Analysis and implementation of volume reflection gratings in photorefractive lithium niobate for edge enhancement.

Diffraction from volume reflection gratings written in bulk photorefractive lithium niobate is modeled for the case of longitudinally varying index modulation depths. Numerical solutions to the Helmholtz equation are found in the spatial frequency domain, leading to transfer functions for the volume reflection grating. These transfer functions are then used to show the spatial frequency filtering effect of the volume reflection grating on input light fields containing 2D spatial information. It is shown, first through simulations and then by experiment, that the 0th order transmitted beam undergoes a 2D edge enhancement.

Transport of intensity and phase: applications to digital holography [Invited].

We first review transport of intensity and phase and show their use as a convenient tool to directly determine the unwrapped phase of an imaged object, either through conventional imaging or using digital holography. For both cases, either the traditional transport of intensity and phase, or with a modification, viz., electrically controllable transport of intensity and phase, can be used. The use of digital holography with transport of intensity for 3D topographic mapping of fingermarks coated with columnar thin films is shown as an illustrative application of this versatile technique.

LP-184, a Novel Acylfulvene Molecule, Exhibits Anticancer Activity against Diverse Solid Tumors with Homologous Recombination Deficiency.

Homologous recombination (HR)-related gene alterations are present in a significant subset of prostate, breast, ovarian, pancreatic, lung, and colon cancers rendering these tumors as potential responders to specific DNA damaging agents. A small molecule acylfulvene prodrug, LP-184, metabolizes to an active compound by the oxidoreductase activity of enzyme prostaglandin reductase 1 (PTGR1), which is frequently elevated in multiple solid tumor types. Prior work demonstrated that cancer cell lines deficient in a spectrum of DNA damage repair (DDR) pathway genes show increased susceptibility to LP-184. Here, we investigated the potential of LP-184 in targeting multiple tumors with impaired HR function and its mechanism of action as a DNA damaging agent. LP-184 induced elevated DNA double-strand breaks in HR deficient (HRD) cancer cells. Depletion of key HR components BRCA2 or ataxia telangiectasia mutated (ATM) in cancer cells conferred up to 12-fold increased sensitivity to the LP-184. LP-184 showed nanomolar potency in a diverse range of HRD cancer models, including prostate cancer organoids, leiomyosarcoma cell lines, and patient-derived tumor graft models of lung, pancreatic, and prostate cancers. LP-184 demonstrated complete, durable tumor regression in 10 patient-derived xenograft (PDX) models of HRD triple-negative breast cancer (TNBC) including those resistant to PARP inhibitors (PARPi). LP-184 further displayed strong synergy with PARPi in ovarian and prostate cancer cell lines as well as in TNBC PDX models. These preclinical findings illustrate the potential of LP-184 as a pan-HRD cancer therapeutic. Taken together, our results support continued clinical evaluation of LP-184 in a large subset of HRD solid tumors. SIGNIFICANCE: New agents with activity against DDR-deficient solid tumors refractory to standard-of-care therapies are needed. We report multiple findings supporting the potential for LP-184, a novel alkylating agent with three FDA orphan drug designations, to fill this void clinically: strong nanomolar potency; sustained, durable regression of solid tumor xenografts; synthetic lethality with HR defects. LP-184 adult phase IA trial to assess safety in advanced solid tumors is ongoing.

Multiplexed digital volume reflection holograms generated from digital transmission holograms.

Interference from co-propagation of the object and reference beams can be digitally recorded for a digital transmission hologram (DTH). Volume holograms, as in display holography, which have been traditionally recorded in bulk photopolymer or photorefractive materials using a counter-propagating object and writing beams, are read out using multispectral light and offer the advantage of excellent wavelength selectivity. In this work, the reconstruction from a single digital volume reflection hologram (DVRH) and wavelength multiplexed DVRHs derived from respective single and multi-wavelength DTHs is investigated, using coupled wave theory and an angular spectral approach. The dependence of the diffraction efficiency on volume grating thickness, wavelength, and incident angle of the reading beam is studied.

Digital Holography and 3D Imaging: introduction to the joint feature issue in Applied Optics and Journal of the Optical Society of America A.

This feature issue is a continuation of a tradition to follow the conclusion of the Optica Topical Meeting on Digital Holography and 3D Imaging (DH+3D). It addresses current research topics in digital holography and 3D imaging that are also in line with the topics of Applied Optics and Journal of the Optical Society of America A.

Digital Holography and 3D Imaging: introduction to the joint feature issue in Applied Optics and Journal of the Optical Society of America A.

This feature issue is a continuation of a tradition to follow the conclusion of the Optica Topical Meeting on Digital Holography and 3D Imaging (DH+3D). It addresses current research topics in digital holography and 3D imaging that are also in line with the topics of Applied Optics and Journal of the Optical Society of America A.

