Tumor alkalization therapy: misconception or good therapeutics perspective? - the case of malignant ascites.

Tumor acidity has been identified as a key factor in promoting cancer progression, metastasis, and resistance. Tumor alkalization therapy has emerged as a potential strategy for cancer treatment. This article provides preclinical and clinical evidence for tumor alkalization therapy as a promising cancer treatment strategy. The potential of tumor alkalization therapy using sodium bicarbonate in the treatment of malignant ascites was studied. The concept of intraperitoneal perfusion with an alkalizing solution to increase the extracellular pH and its antitumor effect were explored. The significant extension in the overall survival of the Ehrlich ascites carcinoma mice treated with sodium bicarbonate solution compared to those treated with a sodium chloride solution was observed. In the sodium bicarbonate group, mice had a median survival of 30 days after tumor cell injection, which was significantly (p<0.05) different from the median survival of 18 days in the sodium chloride group and 14 days in the intact group. We also performed a case study of a patient with ovarian cancer malignant ascites resistant to previous lines of chemotherapy who underwent intraperitoneal perfusions with a sodium bicarbonate solution, resulting in a significant drop of CA-125 levels from 5600 U/mL to 2200 U/mL in and disappearance of ascites, indicating the potential effectiveness of the treatment. The preclinical and clinical results obtained using sodium bicarbonate perfusion in the treatment of malignant ascites represent a small yet significant contribution to the evolving field of tumor alkalization as a cancer therapy. They unequivocally affirm the good prospects of this concept.

Scattering Amplitude of Surface Plasmon Polariton Excited by a Finite Grating.

Unusual optical properties of laser-ablated metal surfaces arise from the excitation of local plasmon resonances in nano- and microstructures produced by laser-processing and from the mutual interaction of those structures through surface plasmon polariton (SPP) waves. This interaction provides a synergistic effect, which can make the optical properties of the composite nanostructure drastically different from the properties of its elements. At the same time, the prediction and analysis of these properties are hampered by the complexity of the analytical solution to the problem of SPP excitation by surface objects of arbitrary configuration. Such a problem can be reduced to a simpler one if one considers the geometry of a structured surface as a superposition of harmonic Fourier components. Therefore, the analytical solution to the problem of surface plasmon polariton excitation through the scattering of light by a sinusoidally perturbed plasmonic metal/vacuum boundary becomes very important. In this work, we show that this problem can be solved using a well-known method for calculating guided-mode amplitudes in the presence of current sources, which is used widely in the waveguide theory. The calculations are carried out for the simplest 2D cases of (1) a sinusoidal current of finite length and (2) a finite-length sinusoidal corrugation on a plasmonic metal surface illuminated by a normally incident plane wave. The analytical solution is compared with the results of numerical simulations. It is shown that, in the first case, the analytical and numerical solutions agree almost perfectly. In the second case, the analytical solution correctly predicts the optimum height of the corrugation xopt, providing the maximum SPP excitation efficiency. At the same time, the analytical and numerical values of the SPP amplitude agree very well when the corrugation height x turns out to be x≪xopt or x≫xopt (at least up to 3xopt); at x=xopt, the mismatch of those does not exceed 25%. The limitations of the analytical model leading to such a mismatch are discussed. We believe that the presented approach is useful for modeling various phenomena associated with SPP excitation.

Molecular Mechanisms of Deregulation of Muscle Contractility Caused by the R168H Mutation in TPM3 and Its Attenuation by Therapeutic Agents.

The substitution for Arg168His (R168H) in γ-tropomyosin (TPM3 gene, Tpm3.12 isoform) is associated with congenital muscle fiber type disproportion (CFTD) and muscle weakness. It is still unclear what molecular mechanisms underlie the muscle dysfunction seen in CFTD. The aim of this work was to study the effect of the R168H mutation in Tpm3.12 on the critical conformational changes that myosin, actin, troponin, and tropomyosin undergo during the ATPase cycle. We used polarized fluorescence microscopy and ghost muscle fibers containing regulated thin filaments and myosin heads (myosin subfragment-1) modified with the 1,5-IAEDANS fluorescent probe. Analysis of the data obtained revealed that a sequential interdependent conformational-functional rearrangement of tropomyosin, actin and myosin heads takes place when modeling the ATPase cycle in the presence of wild-type tropomyosin. A multistep shift of the tropomyosin strands from the outer to the inner domain of actin occurs during the transition from weak to strong binding of myosin to actin. Each tropomyosin position determines the corresponding balance between switched-on and switched-off actin monomers and between the strongly and weakly bound myosin heads. At low Ca2+, the R168H mutation was shown to switch some extra actin monomers on and increase the persistence length of tropomyosin, demonstrating the freezing of the R168HTpm strands close to the open position and disruption of the regulatory function of troponin. Instead of reducing the formation of strong bonds between myosin heads and F-actin, troponin activated it. However, at high Ca2+, troponin decreased the amount of strongly bound myosin heads instead of promoting their formation. Abnormally high sensitivity of thin filaments to Ca2+, inhibition of muscle fiber relaxation due to the appearance of the myosin heads strongly associated with F-actin, and distinct activation of the contractile system at submaximal concentrations of Ca2+ can lead to muscle inefficiency and weakness. Modulators of troponin (tirasemtiv and epigallocatechin-3-gallate) and myosin (omecamtiv mecarbil and 2,3-butanedione monoxime) have been shown to more or less attenuate the negative effects of the tropomyosin R168H mutant. Tirasemtiv and epigallocatechin-3-gallate may be used to prevent muscle dysfunction.

