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Background Breast density is a strong and potentially modifiable breast cancer risk factor. Almost everything we know about breast density has been derived from mammography, and therefore, very little is known about breast density in younger women aged Methods Breast tissue composition (percent water, collagen, and lipid content) was measured in 539 women aged 18–40 using OBS. For a subset of 169 women, breast density was also measured via DXA (percent fibroglandular dense volume (%FGV), absolute dense volume (FGV), and non-dense volume (NFGV)). Acceptability of the measurement procedures was assessed using an adapted validated questionnaire. Performance was assessed by examining the correlation and agreement between the measures and their associations with known determinants of mammographic breast density. Results Over 93% of participants deemed OBS and DXA to be acceptable. The correlation between OBS-%water + collagen and %FGV was 0.48. Age and BMI were inversely associated with OBS-%water + collagen and %FGV and positively associated with OBS-%lipid and NFGV. Conclusions OBS and DXA provide acceptable and viable alternative methods to measure breast density in younger women aged 18–40 years.

Despite a clear link between ataxia-telangiectasia mutated (ATM)–dependent phosphorylation of p53 and cell cycle checkpoint control, the intracellular biology and subcellular localization of p53 phosphoforms during the initial sensing of DNA damage is poorly understood. Using G0-G1 confluent primary human diploid fibroblast cultures, we show that endogenous p53, phosphorylated at Ser15 (p53Ser15), accumulates as discrete, dose-dependent and chromatin-bound foci within 30 minutes following induction of DNA breaks or DNA base damage. This biologically distinct subpool of p53Ser15 is ATM dependent and resistant to 26S-proteasomal degradation. p53Ser15 colocalizes and coimmunoprecipitates with γ-H2AX with kinetics similar to that of biochemical DNA double-strand break (DNA-dsb) rejoining. Subnuclear microbeam irradiation studies confirm p53Ser15 is recruited to sites of DNA damage containing γ-H2AX, ATMSer1981, and DNA-PKcsThr2609 in vivo. Furthermore, studies using isogenic human and murine cells, which express Ser15 or Ser18 phosphomutant proteins, respectively, show defective nuclear foci formation, decreased induction of p21WAF, decreased γ-H2AX association, and altered DNA-dsb kinetics following DNA damage. Our results suggest a unique biology for this p53 phosphoform in the initial steps of DNA damage signaling and implicates ATM-p53 chromatin-based interactions as mediators of cell cycle checkpoint control and DNA repair to prevent carcinogenesis.

Supplementary Figures 1-3 from Evidence for the Direct Binding of Phosphorylated p53 to Sites of DNA Breaks In vivo

Supplementary Figure Legends from Evidence for the Direct Binding of Phosphorylated p53 to Sites of DNA Breaks In vivo

PDT-SPACE is an open-source software tool that automates interstitial photodynamic therapy treatment planning by providing patient-specific placement of light sources to destroy a tumor while minimizing healthy tissue damage. This work extends PDT-SPACE in two ways. The first enhancement allows specification of clinical access constraints on light source insertion to avoid penetrating critical structures and to minimize surgical complexity. Constraining fiber access to a single burr hole of adequate size increases healthy tissue damage by 10%. The second enhancement generates an initial placement of light sources as a starting point for refinement, rather than requiring entry of a starting solution by the clinician. This feature improves productivity and also leads to solutions with 4.5% less healthy tissue damage. The two features are used in concert to perform simulations of various surgery options of virtual glioblastoma multiforme brain tumors.

The editorial introduces the JBO Special Section Celebrating 30 Years of Open Source Monte Carlo Codes in Biomedical Optics for Volume 27, Issue 8.

