Phase-stable source of polarization-entangled photons in a linear double-pass configuration

We demonstrate a compact, robust, and highly efficient source of polarization-entangled photons, based on linear bi-directional down-conversion in a novel 'folded sandwich' configuration. Bi-directionally pumping a single periodically poled KTiOPO$_4$ (ppKTP) crystal with a 405-nm laser diode, we generate entangled photon pairs at the non-degenerate wavelengths 784 nm (signal) and 839 nm (idler), and achieve an unprecedented detection rate of 11.8 kcps for 10.4 $\mu$W of pump power (1.1 million pairs / mW), in a 2.9-nm bandwidth, while maintaining a very high two-photon entanglement quality, with a Bell-state fidelity of $99.3\pm0.3$%

Biomarkers of basal cell carcinoma resistance to methyl-aminolevulinate photodynamic therapy

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Methyl-aminolevulinate photodynamic therapy (MAL-PDT) is an excellent option for the treatment of basal cell carcinoma (BCC). However, up to 25% of cases are resistant to this treatment modality. Objective The aim of this study was to identify potential biomarkers of BCC response to MAL-PDT. Material and methods Clinical, histological, and immunohistochemical (p53, Ki-67, CD-31, COX2, β-catenin, EGFR, and survivin) variables were analyzed in a retrospective study of consecutive BCC patients treated with MAL-PDT at the San Jorge Hospital, Huesca, Spain between January 2006 and December 2015. To deepen on these markers, the effects on p53 and cyclin D1 expression, in vitro response to MAL-PDT of 2 murine BCC cell lines (ASZ and BSZ), was also evaluated. Results The retrospective study examined the response to MAL-PDT of 390 BCCs from 182 patients. The overall clinical response rate was 82.8%, with a mean follow-up time of 35.96 months (SD = 23.46). Immunohistochemistry revealed positive p53 in 84.6% of responders but only 15.4% of nonresponsive tumors (p = 0.011). Tumors with increased peripheral palisading of basal cell islands to immunostaining β-catenin responded poorly to PDT (p = 0.01). In line with our findings in patients, in vitro studies revealed a better response to PDT in the p53-positive ASZ cell line than the p53-negative BSZ cell line (p<0.01). Multivariate analysis revealed that the following variables were significantly associated with response to PDT: age, nBCC, presence of peritumoral inflammatory infiltrate, and p53 immunopositivity. Patients with positive p53 immunostaining were 68.54 times more likely to achieve cure than p53-negative patients (CI95% 2.94–159.8) Conclusion Our finding suggest that certain clinicopathological and immunohistochemical variables, particularly p53 expression, may serve as indicators of BCC response to MAL-PDT, and thus facilitate the selection of patients who are most likely to benefit from this therapyThis project received support from the Instituto de Salud Carlos III and Fondos Feder Europeos, MINECO (FIS PI15/00974). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscrip

Experimental quantum imaging distillation with undetected light

Imaging based on the induced coherence effect makes use of photon pairs to obtain information of an object without detecting the light that probes it. While one photon illuminates the object, only its partner is detected, so no measurement of coincidence events are needed. The sought-after object's information is revealed observing a certain interference pattern on the detected photon. Here we demonstrate experimentally that this imaging technique can be made resilient to noise. We introduce an imaging distillation approach based on the interferometric modulation of the signal of interest. We show that our scheme can generate a high-quality image of an object even against noise levels up to 250 times the actual signal of interest. We also include a detailed theoretical explanation of our findings.Comment: 18 pages, 6 figures, and 1 table + 11 pages, 3 figures, and 1 tabl

Influence of Serum Vitamin D Level in the Response of Actinic Keratosis to Photodynamic Therapy with Methylaminolevulinate