A multi-omics approach identifies pancreatic cancer cell extracellular vesicles as mediators of the unfolded protein response in normal pancreatic epithelial cells.

Although cancer-derived extracellular vesicles (cEVs) are thought to play a pivotal role in promoting cancer progression events, their precise effect on neighbouring normal cells is unknown. In this study, we investigated the impact of pancreatic cancer ductal adenocarcinoma (PDAC) derived EVs on recipient non-tumourigenic pancreatic normal epithelial cells upon internalization. We demonstrate that cEVs are readily internalized and induce endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in treated normal pancreatic epithelial cells within 24 h. We further show that PDAC cEVs increase cell proliferation, migration, and invasion and that these changes are regulated at least in part, by the UPR mediator DDIT3. Subsequently, these cells release several inflammatory cytokines. Leveraging a layered multi-omics approach, we analysed EV cargo from a panel of six PDAC and two normal pancreas cell lines, using multiple EV isolation methods. We found that cEVs were enriched for an array of biomolecules which can induce or regulate ER stress and the UPR, including palmitic acid, sphingomyelins, metabolic regulators of tRNA charging and proteins which regulate trafficking and degradation. We further show that palmitic acid, at doses relevant to those found in cEVs, is sufficient to induce ER stress in normal pancreas cells. These results suggest that cEV cargo packaging may be designed to disseminate proliferative and invasive characteristics upon internalization by distant recipient normal cells, hitherto unreported. This study is among the first to highlight a major role for PDAC cEVs to induce stress in treated normal pancreas cells that may modulate a systemic response leading to altered phenotypes. These findings highlight the importance of EVs in mediating disease aetiology and open potential areas of investigation toward understanding the role of cEV lipids in promoting cell transformation in the surrounding microenvironment.

Digital Holography and 3D Imaging: introduction to the joint feature issue in Applied Optics and Journal of the Optical Society of America A.

This feature issue is a continuation of a tradition, since 2007, to follow the conclusion of the OSA Topical Meeting on Digital Holography and 3D Imaging (DH+3D). It addresses current research topics in digital holography (DH) and 3D imaging that are also in line with the topics of Applied Optics (AO) and the Journal of the Optical Society of America A (JOSA A).

Non-recursive transport of intensity phase retrieval with the transport of phase.

The transport of intensity equation (TIE) is a non-interferometric phase retrieval method that originates from the imaginary part of the Helmholtz equation and is equivalent to the law of conservation of energy. From the real part of the Helmholtz equation, the transport of phase equation (TPE), which represents the Eikonal equation in the presence of diffraction, can be derived. The amplitude and phase for an arbitrary optical field should satisfy these coupled equations simultaneously during propagation. In this work, the coupling between the TIE and TPE is exploited to improve the phase retrieval solutions from the TIE. Specifically, a non-recursive fast Fourier transform (FFT)-based phase retrieval method using both the TIE and TPE is demonstrated. Based on the FFT-based TIE solution, a correction factor calculated by the TPE is introduced to improve the phase retrieval results.

Use of structured light in 3D reconstruction of transparent objects.

A simple non-interferometric incoherent light ray propagation model is introduced to perform three-dimensional profiling of transparent objects with typical thicknesses of the order of mm to cm by analyzing the distorted captured image behind the object. A two-dimensional cosine fringe is used as the incident reference image, whose periodicity is markedly altered by the shape of the object. By monitoring the local change in the period, the surface profile is simulated and optimized to achieve minimal error with experimental data and thus determine the final morphology. Our proposed method is simple, robust, straightforward, and single-shot, and can be used with coherent or incoherent illumination. Its feasibility for more complex applications is verified experimentally through rigorous error calculation. Moreover, the application of this technique for arbitrary transparent objects is theoretically attainable and promising.

Digital Holography and 3D Imaging: introduction to the joint feature issue in Applied Optics and Journal of the Optical Society of America A.

This feature issue is a continuation of a tradition, since 2007, to follow the conclusion of the OSA Topical Meeting on Digital Holography and 3D Imaging (DH+3D). It addresses current research topics in digital holography (DH) and 3D imaging that are also in line with the topics of Applied Optics (AO) and the Journal of the Optical Society of America A (JOSA A).

Novel Paired Normal Prostate and Prostate Cancer Model Cell Systems Derived from African American Patients.