Indirect bandgap MoSe2 resonators for light-emitting nanophotonics.

Transition metal dichalcogenides (TMDs) are promising for new generation nanophotonics due to their unique optical properties. However, in contrast to direct bandgap TMD monolayers, bulk samples have an indirect bandgap that restricts their application as light emitters. On the other hand, the high refractive index of these materials allows for effective light trapping and the creation of high-Q resonators. In this work, a method for the nanofabrication of microcavities from indirect TMD multilayer flakes, which makes it possible to achieve pronounced resonant photoluminescence enhancement due to the cavity modes, is proposed. Whispering gallery mode (WGM) resonators are fabricated from bulk indirect MoSe2 using resistless scanning probe lithography. A micro-photoluminescence (µ-PL) investigation revealed the WGM spectra of the resonators with an enhancement factor up to 100. The characteristic features of WGMs are clearly seen from the scattering experiments which are in agreement with the results of numerical simulations. It is shown that the PL spectra in the fabricated microcavities are contributed by two mechanisms demonstrating different temperature dependences. The indirect PL, which is quenched with the temperature decrease, and the direct PL which almost does not depend on the temperature. The results of the work show that the suggested approach has great prospects in nanophotonics.

Nanoscale Electric Field Probing in a Single Nanowire with Raman Spectroscopy and Elastic Strain.

In this work we investigate the Raman response of extremely strained gallium phosphide nanowires. We analyze new strain-induced spectral phenomena such as 2-fold and 3-fold phonon peak splitting which arise due to nontrivial internal electric field distribution coupled with inhomogeneous strain. We show that high bending strain acts as a probe allowing us to define the electric field distribution with deep subwavelength resolution using the corresponding changes of the Raman spectra. We investigate the nature of the localization with respect to nanowire diameter, excitation spot position, and light polarization, supporting the experiment with 3D numerical modeling. Based on our findings we propose a research tool allowing to precisely localize the electric field in a certain subwavelength region of the nanophotonic resonator.

Tumor acidity: From hallmark of cancer to target of treatment.

Tumor acidity is one of the cancer hallmarks and is associated with metabolic reprogramming and the use of glycolysis, which results in a high intracellular lactic acid concentration. Cancer cells avoid acid stress major by the activation and expression of proton and lactate transporters and exchangers and have an inverted pH gradient (extracellular and intracellular pHs are acid and alkaline, respectively). The shift in the tumor acid-base balance promotes proliferation, apoptosis avoidance, invasiveness, metastatic potential, aggressiveness, immune evasion, and treatment resistance. For example, weak-base chemotherapeutic agents may have a substantially reduced cellular uptake capacity due to "ion trapping". Lactic acid negatively affects the functions of activated effector T cells, stimulates regulatory T cells, and promotes them to express programmed cell death receptor 1. On the other hand, the inversion of pH gradient could be a cancer weakness that will allow the development of new promising therapies, such as tumor-targeted pH-sensitive antibodies and pH-responsible nanoparticle conjugates with anticancer drugs. The regulation of tumor pH levels by pharmacological inhibition of pH-responsible proteins (monocarboxylate transporters, H+-ATPase, etc.) and lactate dehydrogenase A is also a promising anticancer strategy. Another idea is the oral or parenteral use of buffer systems, such as sodium bicarbonate, to neutralize tumor acidity. Buffering therapy does not counteract standard treatment methods and can be used in combination to increase effectiveness. However, the mechanisms of the anticancer effect of buffering therapy are still unclear, and more research is needed. We have attempted to summarize the basic knowledge about tumor acidity.

Topologically Enabled Ultrahigh-Q Chiroptical Resonances by Merging Bound States in the Continuum.

