Analysis of the optical performance of intraocular lenses using profilometric measurements.

PURPOSE: The aim of this study was to develop a methodology, based on profilometer measurements to assess the optical behaviour of Intraocular Lenses (IOls). The "Modulation Transfer Function through-object" (MTF through-object) based on vergence object displacement was calculated for different pupil sizes and pseudophakic eyes. Tilt and decentration were also analysed in a realistic cornea eye model. METHODS: For comparison between the different IOLs, an optical quality criterion based on a minimum value the MTF through-object and the recognition of simulated vision optotypes was introduced. Five IOLs were used in this study: Tecnis Eyhance, Mini Well, Tecnis Symfony, Tecnis Synergy and RayOne EMV. RESULTS: The technique was validated with previous methodologies. A general narrowing of the through-object MTF curve compared to the through-focus MTF curve was shown, resulting in greater distances between near and intermediate points and less depth of field around the far peak. The comparison between the IOLs showed that variations in corneal aberrations, pupil size and decentration caused relevant changes in IOL performance. A decrease of the SA produced a hypermetropic shift of the far focus between + 0.3 D and + 0.4 D. Most of IOLs worsen the optical quality as pupil size increased, even the MTF through-object shape changed. Decentration was an important factor in IOL implantation, causing a significant change in MTF through-object shape in most of IOLs. CONCLUSIONS: This study highlights the need to evaluate pre-operative patients for corneal aberrations and pupillary size to have the best optical success after cataract surgery in multifocal or extended depth of focus IOLs. KEY MESSAGES: What is known MTF(Modulation Transfer Function) through-focus curves (calculated in image space by moving the detector plane) can be obtained from optical bench assembly or from commercial devices. Recently, some studies proposed to characterize the lens surface design based on the profilometric measurements What is new A novel methodology based on profilometer measurements to assess the optical behaviour of Intraocular Lenses (IOls) was shown. The "Modulation Transfer Function through-object" based on vergence object displacement was introduced in order to analyse five premium IOLs. MTF through-object curve is more appropriate for studying clinical behaviour, as it provides further near and intermediate points distances and lower depth of focus around far peak compare to MTF through-focus curves. The optical behaviour of the five IOLs can vary considerably depending on the eye model and pupil size. The effect of tilt and decentration on the MTF through-object the IOLs was analysed.

Ultrathin high-index metasurfaces for shaping focused beams.

The volume size of a converging wave, which plays a relevant role in image resolution, is governed by the wavelength of the radiation and the numerical aperture (NA) of the wavefront. We designed an ultrathin (λ/8 width) curved metasurface that is able to transform a focused field into a high-NA optical architecture, thus boosting the transverse and (mainly) on-axis resolution. The elements of the metasurface are metal-insulator subwavelength gratings exhibiting extreme anisotropy with ultrahigh index of refraction for TM polarization. Our results can be applied to nanolithography and optical microscopy.

Engineered surface waves in hyperbolic metamaterials.

We analyzed surface-wave propagation that takes place at the boundary between a semi-infinite dielectric and a multilayered metamaterial, the latter with indefinite permittivity and cut normally to the layers. Known hyperbolization of the dispersion curve is discussed within distinct spectral regimes, including the role of the surrounding material. Hybridization of surface waves enable tighter confinement near the interface in comparison with pure-TM surface-plasmon polaritons. We demonstrate that the effective-medium approach deviates severely in practical implementations. By using the finite-element method, we predict the existence of long-range oblique surface waves.

Considerations on the electromagnetic flow in Airy beams based on the Gouy phase.

We reexamine the Gouy phase in ballistic Airy beams (AiBs). A physical interpretation of our analysis is derived in terms of the local phase velocity and the Poynting vector streamlines. Recent experiments employing AiBs are consistent with our results. We provide an approach which potentially applies to any finite-energy paraxial wave field that lacks a beam axis.

Left-handed metamaterial coatings for subwavelength-resolution imaging.

We report on a procedure to improve the resolution of far-field imaging by using a neighboring high-index medium that is coated with a left-handed metamaterial. The resulting plot can also exhibit an enhanced transmission by considering proper conditions to retract backscattering. Based on negative refraction, geometrical aberrations are considered in detail since they may cause a great impact in this sort of diffraction-unlimited imaging by reducing its resolution power. We employ a standard aberration analysis to refine the asymmetric configuration of metamaterial superlenses. We demonstrate that low-order centrosymmetric aberrations can be fully corrected for a given object plane. For subwavelength-resolution imaging, however, high-order aberrations become of relevance, which may be balanced with defocus. Not only the point spread function but also numerical simulations based on the finite-element method support our theoretical analysis, and subwavelength resolution is verified in the image plane.

