Wildfires continue to increase in size, intensity, and duration. There is growing evidence that wildfire smoke adversely impacts clinical outcomes; however, few studies have assessed the impact of wildfires on household air quality and subclinical cardiovascular health indicators. We measured continuous indoor and outdoor fine particulate matter (PM _2.5 ) concentrations from July–October 2022 at 20 residences in the rural, mountainous state of Montana in the United States. We used a combination of satellite-derived smoke plume data from the National Oceanic and Atmospheric Administration’s Hazard Mapping System and household-level daily mean PM _2.5 concentrations to classify wildfire-impacted days. One participant from each household self-reported in-home blood pressure (BP) on weekly electronic surveys. We used linear mixed-effects regression models to assess associations between air pollution exposures (PM _2.5 concentrations; number of wildfire-impacted days) and systolic BP (SBP) and diastolic BP (DBP). Models were adjusted for potential time-variant confounders including temperature, humidity, and self-reported exercise. Compared to survey periods with 0 wildfire days, SBP was 3.83 mmHg higher (95% Confidence Interval [95% CI]: 0.22, 7.44) and DBP was 2.36 mmHg higher (95% CI: −0.06, 4.78) during periods with 4+ wildfire days. Across the entire study period, a 10 µ g m ^−3 increase in indoor PM _2.5 was associated with 1.34 mmHg higher SBP (95%CI: 0.39, 2.29) and 0.71 mmHg higher DBP (95% CI: 0.07, 1.35). We observed that wildfire-impacted days and increasing household-level PM _2.5 concentrations are associated with higher in-home BP. Our results support growing literature which indicates that wildfires adversely impact subclinical cardiovascular health. Clinical and public health messaging should emphasize the cardiovascular health impacts of wildfire smoke and educate on exposure-reduction strategies such as indoor air filtration.

AbstractProstatectomy has been the mainstay treatment for men with localized prostate cancer. Surgery, however, often can result in major side effects, which are caused from damage and removal of nerves and muscles surrounding the prostate. A technology that can help surgeons more precisely identify and remove prostate cancer resulting in a more complete prostatectomy is needed. Prostate-specific membrane antigen (PSMA), a type II membrane antigen highly expressed in prostate cancer, has been an attractive target for imaging and therapy. The objective of this study is to develop low molecular weight PSMA-targeted photodynamic therapy (PDT) agents, which would provide image guidance for prostate tumor resection and allow for subsequent PDT to eliminate unresectable or remaining cancer cells. On the basis of our highly negatively charged, urea-based PSMA ligand PSMA-1, we synthesized two PSMA-targeting PDT conjugates named PSMA-1-Pc413 and PSMA-1-IR700. In in vitro cellular uptake experiments and in vivo animal imaging experiments, the two conjugates demonstrated selective and specific uptake in PSMA-positive PC3pip cells/tumors, but not in PSMA-negative PC3flu cells/tumors. Further in vivo photodynamic treatment proved that the two PSMA-1–PDT conjugates can effectively inhibit PC3pip tumor progression. The two PSMA-1–PDT conjugates reported here may have the potential to aid in the detection and resection of prostate cancers. It may also allow for the identification of unresectable cancer tissue and PDT ablation of such tissue after surgical resection with potentially less damage to surrounding tissues. Mol Cancer Ther; 15(8); 1834–44. ©2016 AACR.

Residential wood burning has both practical and traditional values among many indigenous communities of the US Mountain West, although household biomass burning also results in emissions that are harmful to health. In a household-level three-arm placebo-controlled randomized trial, we tested the efficacy of portable filtration units and education interventions on improving pulmonary function and blood pressure measures among elder participants that use wood stoves for residential heating. A total of 143 participants were assigned to the Education ( n = 49), Filter ( n = 47), and Control ( n = 47) arms. Blood pressure and spirometry measures were collected multiple times during a pre-intervention winter period and during a follow-up post-intervention winter period. Despite strong PM 2.5 exposure reduction results with the Filter arm (50% lower compared to Control arm), neither this intervention nor the Education intervention translated to improvements in the selected health measures among this population with a mixture of chronic conditions. Intention to treat analysis failed to demonstrate evidence that either of the intervention arms had beneficial effects on the blood pressure or the spirometry measures. Post hoc evaluation of effect modification for blood pressure and spirometry outcomes did not reveal any interaction influence on the outcomes according to sex, residential smoking, chronic disease history, and study area. ClinicalTrials.gov: NCT02240069.

