Nanomaterials-Incorporated polymeric Microneedles for wound healing applications.

There is a growing and urgent need for developing novel biomaterials and therapeutic approaches for efficient wound healing. Microneedles (MNs), which can penetrate necrotic tissues and biofilm barriers at the wound and deliver active ingredients to the deeper layers in a minimally invasive and painless manner, have stimulated the interests of many researchers in the wound-healing filed. Among various materials, polymeric MNs have received widespread attention due to their abundant material sources, simple and inexpensive manufacturing methods, excellent biocompatibility and adjustable mechanical strength. Meanwhile, due to the unique properties of nanomaterials, the incorporation of nanomaterials can further extend the application range of polymeric MNs to facilitate on-demand drug release and activate specific therapeutic effects in combination with other therapies. In this review, we firstly introduce the current status and challenges of wound healing, and then outline the advantages and classification of MNs. Next, we focus on the manufacturing methods of polymeric MNs and the different raw materials used for their production. Furthermore, we give a summary of polymeric MNs incorporated with several common nanomaterials for chronic wounds healing. Finally, we discuss the several challenges and future prospects of transdermal drug delivery systems using nanomaterials-based polymeric MNs in wound treatment application.

Validation of the Prognostic Performance of Breast Cancer Index in Hormone Receptor-Positive Postmenopausal Breast Cancer Patients in the TEAM Trial.

PURPOSE: Patients with early-stage hormone receptor-positive (HR+) breast cancer face a prolonged risk of recurrence even after adjuvant endocrine therapy. The Breast Cancer Index (BCI) is significantly prognostic for overall (0-10 years) and late (5-10 years) distant recurrence (DR) risk in N0 and N1 patients. Here, BCI prognostic performance was evaluated in HR+ postmenopausal women from the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial. EXPERIMENTAL DESIGN: 3,544 patients were included in the analysis (N = 1,519 N0, N = 2,025 N+). BCI risk groups were calculated using pre-specified cutoff points. Kaplan-Meier analyses and log-rank tests were used to assess the prognostic significance of BCI risk groups based on DR. Hazard ratios (HR) and confidence intervals (CI) were calculated using Cox models with and without clinical covariates. RESULTS: For overall 10-year DR, BCI was significantly prognostic in Ni0 (N = 1,196) and N1 (N = 1,234) patients who did not receive prior chemotherapy (P < 0.001). In patients who were DR-free for 5 years, 10-year late DR rates for low- and high-risk groups were 5.4% and 9.3% (N0 cohort, N = 1,285) and 4.8% and 12.2% (N1 cohort, N = 1,625) with multivariate HRs of 2.25 (95% CI, 1.30-3.88; P = 0.004) and 2.67 (95% CI, 1.53-4.63; P < 0.001), respectively. Late DR performance was substantially improved using previously optimized cutoff points, identifying BCI low-risk groups with even lower 10-year late DR rates of 3.8% and 2.7% in N0 and N1 patients, respectively. CONCLUSIONS: The TEAM trial represents the largest prognostic validation study for BCI to date and provides a more representative assessment of late DR risk to guide individualized treatment decision-making for HR+ patients with early-stage breast cancer.

Reliability of the safety threats and adverse events in trauma (STAT) taxonomy using trauma video review.