In vitro dose escalation experiments are one of the first gatekeepers in therapeutic evaluation and development. This also holds for evaluating novel photosensitizers (PS) and Photodynamic Therapy (PDT) co-therapies as needed to provide dose response guidelines before engaging in further pre-clinical studies. The dose needed to achieve 50% cell kill (LD

Open-source software packages have been extensively used in the past three decades in medical imaging and diagnostics, aiming to study the feasibility of the application ex vivo. Unfortunately, most of the existing open-source tools require some software engineering background to install the prerequisite libraries, choose a suitable computational platform, and combine several software tools to address different applications.To facilitate the use of open-source software in medical applications, enabling computational studies of treatment outcomes prior to the complex in-vivo setting.FullMonteWeb, an open-source, user-friendly web-based software with a graphical user interface for interstitial photodynamic therapy (iPDT) modeling, visualization, and optimization, is introduced. The software can perform Monte Carlo simulations of light propagation in biological tissues, along with iPDT plan optimization. FullMonteWeb installs and runs the required software and libraries on Amazon Web Services (AWS), allowing scalable computing without complex set up.FullMonteWeb allows simulation of large and small problems on the most appropriate compute hardware, enabling cost improvements of 10 × versus always running on a single platform. Case studies in optical property estimation and diffuser placement optimization highlight FullMonteWeb's versatility.The FullMonte open source suite enables easier and more cost-effective in-silico studies for iPDT.

Social environment may influence breast tissue composition and breast cancer risk through shaping risk factors operating in early life, adolescence, and adulthood. Socioeconomic status (SES) has been positively associated with breast cancer risk, and mammography studies in women in middle to late adulthood suggest the association might be mediated by the positive relationship between higher SES and higher breast density. Yet, the impact of SES on breast tissue composition earlier in the lifecourse has not been examined, thus limiting the ability to elucidate lifecourse social influences and pathways in the development of breast cancer. In this study, we examined if SES is associated with breast tissue composition in a New York City cohort of 216 Black and Hispanic adolescent girls (aged 11-20 years) and their mothers (aged 29-55 years). We used optical spectroscopy to measure breast tissue chromophores including water content, lipid content, and collagen content, as well as a combined optical index measure. Previous studies have shown that these measures positively (water, collagen, optical index) or negatively (lipid) correlate with mammographic breast density. Questionnaires captured SES indicators at different timepoints across generations: grandparents’ highest level of education; mother’s highest level of education at daughter’s birth; mother’s highest level of education at breast measurement; household income at daughter’s birth; and public assistance at daughter’s birth. We evaluated associations using multivariable linear regression models adjusted for age at breast measurement, percent body fat at breast measurement, race/ethnicity, and mother’s birth country. We tested for additive effect modification by age at breast measurement. In daughters, higher mother’s education at birth was associated with lower lipid content (≥ bachelor’s degree vs. < high school degree, β: -6.96, 95% CI: -13.64, -0.27), and higher grandmother’s education was associated with higher water content (≥ some college vs. < elementary school, β: 3.77, 95% CI: 0.58, 6.97). In mothers, higher household income was associated with lower lipid content ($20,000-80,000 vs. < $10,000, β: -4.26, 95% CI: -7.93, -0.59) and higher optical index (β: 0.30, 95% CI: 0.01, 0.58), while not being on public assistance was associated with higher collagen content (β: 2.54, 95% CI: 0.74, 4.34). Mothers with some college education vs. high school degree or lower at daughter’s birth had higher water content (β: 3.81, 95% CI: 1.07, 6.54), but no association was found comparing mothers with bachelor’s degree or higher vs. high school degree or lower. Associations were not modified by age at breast measurement. This study provides novel data linking intergenerational and early life SES to breast tissue composition in adolescent girls independent of body fat and provides evidence consistent with previous mammography studies of a positive relationship between SES and breast density in adult women. Further studies are needed to explore the downstream factors mediating these relationships. Citation Format: Rebecca D. Kehm, Parisa Tehranifar, E. Jane Walter, Melissa L. White, Sabine Oskar, Julie B. Herbstman, Frederica Perera, Lothar Lilge, Rachel L. Miller, Mary Beth Terry. Multigenerational socioeconomic status and breast tissue composition in mothers and their adolescent daughters: Findings from a multiethnic cohort in New York City [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B102.