Purpose Prostate specific membrane antigen (PSMA) has been studied in human breast cancer (BCa) biopsies, however, lack of data on PSMA expression in mouse models impedes development of PSMA-targeted therapies, particularly in improving breast conserving surgery (BCS) margins. This study aimed to validate and characterize the expression of PSMA in murine BCa models, demonstrating that PSMA can be utilized to improve therapies and imaging techniques.Methods Murine triple negative breast cancer 4T1 cells, and human cell lines, MDA-MB-231, MDA-MB-468, implanted into the mammary fat pads of BALB/c mice, were imaged by our PSMA targeted theranostic agent, PSMA-1-Pc413, and tumor to background ratios (TBR) were calculated to validate selective uptake. Immunohistochemistry was used to correlate PSMA expression in relation to CD31, an endothelial cell biomarker highlighting neovasculature. PSMA expression was also quantified by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR).Results Accumulation of PSMA-1-Pc413 was observed in 4T1 primary tumors and associated metastases. Average TBR of 4T1 tumors were calculated to be greater than 1.5-ratio at which tumor tissues can be distinguished from normal structures-at peak accumulation with the signal intensity in 4T1 tumors comparable to that in high PSMA expressing PC3-pip tumors. Extraction of 4T1 tumors and lung metastases followed by RT-PCR analysis and PSMA-CD31 co-staining shows that PSMA is consistently localized on tumor neovasculature with no expression in tumor cells and surrounding normal tissues.Conclusion The selective uptake of PSMA-1-Pc413 in these cancer tissues as well as the characterization and validation of PSMA expression on neovasculature in this syngeneic 4T1 model emphasizes their potential for advancements in targeted therapies and imaging techniques for BCa. PSMA holds great promise as an oncogenic target for BCa and its associated metastases.

Prostate cancer is the most prevalent cancer among men in the United States and is a leading cause of cancer-related death. Prostate specific membrane antigen (PSMA) has been established as a biomarker for prostate cancer diagnosis and treatment. This study aimed to develop a novel theranostic agent, PSMA-1-MMAE-Pc413, which integrates a PSMA-targeting ligand, the photosensitizer Pc413, and the microtubular inhibitor monomethyl auristatin E (MMAE) for synergistic therapeutic efficacy. In vitro uptake studies revealed that PSMA-1-MMAE-Pc413 demonstrated selective and specific uptake in PSMA-positive PC3pip cells but not in PSMA-negative PC3flu cells, with the uptake in PC3pip cells being approximately three times higher. In vitro cytotoxicity assays showed that, when exposed to light, PSMA-1-MMAE-Pc413 had a synergistic effect, leading to significantly greater cytotoxicity in PSMA-positive cells (IC50 = 2.2 nM) compared to PSMA-1-Pc413 with light irradiation (IC50 = 164.9 nM) or PSMA-1-MMAE-Pc413 without light irradiation (IC50 = 12.6 nM). In vivo imaging studies further demonstrated the selective uptake of PSMA-1-MMAE-Pc413 in PC3pip tumors. In in vivo studies, PSMA-1-MMAE-Pc413 dramatically improves the therapeutic outcome for prostate cancer by providing a synergistic effect that surpasses the efficacy of each treatment modality alone in PC3pip tumors. These findings suggest that PSMA-1-MMAE-Pc413 has strong potential for clinical application in improving prostate cancer treatment.

Abstract Background Acute viral bronchiolitis is the most common reason for hospitalization of infants in the USA. Infants hospitalized for bronchiolitis are at high risk for recurrent respiratory symptoms and wheeze in the subsequent year, and longer-term adverse respiratory outcomes such as persistent childhood asthma. There are no effective secondary prevention strategies. Multiple factors, including air pollutant exposure, contribute to risk of adverse respiratory outcomes in these infants. Improvement in indoor air quality following hospitalization for bronchiolitis may be a prevention opportunity to reduce symptom burden. Use of stand-alone high efficiency particulate air (HEPA) filtration units is a simple method to reduce particulate matter ≤ 2.5 µm in diameter (PM2.5), a common component of household air pollution that is strongly linked to health effects. Methods BREATHE is a multi-center, parallel, double-blind, randomized controlled clinical trial. Two hundred twenty-eight children < 12 months of age hospitalized for the first time with bronchiolitis will participate. Children will be randomized 1:1 to receive a 24-week home intervention with filtration units containing HEPA and carbon filters (in the child’s sleep space and a common room) or to a control group with units that do not contain HEPA and carbon filters. The primary objective is to determine if use of HEPA filtration units reduces respiratory symptom burden for 24 weeks compared to use of control units. Secondary objectives are to assess the efficacy of the HEPA intervention relative to control on (1) number of unscheduled healthcare visits for respiratory complaints, (2) child quality of life, and (3) average PM2.5 levels in the home. Discussion We propose to test the use of HEPA filtration to improve indoor air quality as a strategy to reduce post-bronchiolitis respiratory symptom burden in at-risk infants with severe bronchiolitis. If the intervention proves successful, this trial will support use of HEPA filtration for children with bronchiolitis to reduce respiratory symptom burden following hospitalization. Trial registration NCT05615870. Registered on November 14, 2022.