PURPOSE: The STAT (Safety Threats and Adverse Events in Trauma) taxonomy was developed through expert consensus, and groups 65 identified trauma resuscitation adverse events (AEs) into nine distinct categories. It provides a framework for standardized analysis of trauma resuscitations and creates a foundation for targeted quality improvement and patient safety initiatives. This study aims to evaluate the reliability of the STAT taxonomy in identifying AEs during video-recorded trauma resuscitations. METHODS: High-definition audiovisual data from 30 trauma resuscitations were reviewed. Videos were assessed and scored by four independent reviewers (two trainees and two staff). The STAT taxonomy was used to identify AEs based on binary responses: yes and no. Inter-rater reliability was calculated using Gwet's AC1. The frequencies of AEs were tallied and reported as counts and percentages. RESULTS: The most common AEs identified in the videos were failure to measure temperature (86.7%) and inadequate personal protective equipment (86.7%), followed by inability to use closed-loop communication (76.7%). The agreement on all AEs between reviewers was 0.94 (95% CI: 0.93-0.95). The Gwet's AC1 agreement across the 9 AE categories was paramedic handover (0.82), airway and breathing (0.99), circulation (0.95), assessment of injuries (0.91), management of injuries (0.96), procedure-related (0.97), patient monitoring and IV access (0.99), disposition (0.98), team communication and dynamics (0.87). CONCLUSION: The STAT taxonomy demonstrated excellent inter-rater reliability between reviewers and can be used to identify AEs in video-recorded trauma resuscitations. These results provide a foundation for adapting video review to objectively quantify and assess AEs in the trauma bay.

Retracted: Obestatin Plays Beneficial Role in Cardiomyocyte Injury Induced by Ischemia-Reperfusion In Vivo and In Vitro.

The Editors of Medical Science Monitor wish to inform you that the above manuscript has been retracted from publication due to concerns with the credibility and originality of the study, the manuscript content, and the Figure images. Reference: Qin Zhang, Xin-wei Dong, Jia-ying Xia, Ke-ying Xu, Zhe-rong Xu. Obestatin Plays Beneficial Role in Cardiomyocyte Injury Induced by Ischemia-Reperfusion In Vivo and In Vitro. Med Sci Monit, 2017; 23: 2127-2136. DOI: 10.12659/MSM.901361.

A bibliometric analysis of programmed cell death in acute lung injury/acute respiratory distress syndrome from 2000 to 2022.

Acute lung injury (ALI) is a prevalent critical disorder that disrupts the body's homeostasis in patients. The progression from ALI to acute respiratory distress syndrome (ARDS) is often accompanied by programmed cell death (PCD). However, there has been a lack of systematic research and comprehensive analysis on the role of different types of PCD in ALI/ARDS. This study aims to analyze the research status, trends, research hotspots, and compare the contribution of publications from different countries, institutions, journals and authors in the field of PCD in ALI/ARDS using bibliometric analysis. We collected publications regard to PCD and ALI/ARDS from Web of Science during 2000-2022. VOSviewer, Citespace, Scimago Graphica, Pajek, and GraphPad Prism 9.0 software were used for further analyzed and visualized. We identified a total of 3495 publications. The number of publications has increased since the beginning of the new century. China produced the most publications (1965), while the United States ranks first in the number of citations (40141). Shanghai Jiao Tong University and American Journal of Physiology-Lung Cellular and Molecular Physiology were the most prolific institution and journal, respectively. Wang, Ping has published most papers (23) while publications from Lee, Pj have most citations (2016). In terms of keywords, "apoptosis" and "inflammation" are the most frequently occurring, but there has been a recent shift from "apoptosis" and "autophagy" to "necroptosis", "pyroptosis", and "ferroptosis". Additionally, COVID-19 and long noncoding RNA (lncRNA) have become research hotspots in recent years. In conclusion, this bibliometric analysis reveals the research directions and frontier hotspots of PCD in ALI/ARDS. China and the United States have made important contributions to the development of this field. The research hotspots have recently focused on necroptosis, pyroptosis, ferroptosiss, COVID-19 and lncRNA.

Differences in directives to limit treatment and discontinue mechanical ventilation between elderly and very elderly patients: a substudy of a multinational observational study.