Algorithm for correcting the keratometric estimation error in normal eyes..

PURPOSE: To obtain an accurate algorithm for calculating the keratometric index that minimizes the errors in the calculation of corneal power assuming only a single corneal surface in the range of corneal curvatures of the normal population. METHODS: Corneal power was calculated by using the classical keratometric index and also by using the Gaussian equation. Differences between types of calculation of corneal power were determined and modeled by regression analysis. RESULTS: We proposed two options for the selection of the most appropriate keratometric index (n(k)) value for each specific case. First was the use of specific linear equations (depending on the ratio of the anterior to the posterior curvature, k ratio) according to the value of the central radius of curvature of the anterior corneal surface (r(1c)) in 0.1 mm steps and the theoretical eye model considered. The second was the use of a general simplified equation only requiring r(1c) (Gullstrand eye model, n(k) = -0.0064286r(1c) + 1.37688; Le Grand eye model, n(k) = -0.0063804r(1c) + 1.37806). CONCLUSIONS: The generalization of the keratometric index (n(k)) value is not an appropriate approximation for the estimation of the corneal power and it can lead to significant errors. We proposed a new algorithm depending on r(1c), with a maximal associated error in the calculation of the corneal power of 0.5 D and without requiring knowledge of the posterior corneal curvature.

Analysis and comparison of monofocal, extended depth of focus and trifocal intraocular lens profiles.

To test the feasibility of using profilometers to extract information about IOL surfaces design. A standard monofocal IOL (Tecnis 1), a monofocal IOL that provided some depth of focus (Eyhance), an extended depth of focus IOL based on refractive optics (Mini Well) and a trifocal IOL based on diffractive optics were used in this study (Tecnis Synergy). The surface topography of the IOLs was measured by using a multimode optical profilometer. Posterior surface of Tecnis 1 IOL was spherical and the anterior surface aspherical. In the Eyhance IOL, posterior surface was spherical and anterior surface did not fit to any of our reference surfaces, indicating a higher order aspheric surface design. In the Mini Well Ready IOL, a best-fit sphere surface was obtained for the second surface and a high order aspherical surface design was deduced for the first surface. The anterior surface of the Synergy IOL was aspherical and the base curve of the diffractive structure fitted very well to a spherical surface. To consider an aspheric surface as possible best-fit surface provided more information than if only best-fit spherical surface was considered. The high order aspheric surface designs employed in the IOLs studied presented differences, regarding best-fit asphere surface, higher than 1 micron. These differences were correlated with the generation of spherical aberration complex profiles (with Zernike terms higher than 4th order) and with the production of distinct amounts of depth of focus. This method was also useful to deduce the base curve of diffractive surfaces.

Comparison of the optical quality vision between real post-LASIK myopic laser surgery and the simulated implantation of a phakic IOL in low myopia.

A phakic intraocular lens (PIOL) of - 4.5 D was characterized from its wavefront aberration profile. A preclinical study was conducted using pre- and post-surgery data from four patients that had undergone myopic laser refractive surgery. All these patients would have needed a PIOL of - 4.5 D. Pre-surgery data were used to simulate the effect of a PIOL implantation. Post myopic refractive surgery data were used to calculate the post-LASIK eye model. Modulation transfer function (MTF), point spread function (PSF) and simulation of optotypes vision were obtained and compared. The PIOL did not worsen the optical quality of the eyes evaluated. High order Aberrations were always higher in the post-LASIK eye model. Optics quality trended to be better in PIOL implantation than post-LASIK surgery as pupil size increased.

MET-Induced CD73 Restrains STING-Mediated Immunogenicity of EGFR-Mutant Lung Cancer.

Immunotherapy has shown limited efficacy in patients with EGFR-mutated lung cancer. Efforts to enhance the immunogenicity of EGFR-mutated lung cancer have been unsuccessful to date. Here, we discover that MET amplification, the most common mechanism of resistance to third-generation EGFR tyrosine kinase inhibitors (TKI), activates tumor cell STING, an emerging determinant of cancer immunogenicity (1). However, STING activation was restrained by ectonucleosidase CD73, which is induced in MET-amplified, EGFR-TKI-resistant cells. Systematic genomic analyses and cell line studies confirmed upregulation of CD73 in MET-amplified and MET-activated lung cancer contexts, which depends on coinduction of FOSL1. Pemetrexed (PEM), which is commonly used following EGFR-TKI treatment failure, was identified as an effective potentiator of STING-dependent TBK1-IRF3-STAT1 signaling in MET-amplified, EGFR-TKI-resistant cells. However, PEM treatment also induced adenosine production, which inhibited T-cell responsiveness. In an allogenic humanized mouse model, CD73 deletion enhanced immunogenicity of MET-amplified, EGFR-TKI-resistant cells, and PEM treatment promoted robust responses regardless of CD73 status. Using a physiologic antigen recognition model, inactivation of CD73 significantly increased antigen-specific CD8+ T-cell immunogenicity following PEM treatment. These data reveal that combined PEM and CD73 inhibition can co-opt tumor cell STING induction in TKI-resistant EGFR-mutated lung cancers and promote immunogenicity. SIGNIFICANCE: MET amplification upregulates CD73 to suppress tumor cell STING induction and T-cell responsiveness in TKI-resistant, EGFR-mutated lung cancer, identifying a strategy to enhance immunogenicity and improve treatment.