Prostate cancer is the most frequently diagnosed solid malignancy in men. African American (AA) men are at greater risk for developing prostate cancer, and experience higher mortality rates, as compared with Caucasian American men. However, mechanistic studies to understand this health disparity have been limited by the lack of relevant in vitro and in vivo models. There is an urgent need for preclinical cellular models to investigate molecular mechanisms underlying prostate cancer in AA men. We collected clinical specimens from radical prostatectomies of AA patients and established 10 paired tumor-derived and normal epithelial cell cultures from the same donors, which were further cultivated to extend the growth under "conditional reprogramming." Clinical and cellular annotations characterized these model cells as intermediate risk and predominantly diploid. Immunocytochemical analyses demonstrated variable expression levels of luminal (CK8) and basal (CK5, p63) markers in both normal and tumor cells. However, expression levels of TOPK, c-MYC, and N-MYC were markedly increased only in tumor cells. To determine cell utility for drug testing, we examined viability of cells following exposure to the antiandrogen (bicalutamide) and two PARP inhibitors (olaparib and niraparib) and observed decreased viability of tumor-derived cells as compared with viability of normal prostate-derived cells. Significance: Cells derived from prostatectomies of AA patients conferred a bimodal cellular phenotype, recapitulating clinical prostate cellular complexity in this model cell system. Comparisons of viability responses of tumor derived to normal epithelial cells offer the potential for screening therapeutic drugs. Therefore, these paired prostate epithelial cell cultures provide an in vitro model system suitable for studies of molecular mechanisms in health disparities.

TGFß Drives Metabolic Perturbations during Epithelial Mesenchymal Transition in Pancreatic Cancer: TGFß Induced EMT in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy wherein a majority of patients present metastatic disease at diagnosis. Although the role of epithelial to mesenchymal transition (EMT), mediated by transforming growth factor beta (TGFß), in imparting an aggressive phenotype to PDAC is well documented, the underlying biochemical pathway perturbations driving this behaviour have not been elucidated. We used high-resolution mass spectrometry (HRMS) based molecular phenotyping approach in order to delineate metabolic changes concomitant to TGFß-induced EMT in pancreatic cancer cells. Strikingly, we observed robust changes in amino acid and energy metabolism that may contribute to tumor invasion and metastasis. Somewhat unexpectedly, TGFß treatment resulted in an increase in intracellular levels of retinoic acid (RA) that in turn resulted in increased levels of extracellular matrix (ECM) proteins including fibronectin (FN) and collagen (COL1). These findings were further validated in plasma samples obtained from patients with resectable pancreatic cancer. Taken together, these observations provide novel insights into small molecule dysregulation that triggers a molecular cascade resulting in increased EMT-like changes in pancreatic cancer cells, a paradigm that can be potentially targeted for better clinical outcomes.

Stress-Mediated Reprogramming of Prostate Cancer One-Carbon Cycle Drives Disease Progression.

One-carbon (1C) metabolism has a key role in metabolic programming with both mitochondrial (m1C) and cytoplasmic (c1C) components. Here we show that activating transcription factor 4 (ATF4) exclusively activates gene expression involved in m1C, but not the c1C cycle in prostate cancer cells. This includes activation of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) expression, the central player in the m1C cycle. Consistent with the key role of m1C cycle in prostate cancer, MTHFD2 knockdown inhibited prostate cancer cell growth, prostatosphere formation, and growth of patient-derived xenograft organoids. In addition, therapeutic silencing of MTHFD2 by systemically administered nanoliposomal siRNA profoundly inhibited tumor growth in preclinical prostate cancer mouse models. Consistently, MTHFD2 expression is significantly increased in human prostate cancer, and a gene expression signature based on the m1C cycle has significant prognostic value. Furthermore, MTHFD2 expression is coordinately regulated by ATF4 and the oncoprotein c-MYC, which has been implicated in prostate cancer. These data suggest that the m1C cycle is essential for prostate cancer progression and may serve as a novel biomarker and therapeutic target. SIGNIFICANCE: These findings demonstrate that the mitochondrial, but not cytoplasmic, one-carbon cycle has a key role in prostate cancer cell growth and survival and may serve as a biomarker and/or therapeutic target.

Performance analysis of phase retrieval using transport of intensity with digital holography [Invited].

The performance of direct and unwrapped phase retrieval, which combines digital holography with the transport of intensity, is examined in detail in this paper. In this technique, digital holography is used to numerically reconstruct the intensities at different planes around the image plane, and phase retrieval is achieved by the transport of intensity. Digital holography with transport of intensity is examined for inline and off-axis geometries. The effect of twin images in the inline case is evaluated. Phase-shifting digital holography with transport of intensity is introduced. The performance of digital holography with transport of intensity is compared with traditional off-axis single- and dual-wavelength techniques, which employ standard phase unwrapping algorithms. Simulations and experiments are performed to determine and compare the accuracy of phase retrieval through a mean-squared-error figure of merit as well as the computational speeds of the various methods.

Single-shot digital phase-shifting Moiré patterns for 3D topography.