Ultrahigh-Q chiroptical resonance metasurfaces based on merging bound states in the continuum (BICs) are investigated and numerically demonstrated. The destruction of C2 symmetry results in the leakage of BICs into quasi-BICs, and a chiral quasi-BIC is obtained by oblique incidence or continuous destruction of the mirror symmetry of the structure. Due to the significant topological properties of merging BICs, the Q factor (over 2 × 105) of the chiral resonance peak obtained is much higher than that of the previous work. Moreover, the proposed structure is easy to fabricate because no additional out-of-plane asymmetry is introduced. The proposed scheme is of importance in chiral biosensing applications.

Bound States in the Continuum in Compact Acoustic Resonators.

We reveal that finite-size solid acoustic resonators can support genuine bound states in the continuum (BICs) completely localized inside the resonator. The developed theory provides the multipole classification of such BICs in the resonators of various shapes. It is shown how breaking of the resonator's symmetry turns BICs into quasi-BICs manifesting themselves in the scattering spectra as high-Q Fano resonances. We believe that the revealed novel states will push the performance limits of acoustic devices and will serve as high-Q building blocks for acoustic sensors, antennas, and topological acoustic structures.

Analytical Calculations of Scattering Amplitude of Surface Plasmon Polaritons Excited by a Spherical Nanoantenna.

Since surface plasmon polaritons (SPPs) are surface waves, they cannot be excited by an incident plane wave, because free-space photons do not possess a sufficient in-plane momentum. Phase matching between the incident light and SPP can be achieved using a high-refractive-index prism, grating, or nanoantennas. In this work, we found an expression for the amplitude of SPP excited by an arbitrary 3D current distribution placed near a metal interface. The developed method is based on the well-known technique used in waveguide theory that enables finding the amplitudes of waveguide modes excited by the external currents. It reduces the SPP excitation problem to the summation of the set of emitters. As a particular example, we considered a spherical dipole nanoantenna on a metal substrate illuminated by a normally incident plane wave. The analytical calculations were in good agreement with the full-wave numerical simulations.

Observation of Ultrafast Self-Action Effects in Quasi-BIC Resonant Metasurfaces.

High-index dielectric metasurfaces can support sharp optical resonances enabled by the physics of bound states in the continuum (BICs) often manifested in experiments as quasi-BIC resonances. They provide a way to enhance light-matter interaction at the subwavelength scale bringing novel opportunities for nonlinear nanophotonics. Strong narrow-band field enhancement in quasi-BIC metasurfaces leads to an extreme sensitivity to a change of the refractive index that may limit nonlinear functionalities for the pump intensities beyond the perturbative regime. Here we study ultrafast self-action effects observed in quasi-BIC silicon metasurfaces and demonstrate how they alter the power dependence of the third-harmonic generation efficiency. We study experimentally a transition from the subcubic to supercubic regimes for the generated third-harmonic power driven by a blue-shift of the quasi-BIC in the multiphoton absorption regime. Our results suggest a way to implement ultrafast nonlinear dynamics in high-index resonant dielectric metasurfaces for nonlinear meta-optics beyond the perturbative regime.

Fractional Charge States in the Magneto-Photoluminescence Spectra of Single-Electron InP/GaInP2 Quantum Dots.

We used photoluminescence spectra of single electron quasi-two-dimensional InP/GaInP2 islands having Wigner-Seitz radius ~4 to measure the magnetic-field dispersion of the lowest s, p, and d single-particle states in the range 0-10 T. The measured dispersion revealed up to a nine-fold reduction of the cyclotron frequency, indicating the formation of nano-superconducting anyon or magneto-electron (em) states, in which the corresponding number of magnetic-flux-quanta vortexes and fractional charge were self-generated. We observed a linear increase in the number of vortexes versus the island size, which corresponded to a critical vortex radius equal to the Bohr radius and closed-packed topological vortex arrangements. Our observation explains the microscopic mechanism of vortex attachment in composite fermion theory of the fractional quantum Hall effect, allows its description in terms of self-localization of ems and represents progress towards the goal of engineering anyon properties for fault-tolerant topological quantum gates.

From Fano to Quasi-BIC Resonances in Individual Dielectric Nanoantennas.

Sharp optical resonances in high-index dielectric nanostructures have recently attracted significant attention for their promising applications in nanophotonics. Fano resonances, as well as resonances associated with bound states in the continuum (BIC), have independently shown a great potential for applications in nanoscale lasers, sensors, and nonlinear optical devices. Here, we demonstrate experimentally a close connection between Fano and quasi-BIC resonances excited in individual dielectric nanoantennas. We analyze systematically the resonant response of AlGaAs nanoantennas pumped with a structured light in the near-infrared range. We trace a variation of the scattering spectrum that fully agrees with an analytical expression governed by a Fano parameter and observe directly a transition to a quasi-BIC resonance. Our results suggest a unified approach toward the analysis of sharp resonances in subwavelength nanostructures originating from strong coupling of optical modes that can provide high energy localization for enhanced light-matter interactions.