Activation of Tumor-Cell STING Primes NK-Cell Therapy.

Activation of the stimulator of interferon genes (STING) pathway promotes antitumor immunity but STING agonists have yet to achieve clinical success. Increased understanding of the mechanism of action of STING agonists in human tumors is key to developing therapeutic combinations that activate effective innate antitumor immunity. Here, we report that malignant pleural mesothelioma cells robustly express STING and are responsive to STING agonist treatment ex vivo. Using dynamic single-cell RNA sequencing of explants treated with a STING agonist, we observed CXCR3 chemokine activation primarily in tumor cells and cancer-associated fibroblasts, as well as T-cell cytotoxicity. In contrast, primary natural killer (NK) cells resisted STING agonist-induced cytotoxicity. STING agonists enhanced migration and killing of NK cells and mesothelin-targeted chimeric antigen receptor (CAR)-NK cells, improving therapeutic activity in patient-derived organotypic tumor spheroids. These studies reveal the fundamental importance of using human tumor samples to assess innate and cellular immune therapies. By functionally profiling mesothelioma tumor explants with elevated STING expression in tumor cells, we uncovered distinct consequences of STING agonist treatment in humans that support testing combining STING agonists with NK and CAR-NK cell therapies.

Nondiffracting Bessel plasmons.

We report on the existence of nondiffracting Bessel surface plasmon polaritons (SPPs), advancing at either superluminal or subluminal phase velocities. These wave fields feature deep subwavelength FWHM, but are supported by high-order homogeneous SPPs of a metal/dielectric (MD) superlattice. The beam axis can be relocated to any MD interface, by interfering multiple converging SPPs with controlled phase matching. Dissipative effects in metals lead to a diffraction-free regime that is limited by the energy attenuation length. However, the ultra-localization of the diffracted wave field might still be maintained by more than one order of magnitude.

Dynamic single-cell RNA sequencing identifies immunotherapy persister cells following PD-1 blockade.

Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed cell death 1 (PD-1) blockade is poorly understood. Here, we performed dynamic single-cell RNA-Seq of murine organotypic tumor spheroids undergoing PD-1 blockade, identifying a discrete subpopulation of immunotherapy persister cells (IPCs) that resisted CD8+ T cell-mediated killing. These cells expressed Snai1 and stem cell antigen 1 (Sca-1) and exhibited hybrid epithelial-mesenchymal features characteristic of a stem cell-like state. IPCs were expanded by IL-6 but were vulnerable to TNF-α-induced cytotoxicity, relying on baculoviral IAP repeat-containing protein 2 (Birc2) and Birc3 as survival factors. Combining PD-1 blockade with Birc2/3 antagonism in mice reduced IPCs and enhanced tumor cell killing in vivo, resulting in durable responsiveness that matched TNF cytotoxicity thresholds in vitro. Together, these data demonstrate the power of high-resolution functional ex vivo profiling to uncover fundamental mechanisms of immune escape from durable anti-PD-1 responses, while identifying IPCs as a cancer cell subpopulation targetable by specific therapeutic combinations.

Diffraction-free beams in thin films.

The propagation and transmission of Bessel beams through nano-layered structures has been discussed recently. Within this framework we recognize the formation of unguided diffraction-free waves with the spot size approaching and occasionally surpassing the limit of a wavelength when a Bessel beam of any order n is launched onto a thin material slab with grazing incidence. On the basis of the plane-wave representation of cylindrical waves, a simple model is introduced providing an exact description of the transverse pattern of this type of diffraction-suppressed localized wave. Potential applications in surface science are put forward for consideration.

Three-dimensional point spread function and generalized amplitude transfer function of near-field flat lenses.

