Penetration depth of low-coherence enhanced backscattered light in sub-diffusion regime

The mechanisms of photon propagation in random media in the diffusive multiple scattering regime have been previously studied using diffusion approximation. However, similar understanding in the low-order (sub-diffusion) scattering regime is not complete due to difficulties in tracking photons that undergo very few scatterings events. Recent developments in low-coherence enhanced backscattering (LEBS) overcome these difficulties and enable probing photons that travel very short distances and undergo only a few scattering events. In LEBS, enhanced backscattering is observed under illumination with spatial coherence length L_sc less than the scattering mean free path l_s. In order to understand the mechanisms of photon propagation in LEBS in the subdiffusion regime, it is imperative to develop analytical and numerical models that describe the statistical properties of photon trajectories. Here we derive the probability distribution of penetration depth of LEBS photons and report Monte Carlo numerical simulations to support our analytical results. Our results demonstrate that, surprisingly, the transport of photons that undergo low-order scattering events has only weak dependence on the optical properties of the medium (l_s and anisotropy factor g) and strong dependence on the spatial coherence length of illumination, L_sc, relative to those in the diffusion regime. More importantly, these low order scattering photons typically penetrate less than l_s into the medium due to low spatial coherence length of illumination and their penetration depth is proportional to the one-third power of the coherence volume (i.e. [l_s \pi L_sc^2 ]^1/3).Comment: 32 pages(including 7 figures), modified version to appear in Phys. Rev.

Real time perfusion and oxygenation monitoring in an implantable optical sensor

Simultaneous blood perfusion and oxygenation monitoring is crucial for patients undergoing a transplant procedure. This becomes of great importance during the surgical recovery period of a transplant procedure when uncorrected loss of perfusion or reduction in oxygen saturation can result in patient death. Pulse oximeters are standard monitoring devices which are used to obtain the perfusion level and oxygen saturation using the optical absorption properties of hemoglobin. However, in cases of varying perfusion due to hemorrhage, blood clot or acute blockage, the oxygenation results obtained from traditional pulse oximeters are erroneous due to a sudden drop in signal strength. The long term goal of the project is to devise an implantable optical sensor which is able to perform better than the traditional pulse oximeters with changing perfusion and function as a local warning for sudden blood perfusion and oxygenation loss. In this work, an optical sensor based on a pulse oximeter with an additional source at 810nm wavelength has been developed for in situ monitoring of transplant organs. An algorithm has been designed to separate perfusion and oxygenation signals from the composite signal obtained from the three source pulse oximetry-based sensor. The algorithm uses 810nm reference signals and an adaptive filtering routine to separate the two signals which occur at the same frequency. The algorithm is initially applied to model data and its effectiveness is further tested using in vitro and in vivo data sets to quantify its ability to separate the signals of interest. The entire process is done in real time in conjunction with the autocorrelation-based time domain technique. This time domain technique uses digital filtering and autocorrelation to extract peak height information and generate an amplitude measurement and has shown to perform better than the traditional fast Fourier transform (FFT) for semi-periodic signals, such as those derived from heart monitoring. In particular, in this paper it is shown that the two approaches produce comparable results for periodic in vitro perfusion signals. However, when used on semi periodic, simulated, perfusion signals and in vivo data generated from an optical perfusion sensor the autocorrelation approach clearly (Standard Error, SE = 0.03) outperforms the FFT-based analysis (Standard Error, SE = 0.62)

Nanoscale changes in chromatin organization represent the initial steps of tumorigenesis: a transmission electron microscopy study

BACKGROUND: Nuclear alterations are a well-known manifestation of cancer. However, little is known about the early, microscopically-undetectable stages of malignant transformation. Based on the phenomenon of field cancerization, the tissue in the field of a tumor can be used to identify and study the initiating events of carcinogenesis. Morphological changes in nuclear organization have been implicated in the field of colorectal cancer (CRC), and we hypothesize that characterization of chromatin alterations in the early stages of CRC will provide insight into cancer progression, as well as serve as a biomarker for early detection, risk stratification and prevention. METHODS: For this study we used transmission electron microscopy (TEM) images of nuclei harboring pre-neoplastic CRC alterations in two models: a carcinogen-treated animal model of early CRC, and microscopically normal-appearing tissue in the field of human CRC. We quantify the chromatin arrangement using approaches with two levels of complexity: 1) binary, where chromatin is separated into areas of dense heterochromatin and loose euchromatin, and 2) grey-scale, where the statistics of continuous mass-density distribution within the nucleus is quantified by its spatial correlation function. RESULTS: We established an increase in heterochromatin content and clump size, as well as a loss of its characteristic peripheral positioning in microscopically normal pre-neoplastic cell nuclei. Additionally, the analysis of chromatin density showed that its spatial distribution is altered from a fractal to a stretched exponential. CONCLUSIONS: We characterize quantitatively and qualitatively the nanoscale structural alterations preceding cancer development, which may allow for the establishment of promising new biomarkers for cancer risk stratification and diagnosis. The findings of this study confirm that ultrastructural changes of chromatin in field carcinogenesis represent early neoplastic events leading to the development of well-documented, microscopically detectable hallmarks of cancer