Nontransecting Anastomotic Urethroplasty Via Ventral Approach Without Full Mobilization of the Corpus Spongiosum Dorsal Semicircumference.

OBJECTIVE: To present a novel surgical approach to performing bulbar urethroplasty and to assess its initial outcomes and safety. MATERIALS AND METHODS: From January 2016 to March 2019, anastomotic urethroplasty without full mobilization and dissection of corpus spongiosum dorsal semicircumference was performed in 8 males with bulbar strictures by a single surgeon. Patients were given uroflowmetry, urethrography, and International Index of Erectile Function (IIEF) questionnaires at their 3- and 12- month follow-up visits postoperatively. RESULTS: Mean stricture length was 2.3 cm (±0.59 cm) and mean surgery time was 131 minutes. No early or late postoperative complications were observed. Median maximum flow rate (Qmax) assessed 3 months after surgery was 22.35 mL/sec (±6.4 mL/sec). There were no significant changes in median IIEF score postoperatively (preoperative IIEF = 18.4 vs postoperative IIEF = 19.6; P >.05). During patients' 1-year observation period, no signs of constriction in the anastomosis were revealed with urethrography. One of the limitations of this technique is a necessity of more precise corpus spongiosum preparation to ensure perioperative hemostasis and good visualization. This outcome may, however, require additional time and increased blood loss during a surgeon's learning curve of the procedure. CONCLUSION: The initial experience of this minimally invasive urethroplasty technique showed high efficiency and no early stricture recurrences. However, the clinical significance of additional preservation of innervation and blood supply, the potential to further optimize this technique's functional outcomes, and applicability of this technique in patients with spongiofibrosis requires further investigation. Our results make it possible to consider this technique as a possible alternative to classic anastomotic urethroplasty.

Scanning Tunneling Microscopy-Induced Light Emission and I(V) Study of Optical Near-Field Properties of Single Plasmonic Nanoantennas.

Electrically driven plasmonic nanoantennas can be integrated as a local source of the optical signal of advanced photonic schemes for on-chip data processing. The inelastic electron tunneling provides the photon generation or launch of surface plasmon waves. This process can be enhanced by the local density of optical states of nanoantennas. In this paper, we used scanning tunnel microscopy-induced light emission to probe the local optoelectronic properties of single gold nanodiscs. The electromagnetic field distribution in the vicinity of plasmonic structures was investigated with high spatial resolution. The obtained photon maps reveal the nonuniform distribution of electromagnetic near-fields, which is consistent with nanoantenna optical modes. Also, the analysis of derived I(V) curves showed a direct correlation between the nanoantenna optical states and the appearance of features on current-voltage characteristics.

Observation of Supercavity Modes in Subwavelength Dielectric Resonators.

Electromagnetic response of dielectric resonators with high refractive index is governed by optically induced electric and magnetic Mie resonances facilitating confinement of light with the amplitude enhancement. Traditionally, strong subwavelength trapping of light was associated only with plasmonic or epsilon-near-zero structures, which however suffer from material losses. Recently, an alternative localization mechanism was proposed allowing the trapping of light in individual subwavelength optical resonators with a high quality factor in the regime of a supercavity mode. Here, the experimental observation of the supercavity modes in subwavelength ceramic resonators in the radio-frequency range is presented. It is experimentally demonstrated that the regime of supercavity modes can be achieved via precise tuning of the resonator's dimensions. A huge growth of the unloaded quality factor is achieved with experimental values up to 1.25 × 104 , limited only by material losses of ceramics. It is revealed that the supercavity modes can be excited efficiently both in the near- and far-field. In both cases, the supercavity mode manifests itself explicitly as a Fano resonance with characteristic peculiarities of spectral shape and radiation pattern. A comparison of supercavities made of diversified materials for the visible, infrared, THz, and radio-frequency regimes is provided.

Subwavelength dielectric resonators for nonlinear nanophotonics.