With the continued development of non-toxic photosensitizer drugs, interstitial photodynamic therapy (iPDT) is showing more favorable outcomes in recent clinical trials. IPDT planning is crucial to further increase the treatment efficacy. However, it remains a major challenge to generate a high-quality, patient-specific plan due to uncertainty in tissue optical properties (OPs), µ a and µ s . These parameters govern how light propagates inside tissues, and any deviation from the planning-assumed values during treatment could significantly affect the treatment outcome. In this work, we increase the robustness of iPDT against OP variations by using machine learning models to recover the patient-specific OPs from light dosimetry measurements and then re-optimizing the diffusers’ optical powers to adapt to these OPs in real time. Simulations on virtual brain tumor models show that reoptimizing the power allocation with the recovered OPs significantly reduces uncertainty in the predicted light dosimetry for all tissues involved.

The study presented a Monte Carlo simulation of light transport in eight commonly used filtered facepiece respirators (FFRs) to assess the efficacy of UV at 254 nm for the inactivation of SARS‐CoV‐2. The results showed different fluence rates across the thickness of the eight different FFRs, implying that some FFR models may be more treatable than others, with the following order being (from most to least treatable): models 1512, 9105s, 1805, 9210, 1870+, 8210, 8110s and 1860, for single side illumination. The model predictions did not coincide well with some previously reported experimental data on virus inactivation when applied to FFR surfaces. The simulations predicted that FFRs should experience higher log reductions (>>6‐log) than those observed experimentally (often limited to ~5‐log). Possible explanations are virus shielding by aggregation or soiling, and a lack of the Monte Carlo simulations considering near‐field scattering effects that can create small, localized regions of low UV photon probability on the surface of the fiber material. If the latter is the main cause in limiting practical UV viral decontamination, improvement might be achieved by exposing the FFR to UV isotropically from all directions, such as by varying the UV source to the FFR surface angle during treatment., The study presented a Monte Carlo simulation of light transport in eight commonly used filtered facepiece respirators (FFRs) to assess the efficacy of UV at 254 nm for the inactivation of SARS‐CoV‐2. The results showed different fluence rates across the thickness of the eight different FFRs, implying that some FFR models may be more treatable than others.

As oncological treatments aim to move towards personalize medicine, increase tissue response monitoring has become the focus of research. In particular, spatially resolved in vivo information of hypoxia and its relationship to cell survival is required to maximize the patient's benefit. At the same time, several preclinical imaging approaches were developed in the past years, including Photoacoustic, Bioluminescence imaging (BLI) to quantify blood flow/volume. Here Photo acoustic Imaging (PAl) is used to study tumor hypoxia for Photodynamic Therapy (PDT) monitoring to predict cell survival. The Photoacoustic and Bioluminescence signals' temporal dynamic are used to detect vascular changes during and post-PDT.

The authors wish to acknowledge the funding support from NSERC and CIHR as well as the contributions of David Han and Erik Alerstam to code development. Research infrastructure support was provided by the Ontario Ministry of Health and Long Term Care (OMHLTC). The views expressed do not necessarily reflect those of OMHLTC.

Background Isolated lung metastases in sarcoma and colorectal cancer patients are inadequately treated with current standard therapies. In Vivo Lung Perfusion, a novel platform, could overcome limitations to photodynamic therapy treatment volumes by using low cellular perfusate, removing blood, theoretically allowing greater light penetration. To develop personalized photodynamic therapy protocols requires in silico light propagation simulations based on optical properties and maximal permissible photodynamic threshold dose of lung tissue. This study presents quantification of optical properties for two perfusates and the photodynamic threshold for 5-ALA and Chlorin e6. Methods Porcine and human lungs were placed on Ex Vivo Lung Perfusion, and perfused with acellular solution or blood. Isotropic diffusers were placed within bronchi and on lung surface for light transmission measurements, from which absorption and light scattering properties were calculated at multiple wavelengths. Separately, pigs were injected with 5-ALA or Chlorin e6, and lung tissue was irradiated at increasing doses. Resultant lesion sizes were measured by CT and histology to quantify the photodynamic threshold. Results Low cellular perfusate reduced the tissue absorption coefficient significantly, increasing penetration depth of light by 3.3 mm and treatment volumes 3-fold. The photodynamic threshold for lung exposed to 5-ALA was consistent with other malignancies. Chlorin e6 levels were undetectable in lung tissue and did not demonstrate photodynamic-induced necrosis. Conclusions Light penetration with low cellular perfusate is significantly greater and could enable treatments for diffuse disease. This data aids photodynamic treatment planning and will guide clinical translation of photodynamic therapy protocols in the lung, especially during lung perfusion.