In mouse models of squamous cell carcinoma, pre-treatment with calcitriol prior to photodynamic therapy with aminolevulinic acid (ALA) enhances tumor cell death. We have evaluated the association between vitamin D status and the response of actinic keratoses to photodynamic therapy with methylaminolevulinate. Twenty-five patients with actinic keratoses on the head received one session of photodynamic therapy with methylaminolevulinate. Biopsies were taken at baseline and six weeks after treatment. Immuno-histochemical staining was performed for VDR, P53, Ki67 and beta-catenin. Basal serum 25(OH)D levels were determined. Cases with a positive histological response to treatment had significantly higher serum 25(OH)D levels (26.96 (SD 7.49) ngr/mL) than those without response (18.60 (SE 7.49) ngr/mL) (p = 0.05). Patients with a complete clinical response displayed lower basal VDR expression (35.71% (SD 19.88)) than partial responders (62.78% (SD 16.735)), (p = 0.002). Our results support a relationship between vitamin D status and the response of actinic keratoses to photodynamic therapy with methylaminolevulinate

Perspectives for applications of quantum imaging

Quantum imaging is a multifaceted field of research that promises highly efficient imaging in extreme spectral ranges as well as ultralow‐light microscopy. Since the first proof‐of‐concept experiments over 30 years ago, the field has evolved from highly fascinating academic research to the verge of demonstrating practical technological enhancements in imaging and microscopy. Here, the aim is to give researchers from outside the quantum optical community, in particular those applying imaging technology, an overview of several promising quantum imaging approaches and evaluate both the quantum benefit and the prospects for practical usage in the near future. Several use case scenarios are discussed and a careful analysis of related technology requirements and necessary developments toward practical and commercial application is provided

Quantum holography with undetected light

Holography exploits the interference of light fields to obtain a systematic reconstruction of the light fields wavefronts. Classical holography techniques have been very successful in diverse areas such as microscopy, manufacturing technology, and basic science. Extending holographic methods to the level of single photons has been proven challenging, since applying classical holography techniques to this regime pose technical problems. Recently the retrieval of the spatial structure of a single photon, using another photon under experimental control with a well-characterized spatial shape as reference, was demonstrated using the intrinsically non-classical Hong-Ou-Mandel interference on a beam splitter. Here we present a method for recording a hologram of single photons without detecting the photons themselves, and importantly, with no need to use a well-characterized companion reference photon. Our approach is based on quantum interference between two-photon probability amplitudes in a nonlinear interferometer. As in classical holography, the hologram of a single photon allows retrieving the complete information about the "shape" of the photon (amplitude and phase) despite the fact that the photon is never detected.Comment: 29 pages with 11 figures, submitted to Nature Communication

Experimental analysis on image resolution of quantum imaging with undetected light through position correlations

Image resolution of quantum imaging with undetected photons is governed by the spatial correlations existing between the photons of a photon pair that has been generated in a nonlinear process. These correlations allow for obtaining an image of an object with light that never interacted with that object. Depending on the imaging configuration, either position or momentum correlations are exploited. We hereby experimentally analyse how the crystal length and pump waist affect the image resolution when using position correlations of photons that have been generated via spontaneous parametric down conversion in a nonlinear interferometer. Our results support existing theoretical models for the dependency of the resolution on the crystal length. In addition, we probe the resolution of our quantum imaging scheme for varying pump waists over one order of magnitude. This analysis reveals the intricate dependency of the resolution on the strength of the correlations within the biphoton states for parameter combinations in which the crystal lengths are much larger than the involved photon wavelengths. We extend the existing models in this parameter regime to properly take nontrivial effects of finite pump waists into account and demonstrate that they match the experimental results.Comment: 28 pages, 9 figure

Metformin overcomes metabolic reprogramming-induced resistance of skin squamous cell carcinoma to photodynamic therapy