PURPOSE: The aim of this study was to characterize differences in directives to limit treatments and discontinue invasive mechanical ventilation (IMV) in elderly (65-80 years) and very elderly (> 80 years) intensive care unit (ICU) patients. METHODS: We prospectively described new written orders to limit treatments, IMV discontinuation strategies [direct extubation, direct tracheostomy, spontaneous breathing trial (SBT), noninvasive ventilation (NIV) use], and associations between initial failed SBT and outcomes in 142 ICUs from 6 regions (Canada, India, United Kingdom, Europe, Australia/New Zealand, United States). RESULTS: We evaluated 788 (586 elderly; 202 very elderly) patients. Very elderly (vs. elderly) patients had similar withdrawal orders but significantly more withholding orders, especially cardiopulmonary resuscitation and dialysis, after ICU admission [67 (33.2%) vs. 128 (21.9%); p = 0.002]. Orders to withhold reintubation were written sooner in very elderly (vs. elderly) patients [4 (2-8) vs. 7 (4-13) days, p = 0.02]. Very elderly and elderly patients had similar rates of direct extubation [39 (19.3%) vs. 113 (19.3%)], direct tracheostomy [10 (5%) vs. 40 (6.8%)], initial SBT [105 (52%) vs. 302 (51.5%)] and initial successful SBT [84 (80%) vs. 245 (81.1%)]. Very elderly patients experienced similar ICU outcomes (mortality, length of stay, duration of ventilation) but higher hospital mortality [26 (12.9%) vs. 38 (6.5%)]. Direct tracheostomy and initial failed SBT were associated with worse outcomes. Regional differences existed in withholding orders at ICU admission and in withholding and withdrawal orders after ICU admission. CONCLUSIONS: Very elderly (vs. elderly) patients had more orders to withhold treatments after ICU admission and higher hospital mortality, but similar ICU outcomes and IMV discontinuation. Significant regional differences existed in withholding and withdrawal practices.

Mental Health Trajectories of Children and Caregivers Using School-Based Health Centers During the COVID-19 Pandemic.

INTRODUCTION: This was a prospective study of children registered at school-based health centers (SBHCs) in Canada. The objectives were to compare mental health trajectories of children and parents/caregivers who accessed SBHCs during the pandemic relative to those who did not. METHOD: Parents/caregivers of children who attended SBHCs completed the Strengths and Difficulties Questionnaire (SDQ) and the Generalized Anxiety Disorder-7 (GAD-7) at three time points during the pandemic. The primary analysis used linear mixed models to examine the relationship between SBHC visits during the pandemic and children's SDQ score trajectories. The secondary analysis was the same for parents'/caregivers' GAD-7 scores. RESULTS: There were 435 children included. SDQ and GAD-7 scores worsened over time for children and parents/caregivers who attended SBHCs during the pandemic compared to those who did not. DISCUSSION: Children and parents/caregivers with worsening mental health symptoms may have sought care at SBHCs since they were accessible during the pandemic.

Discordance between Immunohistochemistry and Erb-B2 Receptor Tyrosine Kinase 2 mRNA to Determine Human Epidermal Growth Factor Receptor 2 Low Status for Breast Cancer.

Novel human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugates have demonstrated efficacy in HER2-low expressing breast cancers, which are currently defined as those with immunohistochemistry (IHC) scores of 1+ or 2+ with a negative in situ hybridization assay. However, current HER2 testing methods are designed to identify HER2-amplified tumors with high expression levels. The true definition of HER2-low expressing breast cancers remains controversial. Using quantitative molecular analysis of breast cancers based on RNA expression, the dynamic range of HER2 expression exceeds that detected by in situ IHC approaches. Erb-B2 receptor tyrosine kinase 2 (ERBB2) mRNA expression levels across IHC groups using patient samples derived from the Tamoxifen Exemestane Adjuvant Multicenter Trial were investigated. The standardized mean differences in ERBB2 mRNA scores in log base 2 are 0.47 (95% CI, 0.36-0.57), 0.58 (95% CI, 0.26-0.70), and 0.32 (95% CI, -0.12 to 0.75) when comparing IHC 0+ without staining versus IHC 0+ with some staining, IHC 0+ with some staining versus IHC 1+, and IHC 1+ versus IHC 2+/fluorescence in situ hybridization-negative, respectively. The results showed immunohistochemical methods have a comparatively limited dynamic range for measuring HER2 protein expression. The range of expression based on RNA abundance suggests a molecular method defining HER2-low cancers may better serve the treatment decision needs of this group. Indeed, the validity of RNA abundance to identify HER2-low cancers and predict treatment response needs to be further evaluated by prospective clinical trials.