We derive a nonsingular, polarization-dependent, 3D impulse response that provides unambiguously the wave field scattered by a negative-refractive-index layered lens and distributed in its image volume. By means of a 3D Fourier transform, we introduce the generalized amplitude transfer function in order to gain a deep insight into the resolution power of the optical element. In the near-field regime, fine details containing some depth information may be transmitted through the lens. We show that metamaterials with moderate absorption are appropriate for subwavelength resolution keeping a limited degree of depth discrimination.

New method to improve the quality of vision in cataractous keratoconus eyes.

To analyze using optical simulations if the proper use of a segmented intraocular lens (IOL) can improve the visual outcomes compared to the implantation of a spherical monofocal IOL. The wavefront profile of the Mplus (Oculentis) and a monofocal IOLs with the phase transformation introduced by each IOL were calculated using a Hartmann-Shack wavefront sensor. In addition, the wavefront profile of schematic eye models of various keratoconus conditions was obtained and was propagated to the IOLs. The optical performance of such combination was obtained after combining ray tracing and Fourier optics. A pre-clinical validation was also evaluated incorporating clinical data from three different keratoconus eyes of three patients. The implantation of the Mplus IOL can compensate or reduce the overall coma of the eye with keratoconus improving the quality of vision compared with a spherical monofocal IOL due to lower displacements of the retinal image or tilting in keratoconus. All theoretical simulations were confirmed afterwards by mean of a preclinical validation. The use of a standard toric segmented IOL with a proper orientation and selection of the addition can improve the optical quality of the keratoconus eye compared to the use of a monofocal spherical IOL.

Suppression of Myeloid Cell Arginase Activity leads to Therapeutic Response in a NSCLC Mouse Model by Activating Anti-Tumor Immunity.

BACKGROUND: Tumor orchestrated metabolic changes in the microenvironment limit generation of anti-tumor immune responses. Availability of arginine, a semi-essential amino acid, is critical for lymphocyte proliferation and function. Levels of arginine are regulated by the enzymes arginase 1,2 and nitric oxide synthase (NOS). However, the role of arginase activity in lung tumor maintenance has not been investigated in clinically relevant orthotopic tumor models. METHODS: RNA sequencing (RNA-seq) of sorted cell populations from mouse lung adenocarcinomas derived from immunocompetent genetically engineered mouse models (GEMM)s was performed. To complement mouse studies, a patient tissue microarray consisting of 150 lung adenocarcinomas, 103 squamous tumors, and 54 matched normal tissue were stained for arginase, CD3, and CD66b by multiplex immunohistochemistry. Efficacy of a novel arginase inhibitor compound 9 in reversing arginase mediated T cell suppression was determined in splenocyte ex vivo assays. Additionally, the anti-tumor activity of this compound was determined in vitro and in an autochthonous immunocompetent KrasG12D GEMM of lung adenocarcinoma model. RESULTS: Analysis of RNA-seq of sorted myeloid cells suggested that arginase expression is elevated in myeloid cells in the tumor as compared to the normal lung tissue. Accordingly, in the patient samples arginase 1 expression was mainly localized in the granulocytic myeloid cells and significantly elevated in both lung adenocarcinoma and squamous tumors as compared to the controls. Our ex vivo analysis demonstrated that myeloid derived suppressor cell (MDSC)s cause T cell suppression by arginine depletion, and suppression of arginase activity by a novel ARG1/2 inhibitor, compound 9, led to restoration of T cell function by increasing arginine. Treatment of KrasG12D GEMM of lung cancer model with compound 9 led to a significant tumor regression associated with increased T cell numbers and function, while it had no activity across several murine and human non-small cell (NSCLC) lung cancer lines in vitro. CONCLUSIONS: We show that arginase expression is elevated in mouse and patient lung tumors. In a KRASG12D GEMM arginase inhibition diminished growth of established tumors. Our data suggest arginase as an immunomodulatory target that should further be investigated in lung tumors with high arginase activity.

Simulation of the Effect of Different Presbyopia-Correcting Intraocular Lenses With Eyes With Previous Laser Refractive Surgery.