Cancer metabolic reprogramming promotes resistance to therapies. In this study, we addressed the role of the Warburg effect in the resistance to photodynamic therapy (PDT) in skin squamous cell carcinoma (sSCC). Furthermore, we assessed the effect of metformin treatment, an antidiabetic type II drug that modulates metabolism, as adjuvant to PDT. Methods: For that, we have used two human SCC cell lines: SCC13 and A431, called parental (P) and from these cell lines we have generated the corresponding PDT resistant cells (10GT). Results: Here, we show that 10GT cells induced metabolic reprogramming to an enhanced aerobic glycolysis and reduced activity of oxidative phosphorylation, which could influence the response to PDT. This result was also confirmed in P and 10GT SCC13 tumors developed in mice. The treatment with metformin caused a reduction in aerobic glycolysis and an increase in oxidative phosphorylation in 10GT sSCC cells. Finally, the combination of metformin with PDT improved the cytotoxic effects on P and 10GT cells. The combined treatment induced an increase in the protoporphyrin IX production, in the reactive oxygen species generation and in the AMPK expression and produced the inhibition of AKT/mTOR pathway. The greater efficacy of combined treatments was also seen in vivo, in xenografts of P and 10GT SCC13 cells. Conclusions: Altogether, our results reveal that PDT resistance implies, at least partially, a metabolic reprogramming towards aerobic glycolysis that is prevented by metformin treatment. Therefore, metformin may constitute an excellent adjuvant for PDT in sSCCThis research was supported by Spanish grants from Instituto de Salud Carlos III MINECO and Feder Funds (FIS PI15/00974; PI18/00858 and PI18/00708) and Ministerio de Ciencia, Innovación y Universidades (PID2019-108674RB-100

Characterisation of resistance mechanisms developed by basal cell carcinoma cells in response to repeated cycles of photodynamic therapy

photodynamic therapy (pDt) with methyl-aminolevulinate acid (MAL-pDt) is being used for the treatment of Basal cell carcinoma (BCC), but recurrences have been reported. In this work, we have evaluated resistance mechanisms to MAL-pDt developed by three BCC cell lines (AsZ, BsZ and CsZ), derived from mice on a ptch+/− background and with or without p53 expression, subjected to 10 cycles of PDT (10thG). the resistant populations showed mesenchymal-like structure and diminished proliferative capacity and size compared to the parental (p) cells. the resistance was dependent on the production of the endogenous photosensitiser protoporphyrin IX in the CsZ cell line and on its cellular localisation in AsZ and BsZ cells. Moreover, resistant cells expressing the p53 gene presented lower proliferation rate and increased expression levels of N-cadherin and Gsk3β (a component of the Wnt/β-catenin pathway) than P cells. In contrast, 10thG cells lacking the p53 gene showed lower levels of expression of Gsk3β in the cytoplasm and of e-cadherin and β-catenin in the membrane. In addition, resistant cells presented higher tumorigenic ability in immunosuppressed mice. Altogether, these results shed light on resistance mechanisms of BCC to pDt and may help to improve the use of this therapeutic approac

Tumor microenvironment in non-melanoma skin cancer resistance to photodynamic therapy

Non-melanoma skin cancer has recently seen an increase in prevalence, and it is estimated that this grow will continue in the coming years. In this sense, the importance of therapy effectiveness has increased, especially photodynamic therapy. Photodynamic therapy has attracted much attention as a minimally invasive, selective and repeatable approach for skin cancer treatment and prevention. Although its high efficiency, this strategy has also faced problems related to tumor resistance, where the tumor microenvironment has gained a well-deserved role in recent years. Tumor microenvironment denotes a wide variety of elements, such as cancer-associated fibroblasts, immune cells, endothelial cells or the extracellular matrix, where their interaction and the secretion of a wide diversity of cytokines. Therefore, the need of designing new strategies targeting elements of the tumor microenvironment to overcome the observed resistance has become evident. To this end, in this review we focus on the role of cancer-associated fibroblasts and tumor-associated macrophages in the resistance to photodynamic therapy. We are also exploring new approaches consisting in the combination of new and old drugs targeting these cells with photodynamic therapy to enhance treatment outcomes of non-melanoma skin cance