Lin28B-high breast cancer cells promote immune suppression in the lung pre-metastatic niche via exosomes and support cancer progression.

The formation of pre-metastatic niche is a key step in the metastatic burden. The pluripotent factor Lin28B is frequently expressed in breast tumors and is particularly upregulated in the triple negative breast cancer subtype. Here, we demonstrate that Lin28B promotes lung metastasis of breast cancer by building an immune-suppressive pre-metastatic niche. Lin28B enables neutrophil recruitment and N2 conversion. The N2 neutrophils are then essential for immune suppression in pre-metastatic lung by PD-L2 up-regulation and a dysregulated cytokine milieu. We also identify that breast cancer-released exosomes with low let-7s are a prerequisite for Lin28B-induced immune suppression. Moreover, Lin28B-induced breast cancer stem cells are the main sources of low-let-7s exosomes. Clinical data further verify that high Lin28B and low let-7s in tumors are both indicators for poor prognosis and lung metastasis in breast cancer patients. Together, these data reveal a mechanism by which Lin28B directs the formation of an immune-suppressive pre-metastatic niche.

Ultrasensitive detection of vitamin E by signal conversion combined with core-satellite structure-based plasmon coupling effect.

The rapid and sensitive surface-enhanced Raman scattering (SERS) detection of molecular biomarkers from real samples is still a challenge because the intrinsically trace analytes may have a low molecular affinity for metal surfaces. Herein, we develop a smart signal conversion and amplification strategy based on silver-gold-silica core-satellite structure nanoparticles (Ag@Au@SiO2 NPs) to sensitively detect low adsorptive vitamin E using SERS, which has been considered a biomarker of neuromuscular disorders when its abnormal content is measured in the serum of patients. Through the reducibility of vitamin E, Ag+ ions are rapidly reduced to Ag atoms, resulting in the epitaxial growth of Ag nanocrystals on gold nanoparticles forming satellite particle-particle gap-narrowed Ag@Au@SiO2 NPs. The generated strong plasmonic field dramatically enhances the Raman signal of the Raman reporter molecule 4-aminothiophenol (4-ATP) and the detected vitamin E molecules at an estimated level of 58.19 nmol L-1. The sensitivity of this operational SERS strategy provides tremendous prospects for the screening of neuromuscular disorders.

The development and application of the Malocclusion Impact Questionnaire (MIQ Chinese version) / 口腔疾病防治

Objective @# To explore the feasibility of applying the Malocclusion Impact Questionnaire (MIQ) of Chinese version among Chinese teenagers, through the verification and evaluation of the Chinese version.@*Methods@# According to the standard procedures of the international quality of life assessment program, the MIQ was translated, back translated, adapted and updated culturally, and the Chinese version was established. The 161 teenagers with the first orthodontic treatment were included. This patient group was assessed for oral health-related quality of life by the Chinese version of the MIQ and Children's Perception Questionnaire (11-14 years old). The reliability and validity of the Chinese version of the MIQ were evaluated statistically by Spearman and factor analysis.@*Results @# A total of 161 valid questionnaires were collected. The internal consistency Cronbach's α of the Chinese scale was 0.887. The correlation coefficient between items and the scale ranged from 0.000 1 to 0.824. A significant positive correlation of the scores was noted between the translated scale and the Children's Perception Questionnaire (11-14 years old), and the correlation coefficient was 0.444 (P<0.001).@*Conclusion @#The reliability and validity of the Chinese version of the MIQ are reliable and can be applied for clinical orthodontic treatment.

Comparative survival analysis of multiparametric tests-when molecular tests disagree-A TEAM Pathology study.