PURPOSE: To simulate the optical performance of three presbyopia-correcting intraocular lenses (IOLs) implanted in eyes with previous laser refractive surgery. METHODS: A simulation of the through-focus modulation transfer function (MTF) was performed for three presbyopia-correcting IOLs (Mplus, Oculentis GmbH, Berlin, Germany; Symfony, Johnson & Johnson Vision, Santa Ana, CA; and Mini Well, SIFI S.p.A., Lavinaio, Italy) in one eye with previous myopic LASIK and another with hyperopic LASIK. Real topographic data and the wavefront aberration profile of each IOL obtained with a Hartmann-Shack sensor were used. RESULTS: In the eye with myopic LASIK, all IOLs lost optical quality at near and intermediate distances for 4- and 4.7-mm pupil size. For 3-mm pupil size, the Mini Well IOL showed the best intermediate and near MTF and maintained the far focus independently of the pupil. In the eye with hyperopic LASIK, the Mini Well IOL showed an intermediate, distance, and -4.00-diopter (D) foci for all pupils. The Symfony IOL showed a depth of focus at far and intermediate distance for 3-mm and a focus at -2.50 D in the rest. The Mplus showed a focus of -4.50 and -3.00 D for the 3- and 4-mm pupil, respectively. CONCLUSIONS: The Mini Well and Symfony IOLs seem to work better than the Mplus IOL in eyes with previous myopic LASIK. With previous hyperopic LASIK, the Mini Well IOL seems to be able to provide acceptable near, intermediate, and far foci for all pupil sizes. These findings should be confirmed in future clinical studies. [J Refract Surg. 2018;34(4):222-227.].

In Vitro Aberrometric Assessment of a Multifocal Intraocular Lens and Two Extended Depth of Focus IOLs.

PURPOSE: To analyze the "in vitro" aberrometric pattern of a refractive IOL and two extended depth of focus IOLs. METHODS: A special optical bench with a Shack-Hartmann wavefront sensor (SH) was designed for the measurement. Three presbyopia correction IOLs were analyzed: Mini WELL (MW), TECNIS Symfony ZXR00 (SYM), and Lentis Mplus X LS-313 MF30 (MP). Three different pupil sizes were used for the comparison: 3, 4, and 4.7 mm. RESULTS: MW generated negative primary and positive secondary spherical aberrations (SA) for the apertures of 3 mm (-0.13 and +0.12 µm), 4 mm (-0.12 and +0.08 µm), and 4.7 mm (-0.11 and +0.08 µm), while the SYM only generated negative primary SA for 4 and 4.7 mm apertures (-0.12 µm and -0.20 µm, resp.). The MP induced coma and trefoil for all pupils and showed significant HOAs for apertures of 4 and 4.7 mm. CONCLUSIONS: In an optical bench, the MW induces negative primary and positive secondary SA for all pupils. The SYM aberrations seem to be pupil dependent; it does not produce negative primary SA for 3 mm but increases for higher pupils. Meanwhile, the HOAs for the MW and SYM were not significant. The MP showed in all cases the highest HOAs.

Novel Small Molecule Inhibitors of Choline Kinase Identified by Fragment-Based Drug Discovery.

Choline kinase α (ChoKα) is an enzyme involved in the synthesis of phospholipids and thereby plays key roles in regulation of cell proliferation, oncogenic transformation, and human carcinogenesis. Since several inhibitors of ChoKα display antiproliferative activity in both cellular and animal models, this novel oncogene has recently gained interest as a promising small molecule target for cancer therapy. Here we summarize our efforts to further validate ChoKα as an oncogenic target and explore the activity of novel small molecule inhibitors of ChoKα. Starting from weakly binding fragments, we describe a structure based lead discovery approach, which resulted in novel highly potent inhibitors of ChoKα. In cancer cell lines, our lead compounds exhibit a dose-dependent decrease of phosphocholine, inhibition of cell growth, and induction of apoptosis at low micromolar concentrations. The druglike lead series presented here is optimizable for improvements in cellular potency, drug target residence time, and pharmacokinetic parameters. These inhibitors may be utilized not only to further validate ChoKα as antioncogenic target but also as novel chemical matter that may lead to antitumor agents that specifically interfere with cancer cell metabolism.

Multiplexed G-protein-coupled receptor Ca2+ flux assays for high-throughput screening.

An early drug discovery approach focusing on gene families can benefit from strategies that exploit common signaling mechanisms to more effectively identify and characterize novel chemical lead structures. Multiplexing, defined as the screening of multiple targets within the same experiment, is an example of this strategy. Here, the authors describe a technique that allows multiplexing of a common assay type used to study G-protein-coupled receptors: changes in intracellular Ca2+ levels as measured by Molecular Device's fluorometric imaging plate reader (FLIPR). The multiplexed FLIPR assays showed the expected pharmacological properties of single assays, with good reproducibility and Z* factors. The authors used them to screen large compound libraries in 2 multiplexed assay designs. The 1st used a single-cell line expressing 2 different receptors and the 2nd a mixture of 2 cell lines of the same type each expressing distinct receptors. Screening using these multiplexed assays produced significant savings in reagents, time, and human resources and allowed the authors to quickly identify specific and selective hits.