Comparison of Mathematical Surface Energy Models and Fuzzy Approach Pertaining to Surface Energy Level of Polylactic Acid and Linear Low-density Polyethylene

The usage of flexible film in the food packaging industries has been rapidly increasing over the past few years. In flexible printing process, the wettability and adhesion of polymer substrates depend on the surface composition, roughness, energy level and tension. Among all these properties, the Surface Energy Level (SEL) of polar and nonpolar polymer substrates were determined by measuring Contact Angle Values (CAV). This study focuses on experimentation based SEL measurement using corona treatment for both treated and untreated LLDPE (Linear Low-Density Poly Ethylene) and PLA (Polylactic Acid) films using MSEM (Mathematical Surface Energy Models) such as Fowkes, Owens-Wendt, and Wu based on the CAV of polymer films and further to develop a Mamdani fuzzy interface based model for predicting optimum SEL with help of experimentally generated data. The observed SEL of untreated and treated PLA and LLDPE films were 40 and 38, 48 and 44 mN/m respectively. Fuzzy-based simulations showed similar results, with treated PLA and LLDPE at 45.4 and 44. Finally, the proposed Mamdani model can predict SEL with high accuracy in comparison with experimental results and the good printability of ink adhesion was achieved in treated than the untreated films

Differential Regulation of Mas-Related G Protein-Coupled Receptor X2- Mediated Mast Cell Degranulation by Antimicrobial Host Defense Peptides and Porphyromonas Gingivalis Lipopolysaccharide

Porphyromonas gingivalis is a keystone pathogen that contributes to periodontal pathogenesis by disrupting host-microbe homeostasis and promoting dysbiosis. The virulence of P. gingivalis likely reflects an alteration in the lipid A composition of its lipopolysaccharide (LPS) from the penta-acylated (PgLPS1690) to the tetra-acylated (PgLPS1435/1449) form. Mast cells play an important role in periodontitis, but the mechanisms of their activation and regulation remain unknown. The expression of epithelium- and neutrophil-derived host defense peptides (HDPs) (LL-37 and human β-defensin-3), which activate mast cells via Mas-related G protein-coupled receptor X2 (MRGPRX2), is increased in periodontitis. We found that MRGPRX2-expressing mast cells are present in normal gingiva and that their numbers are elevated in patients with chronic periodontitis. Furthermore, HDPs stimulated degranulation in a human mast cell line (LAD2) and in RBL-2H3 cells stably expressing MRGPRX2 (RBL-MRGPRX2). PgLPS1690 caused substantial inhibition of HDP-induced mast cell degranulation, but PgLPS1435/1449 had no effect. A fluorescently labeled HDP (FAM-LL-37) bound to RBLMRGPRX2 cells, and PgLPS1690 inhibited this binding, but PgLPS1435/1449 had no effect. These findings suggest that low-level inflammation induced by HDP/MRGPRX2- mediated mast cell degranulation contributes to gingival homeostasis but that sustained inflammation due to elevated levels of both HDPs and MRGPRX2-expressing mast cells promotes periodontal disease. Furthermore, differential regulation of HDP-induced mast cell degranulation by PgLPS1690 and PgLPS1435/1449 may contribute to the modulation of disease progression. © 2017 American Society for Microbiology

A Novel murine model identifies cooperating mutations and therapeutic targets critical for chronic myeloid leukemia progression