Multiparametric assays for risk stratification are widely used in the management of both node negative and node positive hormone receptor positive invasive breast cancer. Recent data from multiple sources suggests that different tests may provide different risk estimates at the individual patient level. The TEAM pathology study consists of 3284 postmenopausal ER+ve breast cancers treated with endocrine therapy Using genes comprising the following multi-parametric tests OncotypeDx®, Prosigna™ and MammaPrint® signatures were trained to recapitulate true assay results. Patients were then classified into risk groups and survival assessed. Whilst likelihood χ2 ratios suggested limited value for combining tests, Kaplan-Meier and LogRank tests within risk groups suggested combinations of tests provided statistically significant stratification of potential clinical value. Paradoxically whilst Prosigna-trained results stratified Oncotype-trained subgroups across low and intermediate risk categories, only intermediate risk Prosigna-trained cases were further stratified by Oncotype-trained results. Both Oncotype-trained and Prosigna-trained results further stratified MammaPrint-trained low risk cases, and MammaPrint-trained results also stratified Oncotype-trained low and intermediate risk groups but not Prosigna-trained results. Comparisons between existing multiparametric tests are challenging, and evidence on discordance between tests in risk stratification presents further dilemmas. Detailed analysis of the TEAM pathology study suggests a complex inter-relationship between test results in the same patient cohorts which requires careful evaluation regarding test utility. Further prognostic improvement appears both desirable and achievable.

A simplified decision rule to rule out deep vein thrombosis using clinical assessment and D-dimer.

BACKGROUND: Current clinical decision rules to exclude deep vein thrombosis (DVT) are underused partly because of their complexity. A simplified rule that can be easily applied would be more appealing to use in clinical practice. METHODS: We used individual patient data from prospective diagnostic studies of patients suspected of DVT to develop a new clinical decision rule. The primary outcome was presence of DVT either at initial testing or during follow-up. DVT was considered safely excluded if the upper 95% confidence interval (CI) of DVT prevalence was <2%. RESULTS: Four studies and 3368 patients were eligible for this analysis. Overall prevalence of DVT was 17%. In addition to D-dimer, two variables, calf swelling and DVT as the most likely diagnosis, are included in the new rule. Based on these two variables, two clinical pretest probability (CPTP) groups were defined; low (none of the two items present) and high (at least one of the items present). DVT can be safely excluded in patients with low CPTP with a D-dimer <500 ng/mL (prevalence = 0.1%; 95% CI, 0.0-0.8), low CPTP with a D-dimer between 500 ng/ml and 1000 ng/ml (prevalence = 0.3%; 95% CI, 0.0-1.7), and D-dimer <500 ng/ml in patients with high CPTP (prevalence = 0.3%; 95% CI, 0.0-1.0). CONCLUSIONS: The combination of D-dimer and Wells items resulted in a simple clinical decision rule with 3 items. The results suggest that the rule can safely exclude DVT. Prospective validation is required.

Feasibility of improving patient's safety with in vivo dose tracking in intracavitary and interstitial HDR brachytherapy.

PURPOSE: The in vivo dosimetric monitoring in HDR brachytherapy is important for improving patient safety. However, there are very limited options available for clinical application. In this study, we present a new in vivo dose measurement system with a plastic scintillating detector (PSD) for GYN HDR brachytherapy. METHODS: An FDA approved PSD system, called OARtrac (AngioDynamics, Latham, NY), was used with various applicators for in vivo dose measurements for GYN patients. An institutional workflow was established for the clinical implementation of the dosimetric system. Action levels were proposed based on the measurement and system uncertainty for measurement deviations. From October 2018 to September 2019, a total of 75 measurements (48 fractions) were acquired from 14 patients who underwent HDR brachytherapy using either a multichannel cylinder, Venezia applicator, or Syed-Neblett template. The PSDs were placed in predetermined catheters/channels. A planning CT was acquired for treatment planning in Oncentra (Elekta, Version-4.5.2) TPS. The PSDs were contoured on the CT images, and the PSD D90% values were used as the expected doses for comparison with the measured doses. RESULTS: The mean difference from patient measurements was -0.22% ± 5.98%, with 26% being the largest deviation from the expected value (Syed case). Large deviations were observed when detectors were placed in the area where dose rates were less than 1 cGy/s. CONCLUSIONS: The establishment of clinical workflow for the in vivo dosimetry for both the intracavitary and interstitial GYN HDR brachytherapy will potentially improve the safety of the patient treatment.

