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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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.
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.
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.
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 Kras
GEMM of lung adenocarcinoma model.
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 Kras
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.
We show that arginase expression is elevated in mouse and patient lung tumors. In a KRAS
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.
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.
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.
Activating gene rearrangements of anaplastic lymphoma kinase (ALK) have been identified as driver mutations in non‐small‐cell lung cancer, inflammatory myofibroblastic tumors, and other cancers. ...Crizotinib, a dual MET/ALK inhibitor, has demonstrated promising clinical activity in patients with non‐small‐cell lung cancer and inflammatory myofibroblastic tumors harboring ALK translocations. Inhibitors of driver kinases often elicit kinase domain mutations that confer resistance, and such mutations have been successfully predicted using in vitro mutagenesis screens. Here, this approach was used to discover an extensive set of ALK mutations that can confer resistance to crizotinib. Mutations at 16 residues were identified, structurally clustered into five regions around the kinase active site, which conferred varying degrees of resistance. The screen successfully predicted the L1196M, C1156Y, and F1174L mutations, recently identified in crizotinib‐resistant patients. In separate studies, we demonstrated that crizotinib has relatively modest potency in ALK‐positive non‐small‐cell lung cancer cell lines. A more potent ALK inhibitor, TAE684, maintained substantial activity against mutations that conferred resistance to crizotinib. Our study identifies multiple novel mutations in ALK that may confer clinical resistance to crizotinib, suggests that crizotinib’s narrow selectivity window may underlie its susceptibility to such resistance and demonstrates that a more potent ALK inhibitor may be effective at overcoming resistance.
A mutagenesis screen identified multiple mutations in the kinase domain that confer resistance to the first generation ALK inhibitor crizotinib. Our studies suggest that crizotinib’s low potency and narrow selectivity window for ALK may underlie its susceptibility to such resistance. These results provide guidance for the rational design and optimization of potent and selective second generation drugs that may be able to overcome ALK‐based mechanisms of resistance.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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In this work we try to understand the real effect of increase in aberrations after Femto-LASIK surgery on the patient’s final visual quality, specifically when the visual acuity measurement is ...considered. A clinical study with 37 eyes of 20 patients that underwent myopic Femto-LASIK surgery and different personalized eye model simulations were carried out. In clinical study, correlations between pre- and postoperative parameters with visual acuity were analysed. Eye simulations (based on real data) provided simulations of vision quality before and after surgery. Our main results showed a significant increase in aberrations was obtained after surgery; however, no differences were found between the preoperative corrected distance visual acuity (CDVA) and the postoperative uncorrected distance visual acuity (UDVA). This absence of differences in visual quality could be explained by performing different simulations on three eyes that would cover most of the possible clinical situations. Simulations were implemented considering a pupil size of 2.5 mm and the personalized data of each patient. Results showed that final visual acuity (VA) change are determined by the final high-order aberrations (HOAS) and their increase after surgery but measured under photopic conditions. In conclusion, customized analysis of higher-order aberrations in scotopic pupils better predicts patient visual acuity after Lasik surgery.
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