Up to 40 % of breast cancer patients have a tumor-positive resection margin (TPRM) - defined as cancer cells at the surface of the resected specimen - after breast-conserving surgery (BCS), necessitating re-resection or boost radiation. To prevent these additional treatments, intraoperative near-infrared (NIR) fluorescence imaging with the topically applied, cathepsin-activatable imaging agent AKRO-6qcICG might be used to detect TPRMs and guide additional resection. Here, to validate its performance, the agent is topically applied to all surfaces of freshly resected breast cancer specimens (n =11 patients) and to 3-5 mm thick tissue slices of the specimens (n = 26 patients). NIR fluorescence images of the resection surfaces and tissue slices are acquired and correlated to final histopathology. AKRO-6qcICG detects TPRMs with a sensitivity, specificity, PVV, and NPV of 100%, 67%, 10%, and 100%, respectively. On the tissue slices, the fluorescence signal has a median tumor-to-background ratio of 1.8. These findings indicate that topically applied AKRO-6qcICG can visualize TPRMs ex vivo with a high sensitivity and NPV, with sufficient contrast to adjacent healthy breast tissue.

Although climate change is increasing wildfire and smoke events globally, public health messaging and individual access to resources for protection are limited. Individual interventions can be highly effective at reducing wildfire smoke exposure. However, studies related to individual responses to wildfire smoke are limited and demonstrate mixed protective behaviors and risk perception. Our research helps fill this gap by assessing the self-reported behavior of 20 participants during wildfire season in Western Montana from 28 June through 1 November, 2022. We also measured continuous outdoor and indoor fine particulate matter (PM2.5) concentrations at participant residencies during this time period using PurpleAir sensors (PAII-SD, PurpleAir, Inc, USA) while participants took up to 16 self-reported online weekly activity surveys. Mixed-effect Poisson regression models were used to assess associations between exposure variables and participant reported behaviors. These results were compared with end-of-study interview findings. Wildfire smoke impacted days and increased concentrations of PM2.5 were associated with decreased outdoor exercise and opening of windows for ventilation. Interview themes were congruent with the regression analysis, with the additional finding of high portable air cleaner (PAC) use among participants. Additionally, these interviews gave context to both the tradeoffs participants face when making protective decisions and the importance of personal air quality data in increasing awareness about wildfire smoke risks. Future wildfire smoke studies can build off this research by providing personally relevant air quality data and PACs to participants and by improving public health messaging to address the compounding risks of wildfire smoke exposure and heat.

Cysteine cathepsins are proteases that play a role in normal cellular physiology and neoplastic transformation. Elevated expression and enzymatic activity of cathepsins in breast cancer (BCa) indicates their potential as a target for tumor imaging. In particular cathepsin B (CTSB), L (CTSL), and S (CTSS) are used as targets for near-infrared (NIR) fluorescence imaging (FI), a technique that allows real-time intraoperative tumor visualization and resection margin assessment. Therefore, this immunohistochemical study explores CTSB, CTSL, and CTSS expression levels in a large breast cancer patient cohort, to investigate in which BCa patients the use of cathepsin-targeted NIR FI may have added value. Protein expression was analyzed in tumor tissue microarrays (TMA) of BCa patients using immunohistochemistry and quantified as a total immunostaining score (TIS), ranging from 0–12. In total, the tissues of 557 BCa patients were included in the TMA. CTSB, CTSL, and CTSS were successfully scored in respectively 340, 373 and 252 tumors. All tumors showed CTSB, CTSL, and/or CTSS expression to some extent (TIS > 0). CTSB, CTSL, and CTSS expression was scored as high (TIS > 6) in respectively 28