Laparoscopic hepatectomy is safe and effective for the management of patients with colorectal cancer liver metastases in a population-based analysis in Ontario, Canada. A retrospective cohort study.

BACKGROUND: Laparoscopic hepatectomy (LH) has been deemed safe, and, in the case of minor hepatectomy, the standard of care. Short-, long-term outcomes and costs of LH compared with open hepatectomy (OH) in patients with colorectal cancer liver metastases have not been well described at the population level. MATERIALS AND METHODS: Patients diagnosed with colorectal cancer undergoing hepatectomy were included in this population-based retrospective cohort study from 2006- to 2014. Postoperative complications (per Clavien-Dindo) and survival were analyzed using a linear mixed model and Cox-Proportional hazards model respectively. Costs of surgery and the 90-day postoperative period were considered in 2018 Canadian dollars and compared from the perspective of a third-party payer. RESULTS: Over a median follow-up of 56 months, 95% confidence interval (CI): 51 to 68), there were 2991 hepatectomies (OH: 2551 (85%) and LH: 440 (15%)). LH compared to OH was more common for patients >70 years-old (30% vs. 22%, p = 0.004) and for minor hepatectomy (52% vs. 32%, p < 0.001) respectively. By multivariable analyses, OH was associated with similar 90-day mortality (Odds Ratio (OR) 1.05, 95% CI: 0.56-1.97), and overall survival (Hazard Ratio (HR) 1.08, 95% CI: 0.90-1.29), but higher rates of major postoperative complications (OR 1.34, 95% CI: 1.03-1.76), higher cost (median difference $6,163, 95% CI: $3229 to $9096), and longer length of hospital stay (LOS) (mean difference 3.04 days, 95% CI: 2.7 to 3.91). CONCLUSION: LH was associated with lower postoperative complications, shorter LOS, which translated into lower costs to the healthcare system, without differences in postoperative mortality and survival.

A Multimodality Image Guided Precision Radiation Research Platform: Integrating X-ray, Bioluminescence, and Fluorescence Tomography With Radiation Therapy.

PURPOSE: Small animal irradiation is crucial to the investigation of radiobiological mechanisms. The paradigm of clinical radiation therapy is trending toward high-precision, stereotactic treatment. However, translating this scheme to small animal irradiation is challenging owing to the lack of high-quality image guidance. To overcome this obstacle, we developed a multimodality image guided precision radiation platform. METHODS AND MATERIALS: The platform consists of 4 modules: x-ray computed tomography (CT), bioluminescence tomography (BLT), fluorescence molecular tomography (FMT), and radiation therapy. CT provides animal anatomy and material density for radiation dose calculation, as well as body contour for BLT and FMT reconstruction. BLT and FMT provide tumor localization to guide radiation beams and molecular activity to evaluate treatment outcome. Furthermore, we developed a Monte Carlo-based treatment planning system (TPS) for 3-dimensional dose calculation, calibrated it using radiochromic films sandwiched in a water-equivalent phantom, and validated it using in vivo dosimeters surgically implanted into euthanized mice (n = 4). Finally, we performed image guided irradiation on mice bearing orthotopic breast and prostate tumors and confirmed radiation delivery using γH2AX histology. RESULTS: The Monte Carlo-based TPS was successfully calibrated by benchmarking simulation dose against film measurement. For in vivo dosimetry measured in the euthanized mice, the average difference between the TPS calculated dose and measured dose was 3.86% ± 1.12%. Following the TPS-generated treatment plan, we successfully delivered 20 Gy dose to an animal bearing an orthotopic prostate tumor using 4 BLT-guided radiation beams and 5 Gy dose to an animal bearing an orthotopic breast tumor using a single FMT-guided radiation beam. γH2AX histology presented significantly more DNA damage in irradiated tumors and thus validated the dose delivery accuracy. CONCLUSIONS: Combined with Monte Carlo TPS, this multimodality CT/BLT/FMT image guided small animal radiation platform can specifically localize tumors, accurately calculate dose distribution, precisely guide radiation delivery, and molecularly evaluate treatment response. It provides an advanced toolset for radiobiology and translational cancer research.