A simple and robust technique of Moiré topography with single-image capture and incorporating digital filtering along with a four-step digitally implemented phase-shifting method is introduced for three-dimensional (3D) surface mapping. Feature details in the order of tens to hundreds of microns can be achieved using interferometrically generated structured light to illuminate the object surface. Compared to the traditional optical phase-shifting method, a digital phase-shifting method based on Fourier processing is implemented with computer-generated sinusoidal patterns derived from the recorded deformed fringes. This enables a single capture of the image that can be used to reconstruct the 3D topography of the surface. Single-shot imaging is simple to implement experimentally and avoids errors in introducing the correct phase shifts. The feasibility of this technique is verified experimentally, and applications to metallic surfaces are demonstrated.

T-LAK cell-originated protein kinase (TOPK) enhances androgen receptor splice variant (ARv7) and drives androgen-independent growth in prostate cancer.

Despite impressive advances in the treatment of prostate cancer with various efficacious inhibitors along the androgen/androgen receptor axis, eventual development of incurable metastatic Castration-Resistant Prostate Cancer (mCRPC) is inevitable and remains a major clinical challenge. Constitutively active androgen receptor (AR) spliced variants have emerged as primary means of resistance to anti-androgens and androgen synthesis inhibitors. The alternatively spliced AR variant, ARv7, has attracted significant interest due to its constitutively active status in CRPC that drives androgen-independence. Factors that are involved in regulating ARv7 levels in CRPC are not clearly known. We recently demonstrated that a protein kinase, T-LAK cell-originated protein kinase (TOPK) level correlates with the aggressiveness of prostate cancer and its invasive behavior. In this study, we investigated whether TOPK plays a role in driving androgen-independence in prostate cancer cells. Our data demonstrate that TOPK overexpression in androgen-dependent LNCaP and VCaP induces ARv7 and drives androgen-independent growth. On the other hand, pharmacological inhibition of TOPK in androgen-independent LNCaP95 and 22Rv1 represses AR transactivation, and AR stability. In summary, this study illustrates a direct role of TOPK in regulating ARv7 and driving androgen-independence in prostate cancer cells.

2 × 2 anisotropic transfer matrix approach for optical propagation in uniaxial transmission filter structures.

Multi-layered metamaterial structures show promise in a wide variety of optical applications such as superlenses, electromagnetic cloaking, tunable filters, sensors, and spatial light modulators. Optical transmission analysis of multilayer metallo-dielectric stacks with overall thickness less than the wavelength of light can be modeled using effective medium theory and the Berreman matrix method. For multilayer anisotropic stacks of arbitrary thickness, a rigorous 4 × 4 transfer matrix embodiment is typically used. In this work, a 2 × 2 anisotropic transfer matrix method is developed to analyze optical propagation through multilayer uniaxial stacks of arbitrary thicknesses. Optical transmission of a multilayer silver-zinc oxide stack deposited on a quartz substrate is modeled with this 2 × 2 anisotropic transfer matrix method and reconciled with experimental observations. Results indicate that this numerical approach is applicable to in situ assessment of the complex refractive indices of constituent metal and dielectric layers. Additionally, the anisotropic 2 × 2 transfer matrix method enables the possibility of modeling the transmission of the same metallo-dielectric structure deposited on an electro-optic, uniaxial substrate. Simulation results predict that adjusting the bias field across the substrate results in an electrically tunable transmission filter.

Digital correlation of computer-generated holograms for 3D face recognition.

Three-dimensional (3D) face recognition has been a crucial task in human biometric verification and identification. A digital correlation method of a computer-generated hologram (CGH) for 3D face recognition is proposed, which encodes 3D data into a 2D hologram for recognition. The 3D face models are preprocessed and compressed to into groups of feature points. The CGH templates corresponding to the 3D feature points are generated by point- and layer-oriented algorithms based on three different numerical algorithms to encode depth values into 2D holograms. A 2D digital correlation is performed between the CGH templates. It is demonstrated that the generated CGHs templates could be effectively classified based on the correlation performance metrics of discrimination ratio, peak-to-correlation plane energy, and peak-to-noise ratio. With the essence of the CGH algorithm being the conversion of 3D data to a 2D hologram, the proposed encoding and decoding method has great advantages in reducing computational efforts and potential applications in 3D face recognition, storage, and display.

3D object recognition through processing of 2D holograms.

Correlation of two-dimensional digitally recorded holograms is introduced as a novel approach for object recognition without the need for quantitative assessment of the retrieved complex field, based on the fact that a hologram contains the three-dimensional information of the object. Actual objects with different three-dimensional features such as depth and surface roughness are assessed through processing of the correlation of their two-dimensional holograms. Correlation peak values are extracted as a metric to evaluate correlation of three-dimensional objects. The effect of hologram windowing size on correlation of three-dimensional objects is investigated, and improvements in computation time and dynamic range are assessed. Critical figures of merit used for assessment of correlation of images are applied to the correlation of holograms for object recognition.