Subwavelength optical resonators made of high-index dielectric materials provide efficient ways to manipulate light at the nanoscale through mode interferences and enhancement of both electric and magnetic fields. Such Mie-resonant dielectric structures have low absorption, and their functionalities are limited predominantly by radiative losses. We implement a new physical mechanism for suppressing radiative losses of individual nanoscale resonators to engineer special modes with high quality factors: optical bound states in the continuum (BICs). We demonstrate that an individual subwavelength dielectric resonator hosting a BIC mode can boost nonlinear effects increasing second-harmonic generation efficiency. Our work suggests a route to use subwavelength high-index dielectric resonators for a strong enhancement of light-matter interactions with applications to nonlinear optics, nanoscale lasers, quantum photonics, and sensors.

Investigation of effective media applicability for ultrathin multilayer structures.

Multilayer hyperbolic metamaterials (HMMs) are highly anisotropic media consisting of alternating metal and dielectric layers with their electromagnetic properties defined by the effective medium approximation (EMA). EMA is generally applied for a large number of subwavelength unit cells or periods of a multilayer HMM. However, in practice, the number of periods is limited. To the best of our knowledge, a comparison between rigorous theory, EMA and experiments to investigate the minimum number of layers that allow for the low error of EMA results has not yet been investigated. In this article, we compared the reflectance response of the effective anisotropic HMMs predicted by the scattering matrix method (SMM) and EMA with optical characterization data, having the unit cell twenty times smaller than the vacuum wavelength in the visible range. The fabricated HMM structures consist of up to ten periods of alternating 10 nm thick Au and Al2O3 layers deposited by sputtering and atomic layer deposition, respectively. The two deposition techniques enable us to achieve a high quality HMM with low roughness: the root mean square (RMS) is less than 1 nm. We showed that the multilayer structure behaves like an effective medium from the fourth period onwards as the EMA calculation and experimental results agree well having below 4% mean square standard deviation of reflectance (MSDR) for the wavelength range from 500 to 1750 nm with a wide incident angle range. These results could have an impact on the design and development of active metamaterials and their applications ranging from imaging to nonlinear optics and sensing.

Single-Mode Lasing from Imprinted Halide-Perovskite Microdisks.

Halide-perovskite microlasers have demonstrated fascinating performance owing to their low-threshold lasing at room temperature and low-cost fabrication. However, being synthesized chemically, controllable fabrication of such microlasers remains challenging, and it requires template-assisted growth or complicated nanolithography. Here, we suggest and implement an approach for the fabrication of microlasers by direct laser ablation of a thin film on glass with donut-shaped femtosecond laser beams. The fabricated microlasers represent MAPbBr xI y microdisks with 760 nm thickness and diameters ranging from 2 to 9 µm that are controlled by a topological charge of the vortex beam. As a result, this method allows one to fabricate single-mode perovskite microlasers operating at room temperature in a broad spectral range (550-800 nm) with Q-factors up to 5500. High-speed fabrication and reproducibility of microdisk parameters, as well as a precise control of their location on a surface, make it possible to fabricate centimeter-sized arrays of such microlasers. Our finding is important for direct writing of fully integrated coherent light sources for advanced photonic and optoelectronic circuitry.

Direct Near-Field Observation of Surface Plasmon Polaritons on Silver Nanowires.

Surface plasmon polaritons on (silver) nanowires are promising components for future photonic technologies. Here, we study near-field patterns on silver nanowires with a scattering-type scanning near-field optical microscope that enables the direct mapping of surface waves. We analyze the spatial pattern of the plasmon signatures for different excitation geometries and polarization and observe a plasmon wave pattern that is canted relative to the nanowire axis, which we show is due to a superposition of two different plasmon modes, as supported by electromagnetic simulations including the influence of the substrate. These findings yield new insights into the excitation and propagation of plasmon polaritons for applications in nanoplasmonic devices.

Meta-optics and bound states in the continuum.

We discuss the recent advances in meta-optics and nanophotonics associated with the physics of bound states in the continuum (BICs). Such resonant states appear due to a strong coupling between leaky modes in optical guiding structures being supported by subwavelength high-index dielectric Mie-resonant nanoantennas or all-dielectric metasurfaces. First, we review briefly very recent developments in the BIC physics in application to isolated subwavelength particles. We pay a special attention to novel opportunities for nonlinear nanophotonics due to the large field enhancement inside the particle volume creating the resonant states with high-quality (high-Q) factors, the so-called quasi-BIC, that can be supported by the subwavelength particles. Second, we discuss novel applications of the BIC physics to all-dielectric optical metasurfaces with broken-symmetry meta-atoms when tuning to the BIC conditions allows to enhance substantially the Q factor of the flat-optics dielectric structures. We also present the original results on nonlinear high-Q metasurfaces and predict that the frequency conversion efficiency can be boosted dramatically by smart engineering of the asymmetry parameter of dielectric metasurfaces in the vicinity of the quasi-BIC regime.