The association between gut butyrate-producing bacteria and non-small-cell lung cancer.

BACKGROUND: Recently, it has been found that the gut microbiota may affect the development of lung cancer through the "gut-lung axis." To investigate this relationship, we performed this study to determine whether the gut microbiota in non-small-cell lung cancer (NSCLC) patients is different from that in healthy adults. METHODS: Quantitative PCR (qPCR) was used to detect the expression levels of eight gut butyrate-producing bacteria in healthy adults and NSCLC patients. We enrolled 30 patients with NSCLC and 30 subjects from 100 healthy adults after matching for age and sex. RESULTS: Compared to healthy adults, most of the gut butyrate-producing bacteria in NSCLC patients were significantly decreased; these included Faecalibacterium prausnitzii, Clostridium leptum, Clostridial cluster I, Ruminococcus spp., Clostridial Cluster XIVa, and Roseburia spp. Among the gut butyrate-producing bacteria, we analyzed Clostridial cluster IV and Eubacterium rectale were not decreased in NSCLC patients. CONCLUSIONS: We conclude that NSCLC patients had gut butyrate-producing bacteria dysbiosis. Further studies should be performed to investigate the underlying mechanisms of how these specific bacteria affect lung cancer progression and prognosis.

Quantitative X-ray fluorescence imaging of gold nanoparticles using joint L1 and total variation regularized reconstruction.

BACKGROUND: This work proposed a joint L1 and total variation (TV) regularized reconstruction method for X-ray fluorescence tomography (XFT), and investigated the performance of this method in quantitative imaging of gold nanoparticles (GNPs). METHODS: We developed a dual-modality XFT/CT imaging system which consisted of a benchtop X-ray source, a translation/rotation stage, a silicon drift detector for X-ray fluorescence (XRF) detection, and a flat panel detector for transmission X-ray detection. A pencil-beam collimator was 3D printed with steel and employed in sample excitation. The sensitivity of the XFT imaging system was determined by imaging water phantoms with multiple inserts containing GNP solutions of various concentrations (0.02-0.16 wt.%). A joint L1 and total variation (TV) regularized algorithm was developed for XFT reconstruction, where the L1 regularization was used to reduce image artifacts and the TV regularization was used to preserve the shape of targets. Nonlinear conjugate gradient (NCG) descent algorithm with backtracking line search was adopted to solve the reconstruction problem. We compared the L1 + TV regularization method with filtered back projection (FBP), maximum likelihood expectation maximization (ML-EM), L1 regularization, and TV regularization methods. Contrast-to-noise ratio (CNR), Dice similarity coefficient (DSC) and localization error (LE) metrics were used to compare the performance of different methods. The CT and XFT imaging doses were also measured using EBT2 radiochromic films. RESULTS: The 3D printed pencil-beam collimator shaped an excitation beam with a 2 mm full width at half maximum at the imaging isocenter. Based on the phantom imaging experiments, the joint L1 and TV regularization method performed better than FBP, ML-EM, L1 regularization and TV regularization methods, with higher localization accuracy (offset <0.6 mm), CNR and DSC values. Compared with CT, XFT with L1 + TV regularized reconstruction demonstrated higher sensitivity in GNP imaging, and could detect GNP at a concentration of 0.02 wt.% or lower. Moreover, there existed a significant linear correlation (R2>0.99) between the reconstructed and true GNP concentration. The estimated XFT imaging dose is about 41.22 cGy under current setting. CONCLUSIONS: The joint L1 + TV regularized reconstruction algorithm performed better in noise suppression and shape preservation. Using the L1 + TV regularized reconstruction, the XFT system is able to localize GNP targets with submillimeter accuracy and quantify GNP distribution at a concentration of 0.02 wt.% or lower.