BackgroundMale dogs can develop spontaneous prostate cancer, which is similar physiologically to human disease. Recently, Tweedle and coworkers have developed an orthotopic canine prostate model allowing implanted tumors and therapeutic agents to be tested in a more translational large animal model. We used the canine model to evaluate prostate-specific membrane antigen (PSMA)-targeted gold nanoparticles as a theranostic approach for fluorescence (FL) imaging and photodynamic therapy (PDT) of early stage prostate cancer. MethodsDogs (four in total) were immunosuppressed with a cyclosporine-based immunosuppressant regimen and their prostate glands were injected with Ace-1-hPSMA cells using transabdominal ultrasound (US) guidance. Intraprostatic tumors grew in 4-5 weeks and were monitored by ultrasound (US). When tumors reached an appropriate size, dogs were injected intravenously (iv) with PSMA-targeted nano agents (AuNPs-Pc158) and underwent surgery 24 h later to expose the prostate tumors for FL imaging and PDT. Ex vivo FL imaging and histopathological studies were performed to confirm PDT efficacy. ResultsAll dogs had tumor growth in the prostate gland as revealed by US. Twenty-four hours after injection of PSMA-targeted nano agents (AuNPs-Pc158), the tumors were imaged using a Curadel FL imaging device. While normal prostate tissue had minimal fluorescent signal, the prostate tumors had significantly increased FL. PDT was activated by irradiating specific fluorescent tumor areas with laser light (672 nm). PDT bleached the FL signal, while fluorescent signals from the other unexposed tumor tissues were unaffected. Histological analysis of tumors and adjacent prostate revealed that PDT damaged the irradiated areas to a depth of 1-2 mms with the presence of necrosis, hemorrhage, secondary inflammation, and occasional focal thrombosis. The nonirradiated areas showed no visible damages by PDT. ConclusionWe have successfully established a PSMA-expressing canine orthotopic prostate tumor model and used the model to evaluate the PSMA-targeted nano agents (AuNPs-Pc158) in the application of FL imaging and PDT. It was demonstrated that the nano agents allowed visualization of the cancer cells and enabled their destruction when they were irradiated with a specific wavelength of light.

Figure S1 shows fluorescence that correlates with the presence of benign lesions

Supplementary Methods include description of: 1) "Puzzle"-fit" analysis, 2) Intensity-based objective sensitivity and specificity analysis, 3) Blinded physician "Reader Study" analysis, and 4) Evaluation of reader responses regarding intensity.

Nanoparticles offer great opportunities for precision medicine. However, the use of nanoparticles as smart photosensitizers that target tumor biomarkers and are responsive to the tumor microenvironment has yet to be explored. Herein, prostate cancer (PCa)-selective theranostic gold nanoparticles (AuNPs) for precise cancer imaging and therapy are developed. Silicon phthalocyanine, Pc158, was synthesized and deactivated by conjugating it to AuNPs via a biocleavable linker. In vitro and in vivo, the targeted AuNPs show excellent selectivity for PSMA-positive tumor cells. Triggered release of the therapeutic, Pc158, followed by sequential photodynamic therapy (PDT) results in significant inhibition of tumor growth. Further, we demonstrate that multiple sequential PDT greatly enhances nanoparticle uptake and therapeutic efficacy. PSMA is highly expressed in the neovasculature of most other solid tumors in humans, as well as PCa, making this approach of great practical interest for precision PDT in a wide range of cancers.

Figure S2 shows histology of all false negative (FN) skin cancer samples.

Figure S3D shows histology of false positive (FP) skin samples with presence of healing area and inflammation.

Table S1 shows cancer type and histologic detection status following excision; Table S2 characterizes patients and specimens

