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 anti-cancer 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 (DSB) in HR deficient (HRD) cancer cells. Depletion of key HR components BRCA2 or 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 PDX models of HRD triple-negative breast cancer (TNBC) including those resistant to Poly-ADP ribose polymerase 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.

Understanding the patient and supporter journey in cocaine use disorder.

Background: There is a paucity of literature describing experiences and journey of individuals with cocaine use disorder (CUD) and supporters who care for them. The aim of this study was to understand and document the journey of individuals with current CUD, those in CUD remission, and supporters. Methods: The online bulletin board (OBB) is a qualitative tool where participants engage in an interactive discussion on a virtual forum. After completing a 15-minute screening questionnaire determining eligibility, individuals in CUD remission and supporters participated in an OBB for 60 minutes, split across 8 days over 2 weeks. Individuals with current CUD participated in a one-time virtual focus group discussion for 90 minutes. Results: Individuals in CUD remission (n=35) were from Brazil, France, Spain, the UK, and the US; those with current CUD (n=5) and supporters (n=6) were from the US. Key insights were that individuals with current CUD were seeking a 'euphoric high' that cocaine provides. Those in CUD remission described a 'euphoric high' when they first tried cocaine, but over time it became harder to re-create this feeling. Individuals in CUD remission expressed a 'rollercoaster' of emotions from when they first started using cocaine to when they stopped. Supporters were sad, isolated, and worried about a potential cocaine overdose for their loved ones with CUD. Conclusion: The study provides valuable insights into the experiences and journey of individuals with CUD and their supporters. Data generated from this study gives insights into this under-served and growing population.

Patient perspectives on current and potential therapies and clinical trial approaches for cocaine use disorder.

Background: Cocaine use disorder (CUD) is characterized by the continued use of cocaine despite serious impacts on life. This study focused on understanding the perspective of individuals with current CUD, individuals in CUD remission, and their supporters regarding current therapies, future therapies, and views on clinical trials for CUD. Methods: The online bulletin board (OBB) is a qualitative tool where participants engage in an interactive discussion on a virtual forum. Following completion of a screening questionnaire to determine eligibility, individuals in CUD remission and their supporters logged in to the OBB and responded to questions posed by the moderator. Individuals with current CUD participated in a one-time virtual focus group. Results: All individuals with current CUD and 94% of those in CUD remission reported a diagnosis consistent with CUD or substance use disorder during screening. Individuals with current CUD and their supporters were recruited from the United States (US). Individuals in CUD remission were recruited from five countries, including the US. Individuals with current CUD reported hesitation about seeking treatment due to stigma, a lack of privacy, and being labeled as a drug seeker; barriers to therapy included time, cost, and a lack of privacy. Participants wanted a safe therapy to stop cravings and withdrawal symptoms. Seven clinical trial outcomes, including long-term abstinence and craving control, were suggested based on collected insights. Conclusion: This study can help inform the design of clinical trials and emphasize the need for effective, safe, and accessible therapies. Recruiting participants will require significant trust building.

Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND: Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients. METHODS: In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. RESULTS: In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan. CONCLUSIONS: Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).

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.

Nonlinear optical properties and carrier recombination lifetime of GaN.

Nonlinear optical properties of a selection of gallium nitride samples have been measured using picosecond and nanosecond duration laser pulses at 532 nm. The values of the two-photon absorption coefficient, free carrier absorption cross section, and free carrier refraction cross section are determined along with the recombination lifetime of photogenerated carriers. The effect of hot isostatic pressing on these properties in samples with linear absorption at the band edge due to defects is explored.

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.

Novel chimeric monoclonal antibodies that block fentanyl effects and alter fentanyl biodistribution in mice.

The prevalence and societal impact of opioid use disorder (OUD) is an acknowledged public health crisis that is further aggravated by the current pandemic. One of the devastating consequences of OUD is opioid overdose deaths. While multiple medications are now available to treat OUD, given the prevalence and societal burden, additional well-tolerated and effective therapies are still needed. To this point, we have developed chimeric monoclonal antibodies (mAb) that will specifically complex with fentanyl and its analogs in the periphery, thereby preventing them from reaching the central nervous system. Additionally, mAb-based passive immunotherapy offers a high degree of specificity to drugs of abuse and does not interfere with an individual's ability to use any of the medications used to treat OUD. We hypothesized that sequestering fentanyl and its analogs in the periphery will mitigate their negative effects on the brain and peripheral organs. This study is the first report of chimeric mAb against fentanyl and its analogs. We have discovered, engineered the chimeric versions, and identified the selectivity of these antibodies, through in vitro characterization and in vivo animal challenge studies. Two mAb candidates with very high (0.1-1.3 nM) binding affinities to fentanyl and its analogs were found to be effective in engaging fentanyl in the periphery and blocking its effects in challenged animals. Results presented in this work constitute a major contribution in the field of novel therapeutics targeting OUD.

Genetic diversity in the Tams1 gene of Theileria annulata (Duschunkowsky and Luhs, 1904) infecting cattle.

The present study describes the genetic diversity in the Tams1 gene (733 bp) of Theileria annulata along with the sequence, phylogenetic and haplotype analyses of the Indian isolates. The phylogenetic analyses displayed distinct clustering of the Indian isolates into three groups suggesting the presence of three genotypes, hitherto designated as T. annulata genotypes 1-3 (G1-G3). Genotype 3 seems to be novel containing only two newly generated sequences. Indian isolates displayed 88.4-100% and 82.2-100% similarity with each other at nucleotide (nt) and amino acid (aa) levels, respectively. However, the newly generated sequences (n = 36) showed 90.5-100% and 84.3-100% identity between them at nt and aa levels, respectively. The most diverse and heterogeneous genotype, G1, exhibited the highest number of polymorphic sites (S = 148), haplotypes (h = 16) and nucleotide differences (k = 43.23) besides haplotype (Hd = 0.903 ± 0.031) and nucleotide (π = 0.059 ± 0.005) diversities. Neutrality indices suggested a respective decrease and increase in population sizes of G1 and G2 genotypes in India. The nucleotide sequence analyses indicated the presence of extensive sequence variations between nucleotide positions 1-124, 194-257 and 396-494. The N-terminus of Tams1 protein displayed a considerable sequence variability with extensive variations in two regions, between amino acid positions 1-39 and 127-172, as compared to the conserved carboxyl terminus.

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.