Plasmonic Optical Imaging of Gold Nanorods Localization in Small Animals.

Gold nanoparticles (GNP) have been intensively investigated for applications in cancer imaging and therapy. Most imaging studies focused on microscopic imaging. Their potential as optical imaging probes for whole body small animal imaging has rarely been explored. Taking advantage of their surface plasmon resonance (SPR) properties, we aim to develop a noninvasive diffuse optical imaging method to map the distribution of a special type of GNP, gold nanorods (GNR), in small animals. We developed an integrated dual-modality imaging system capable of both x-ray computed tomography (XCT) and diffuse optical tomography (DOT). XCT provides the animal anatomy and contour required for DOT; DOT maps the distribution of GNR in the animal. This SPR enhanced optical imaging (SPROI) technique was investigated using simulation, phantom and mouse experiments. The distribution of GNR at various concentrations (0.1-100 nM, or 3.5 ug/g-3.5 mg/g) was successfully reconstructed from centimeter-scaled volumes. SPROI detected GNR at 18 µg/g concentration in the mouse breast tumor, and is 3 orders more sensitive than x-ray imaging. This study demonstrated the high sensitivity of SPROI in mapping GNR distributions in small animals. It does not require additional imaging tags other than GNR themselves. SPROI can be used to detect tumors targeted by GNR via passive targeting based on enhanced permeability and retention or via active targeting using biologically conjugated ligands.

Bioluminescence Tomography Guided Small-Animal Radiation Therapy and Tumor Response Assessment.

PURPOSE: The image guided small animal arc radiation treatment platform has adopted onboard cone beam computed tomography and bioluminescence tomography (BLT). We used BLT to guide irradiation delivery and quantitatively assess irradiation-induced tumor response. METHODS AND MATERIALS: BLT was first validated on a tissue-simulating phantom, where the internal chemiluminescent liquid had a constant volume while its luminescence intensity gradually decayed. Then, in vivo experiments were performed on BALB/c mice orthotopically inoculated with 4T1 breast carcinoma cells expressing luciferase. Animals either received radiation treatment (radiation therapy [RT] group, n = 9) or did not (control group, n = 9). BLT was used to guide delivery of a single-fraction 5-Gy radiation dose to the tumor and to evaluate the treatment response. Terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) staining was used to evaluate irradiation-induced DNA damage and cell apoptosis. RESULTS: Phantom results showed that BLT not only recovered the constant target volume with <2% deviation but also accurately monitored the decay of the chemiluminescent molecules. For the RT group of animals, there was significant reduction in both the BLT-based tumor volume (21% ± 10%, P = .001) and bioluminescence intensity (48% ± 17%, P = .0008). For the control group, a significant increase was detected in the BLT tumor volume (35% ± 12%, P < .0001) but not the BLT bioluminescence intensity (P = .4). There was a significant difference in the BLT tumor volume between the RT and control groups 7 days after irradiation (P = .03). Regression analysis suggests a strong correlation between the BLT and cone beam computed tomography tumor volume (R2 = 0.93). Analysis using terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling staining showed a significant difference in tumor cell apoptosis between the RT and control groups (20.6% ± 2.9% and 3.2% ± 1.7%, respectively; P < .05). CONCLUSIONS: BLT onboard the image guided small animal arc radiation treatment platform can be used to accurately guide irradiation delivery and to quantitatively assess treatment response by simultaneously monitoring tumor volume and cancer cell population.