BACKGROUND/AIMS:Wildfire air pollution is a growing public health concern as wildfires increase in size, intensity, and duration in the United States. The public is often encouraged to stay indoors during wildfire smoke events to reduce exposure. However, there is limited information on how much wildfire smoke infiltrates indoors at residences and what household/behavioral characteristics contribute to higher infiltration. We assessed fine particulate matter (PM2.5) infiltration into Western Montana residences during wildfire season. METHODS:We measured continuous outdoor and indoor PM2.5 concentrations from July-October 2022 at 20 residences in Western Montana during wildfire season using low-cost PM2.5 sensors. We used paired outdoor/indoor PM2.5 data from each household to calculate infiltration efficiency (Finf; range 0-1; higher values indicate more outdoor PM2.5 infiltration to the indoor environment) using previously validated methods. Analyses were conducted for all households combined and for various household subgroups. RESULTS:Median (25th percentile, 75th percentile) daily outdoor PM2.5 at the households was 3.7 μg/m3 (2.1, 7.1) during the entire study period and 29.0 μg/m3 (19.0, 49.4) during a 2-week period in September impacted by wildfire smoke. Median daily indoor PM2.5 at the households was 2.5 μg/m3 (1.3, 5.5) overall and 10.4 μg/m3 (5.6, 21.0) during the wildfire period. Overall Finf was 0.34 (95 % Confidence Interval [95%CI]: 0.33, 0.35) with lower values during the wildfire period (0.32; 95%CI: 0.28, 0.36) versus non-wildfire period (0.39; 95%CI: 0.37, 0.42). Indoor PM2.5 concentrations and Finf varied substantially across household subgroups such as household income, age of the home, presence of air conditioning units, and use of portable air cleaners. CONCLUSIONS:Indoor PM2.5 was substantially higher during wildfire-impacted periods versus the rest of the study. Indoor PM2.5 and Finf were highly variable across households. Our results highlight potentially modifiable behaviors and characteristics that can be used in targeted intervention strategies.

Traditional cooking with solid fuels (biomass, animal dung, charcoals, coal) creates household air pollution that leads to millions of premature deaths and disability worldwide each year. Exposure to household air pollution is highest in low- and middle-income countries. Using data from a stepped-wedge randomized controlled trial of a cookstove intervention among 230 households in Honduras, we analyzed the impact of household and personal variables on repeated 24-h measurements of fine particulate matter (PM2.5) and black carbon (BC) exposure. Six measurements were collected approximately six-months apart over the course of the three-year study. Multivariable mixed models explained 37% of variation in personal PM2.5 exposure and 49% of variation in kitchen PM2.5 concentrations. Additionally, multivariable models explained 37% and 47% of variation in personal and kitchen BC concentrations, respectively. Stove type, season, presence of electricity, primary stove location, kitchen enclosure type, stove use time, and presence of kerosene for lighting were all associated with differences in geometric mean exposures. Stove type explained the most variability of the included variables. In future studies of household air pollution, tracking the cooking behaviors and daily activities of participants, including outdoor exposures, may explain exposure variation beyond the household and personal variables considered here.

BACKGROUND:Prostate cancer (PCa) models in mice and rats are limited by their size and lack of a clearly delineated or easily accessible prostate gland. The canine PCa model is currently the only large animal model which can be used to test new preclinical interventions but is costly and availability is sparse. As an alternative, we developed an orthotopic human prostate tumor model in an immunosuppressed New Zealand White rabbit. Rabbits are phylogenetically closer to humans, their prostate gland is anatomically similar, and its size allows for clinically-relevant testing of interventions. METHODS:Rabbits were immunosuppressed via injection of cyclosporine. Human PC3pipGFP PCa cells were injected into the prostate via either (a) laparotomy or (b) transabdominal ultrasound (US) guided injection. Tumor growth was monitored using US and magnetic resonance imaging (MRI). Contrast-enhanced ultrasound (CEUS) imaging using nanobubbles and Lumason microbubbles was also performed to examine imaging features and determine the optimal contrast dose required for enhanced visualization of the tumor. Ex vivo fluorescence imaging, histopathology, and immunohistochemistry analyses of the collected tissues were performed to validate tumor morphology and prostate-specific membrane antigen (PSMA) expression. RESULTS:Immunosuppression and tumor growth were, in general, well-tolerated by the rabbits. Fourteen out of 20 rabbits, with an average age of 8 months, successfully grew detectable tumors from Day 14 onwards after cell injection. The tumor growth rate was 39 ± 25 mm2 per week. CEUS and MRI of tumors appear hypoechoic and T2 hypointense, respectively, relative to normal prostate tissue. Minimally invasive US-guided tumor cell injection proved to be a better method compared to laparotomy due to the shorter recovery time required for the rabbits following injection. Among the rabbits that grew tumors, seven had tumors both inside and outside the prostate, three had tumors only inside the prostate, and four had tumors exclusively outside of the prostate. All tumors expressed the PSMA receptor. CONCLUSIONS:We have established, for the first time, an orthotopic PCa rabbit model via percutaneous US-guided tumor cell inoculation. This animal model is an attractive, clinically relevant intermediate step to assess preclinical diagnostic and therapeutic compounds.