The introduction of highly selective ABL-tyrosine kinase inhibitors (TKIs) has revolutionized therapy for chronic myeloid leukemia (CML). However, TKIs are only efficacious in the chronic phase of the disease and effective therapies for TKI-refractory CML, or after progression to blast crisis (BC), are lacking. Whereas the chronic phase of CML is dependent on BCR-ABL, additional mutations are required for progression to BC. However, the identity of these mutations and the pathways they affect are poorly understood, hampering our ability to identify therapeutic targets and improve outcomes. Here, we describe a novel mouse model that allows identification of mechanisms of BC progression in an unbiased and tractable manner, using transposon-based insertional mutagenesis on the background of chronic phase CML. Our BC model is the first to faithfully recapitulate the phenotype, cellular and molecular biology of human CML progression. We report a heterogeneous and unique pattern of insertions identifying known and novel candidate genes and demonstrate that these pathways drive disease progression and provide potential targets for novel therapeutic strategies. Our model greatly informs the biology of CML progression and provides a potent resource for the development of candidate therapies to improve the dismal outcomes in this highly aggressive disease.Work in the Huntly laboratory is funded by CRUK, The European Research Council (ERC), Leukaemia Lymphoma Research, the Kay Kendall Leukaemia Fund, Wellcome Trust, the Medical Research Council (UK), the Leukemia Lymphoma Society America and the Cambridge NIHR Biomedical Research centre. David Adams is funded by Cancer Research UK and Wellcome Trust. Steffen Koschmieder has received funding from Deutsche José Carreras Leukämie-Stiftung (DJCLS; grant 10/23).This is the final published version. It first appeared at http://dx.doi.org/10.1084/jem.2014166

Photon random walk model of low-coherence enhanced backscattering (LEBS) from anisotropic disordered media: a Monte Carlo simulation

Constructive interference among coherent waves traveling time-reversed paths in a random medium gives rise to the enhancement of light scattering observed in directions close to backscattering. This phenomenon is known as enhanced backscattering (EBS). According to diffusion theory, the angular width of an EBS cone is proportional to the ratio of the wavelength of light λ to the transport mean free path length l s * of a random medium. In biological media, large l s * ~ 0.5-2 mm >> λ results in an extremely small (~0.001˚) angular width of the EBS cone making the experimental observation of such narrow peaks difficult. Recently, the feasibility of observing EBS under low spatial coherence illumination (spatial coherence length L sc <<l s * ) was demonstrated. Low spatial coherence behaves as a spatial filter rejecting longer path-lengths and, thus, resulting in more than 100 times increase in the angular width of low coherence EBS (LEBS) cones. However, conventional diffusion approximation-based model of EBS has not been able to explain such dramatic increase in LEBS width. Here we present a photon random walk model of LEBS using Monte Carlo simulation to elucidate the mechanism accounting for the unprecedented broadening of LEBS peaks. Typically, the exit angles of the scattered photons are not considered in modeling EBS in diffusion regime. We show that small exit angles are highly sensitive to low order scattering, which is crucial for accurate modeling of LEBS. Our results show that the predictions of the model are in excellent agreement with experimental data

Efficacy and safety of avelumab treatment in patients with metastatic Merkel cell carcinoma: experience from a global expanded access program

BackgroundAvelumab, a human anti–programmed death-ligand 1 immunoglobulin G1 monoclonal antibody, showed favorable efficacy and safety in patients with metastatic Merkel cell carcinoma (mMCC) in the phase II JAVELIN Merkel 200 trial, leading to approval in multiple countries. We describe real-world experience with avelumab in patients with mMCC from an expanded access program.MethodsEligible patients had mMCC and progressive disease during or after chemotherapy or were ineligible for chemotherapy or clinical trial participation. Patients received an initial 3-month supply of avelumab (administered as 10 mg/kg intravenously every 2 weeks until progressive disease or unacceptable toxicity); resupply was allowed following complete response, partial response, stable disease, or clinical benefit per physician assessment.ResultsBetween December 15, 2015, and March 4, 2019, 558 of 620 requests from 38 countries were medically approved, and 494 patients received avelumab. Among 240 evaluable patients, the objective response rate was 46.7% (complete response in 22.9%, including 3 of 16 potentially immunocompromised patients), and the disease control rate was 71.2%. The median duration of treatment in evaluable patients with response was 7.9 months (range, 1.0–41.7) overall and 5.2 months (range, 3.0–13.9) in immunocompromised patients. No new safety signals were identified. The expanded access program closed for new requests on December 31, 2018, as required after regulatory approval; benefitting patients continued to receive avelumab.ConclusionsThe avelumab expanded access program for patients with mMCC demonstrated efficacy and safety in a real-world setting, consistent with the results from JAVELIN Merkel 200, and provided a treatment for patients with limited options