scarring of esophageal defect was observed in others. Seam failure after esophageal leuomyoma removal was diagnosed in 2 patients that required video-assisted laparotranshiatal drainage of posterior mediastinum and Maydl jejunostomy. Seam failure in thoracic esophagus after thoracoscopic removal of diverticulum was observed in 1 case. The complication was cured by video-assisted laparotranshiatal drainage of posterior mediastinum.

[Life Span of F1 Progeny of Female Drosophila Exposed to Low Intensity Terahertz Irradiation].

Virgin female fruit flies were stressed by placement into a confined space without food for 3 hours. Some flies were subjected to terahertz irradiation (0,1-2,2 THz) for the last 30 min. Irradiated and nonirradiated females were then copulated with males. We investigated the F1 progeny of fruit flies with mature and immature oocytes at the moment of irradiation (days of oviposition: 1-2 and 9-10 after irradiation). Life span of individual flies was evaluated. It was demonstrated that terahertz radiation does not influence the absolute and average lifespan of the F1 progeny in both sexes. In response to terahertz irradiation the sexual dimorphism was detected. Survival curves of males, developed from mature and immature oocytes at the time of irradiation, differ significantly from the appropriate control, whereas in the case of females the survival curves are similar to the control. It is concluded that terahertz radiation has a remote effect on a survival of the F1 male progeny.