This study presents numerical simulations of UVC light propagation through seven different filtered face respirators (FFR) to determine their suitability for UV germicidal inactivation (UVGI). UV propagation was modelled using the FullMonte program for two external light illuminations. The optical properties of the dominant three layers were determined using the inverse adding doubling method.The resulting fluence rate volume histograms and the lowest fluence rate recorded in the modelled volume, sometimes in the nW cm-2, provide feedback on a respirator’s suitability for UVGI and the required exposure time for a given light source. While UVGI can present an economical approach to extend an FFR’s useable lifetime, it requires careful optimization of the illumination setup and selection of appropriate respirators.Abstract Figure

Mammographic breast density is a strong breast cancer risk factor, and its routine clinical measurement could potentially be used to identify women at higher risk of breast cancer and/or monitor primary prevention strategies. Previous reports of optical breast spectroscopy (OBS), a novel approach to measuring breast density, demonstrated that it is safe (no ionizing radiation), portable, low-cost, and does not require image interpretation but have been limited to small, single-center studies. Reference measurements taken on a phantom breast prior to and after each woman’s OBS assessment are required for the calibration of the system transfer function as a part of processing participant data. To inform the validity of participant data, a detailed description of the reference measurements and a repeatability analysis of these measurements taken before and after participant assessment is presented. Reference measurements for OBS from 539 women aged 18–40 years were obtained as a part of a high-throughput epidemiological pilot study. Of these, measurements from 20 women with no useable data due to device failure (3.7%) were excluded and from another 12 women due to user error. The intra-class correlation (ICC) within complete pairs of reference data (taken before and after assessment) was high (all ICC > 0.84). The analysis presented here confirms the OBS participant data as valid for use in ongoing epidemiological research, providing further supporting evidence of OBS as a measure of breast density. A novel method of measuring breast density is needed to bridge large gaps in the knowledge of breast density in younger women and its relation to later-life breast cancer risk.

Background: The Pakistani Salt Range has a rich floral diversity including Withania coagulans from the Solanaceae family. Methods: The crude methanolic extracts of the root, leaf, leaf stalk, and fruit of this plant were screened for their cytotoxic activity against human (HeLa, MCF-7, RD) and rat (RG2 and INS-1) cancer cell lines at 20 μg/mL and compared to methotrexate. The IC50 values indicated that leaf stalk and fruit extracts exert an 80% or higher cytotoxic activity against all cell lines at 24 hours. Results: The leaf stalk extract showed the highest cytotoxic efficacy against all tested cell lines, with IC50 values ranging from 0.96 ± 0.01 μg/mL to 4.73 ± 0.05 μg/mL followed by the fruit extract with IC50 values of 0.69 ± 0.01–6.69 ± 0.06 μg/mL after 48–72 hours incubation. The leaf stalk and seed extracts were analyzed for polyphenols and flavonoids using RP-HPLC. The total flavonoid content (TFC) was calculated for all tested samples, and the highest TFC was recorded for the root extract (394.34 ± 1.26 μg/g). The total phenolic content (TPC) was found in the seed extract (307.86 ± 9.42 μg/g) of W. coagulans. The highest contents of myricetin (358.46 ± 2.91 μg/g) were noted in the leaf extract, and highest quercetin was recorded in the seed extract (21.43 ± 0.13 μg/g). The highest gallic acid concentration (83.62 ± 0.71 μg/g) was recorded in leaf stalk extract and p-hydroxybenzoic acid in the seed extract (157.46 ± 1.43 μg/g). Conclusion: The present study gives a scientific insight and comparative analysis of various plant parts in this medicinally important plant species from the Salt Range of Pakistan against both human and rat cancer cells. Keywords: Anticancer, Presto Blue cell metabolic assay, Total phenolic contents, Total flavonoid contents

To improve a cancer patient’s quality of life, short treatment duration resulting in rapid tumour removal while sparing normal tissue are highly desirable. Photodynamic therapy (PDT) commonly applied in a single treatment, while often effective can be limited at low photosensitizer or light doses. Combination therapies can overcome the efficacy limitations while not increasing treatment-associated morbidity. Here the efficacy of combination therapy comprised of doxorubicin (DOX) or methotrexate (MTX) with Photosens mediated PDT was investigated in three cell lines in vitro, employing multiple incubation sequences. Photosense is a mixture of aluminium phthalocyanines with different sulfonation. The results demonstrated higher synergistic effects when DOX or MTX-mediated chemotherapy preceded PDT light activation by 24 h. MTX is marginally more cytotoxic than DOX, when combined with Photosens (AlPcS2-4) mediated PDT. While MTX and DOX exposure prior to AlPcS2-4 incubation may enhance mitochondrial localisation photosensitizer, the simultaneous targeting of DNA, proteins, and lipids of the combination therapies leads to the observed high cytotoxicity at sub μM drug doses. Keywords: Photodynamic Therapy, Chemotherapy, Cancer, Combination therapy

Objective To examine the role of skin color and tissue thickness on transmittance, reflectance, and skin heating using red and infrared laser light. Methods Forty volunteers were measured for skin color and skin-fold thickness at a standardized site near the elbow. Transmittance, reflectance and skin temperature were recorded for energy doses of 2, 6, 9, and 12 Joules using 635 nm (36 mW) and 808 nm (40 mW) wavelength laser diodes with irradiances within American National Standards Institute safety guidelines (4.88 mm diameter, 0.192 W/cm2 and 4.88 mm diameter, 0.214 W/cm2 , respectively). Results The key factors affecting reflectance to an important degree were skin color and wavelength. However, the skin color effects were different for the two wavelengths: reflectance decreased for darker skin with a greater decrease for red light than near infrared light. Transmittance was greater using 808 nm compared with 635 nm. However, the effect was partly lost when the skin was dark rather than light, and was increasingly lost as tissue thickness increased. Dose had an increasing effect on temperature (0.7-1.6°C across the 6, 9, and 12 J doses); any effects of wavelength, skin color, and tissue thickness were insignificant compared to dose effects. Subjects themselves were not aware of the increased skin temperature. Transmittance and reflectance changes as a function of energy were very small and likely of no clinical significance. Absorption did not change with higher energy doses and increasing temperature. Conclusion Skin color and skin thickness affect transmittance and reflectance of laser light and must be accounted for when selecting energy dose to ensure therapeutic effectiveness at the target tissue. Skin heating appears not to be a concern when using 635 and 808 nm lasers at energy doses of up to 12 J and irradiance within American National Standards Institute standards. Photobiomodulation therapy should never exceed the American National Standards Institute recommendation for the maximum permissible exposure to the skin. Lasers Surg. Med. 50:291-301, 2018. © 2017 Wiley Periodicals, Inc.

Acute arthritis is an inflammation that affects many joints. The principal treatment options comprise drugs (corticosteroids), invasive and painful surgery. The objective of this study was to evaluate the efficacy of low intensity laser therapy (LILT), a non-invasive treatment, in a murine model of acute inflammation model. 48 mice received a synovial injection of Zymosan A into one knee. Mice were treated with LILT by three different wavelengths, either as a single (S) or dual (D) application immediately after the injury or after 24h following initiation of an inflammatory response. The histological analysis aimed at identifying inflammatory infiltrate and the structure of the articular surfaces as an indicator of a long-term damage due to inflammation. Statistical analysis (Kruskal-Wallis test), did not allow to reject the null hypothesis. However, LILT promoted histological alterations in some treatment groups. Histological evidence (Median and confidence interval) of anti-inflammatory effects was especially noticeable in knees of mice irradiated with lasers emitting moderate intensity and continuous 660nm (S=18.5 (11.4; 27.6); D=16.0 (6.93; 27.0)) and high intensity and pulsed 905nm (S=17.5 (10.2; 24.79), with decrease of the resorbed region. However, the 905nm pulsed laser was responsible for exacerbation of inflammation for multiple LILT sessions with a short delay (D=45.0 (22.84; 63.83)), tending to aggravate the resorption of the articular surface (p