Volume Mm3 Research Articles

Return to Sports Activity After Microfracture for Osteochondral Lesion of the Talus in Skeletally Immature Children.

Osteochondral lesions of the talus (OLTs) are among the common sports-related injuries. However, there are few reports on the return to sports after OLT surgery in skeletally immature children. This study was performed to evaluate the return to sports after microfracture for OLTs in skeletally immature children. This study involved 17 ankles of 16 patients (mean age, 13.2 years; range, 10-16 years) with open tibial epiphyses on magnetic resonance imaging (MRI) who underwent microfracture for OLTs <10 mm in diameter and confirmation of lesion instability under arthroscopy. Nine of 17 ankles had additional lateral ankle ligament stabilization. All patients were participating in some form of sports. The Japanese Society for Surgery of the Foot (JSSF) score, Ankle Activity Score (AAS), return to sports rate, lesion size, grade of subchondral bone marrow edema, and Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score on MRI were evaluated after microfracture. The mean postoperative follow-up period was 53.5 months. The mean JSSF score significantly improved from 76.1 points preoperatively to 94.9 points at the final follow-up (P < .01). The mean AAS showed no change from preoperative state to final follow-up. The return to sports rate was 100%. The lesion size significantly decreased from 76.3 to 56.7 mm2 in area (P = .02) and from 283.2 to 185.6 mm3 in volume (P = .05). The bone marrow edema grade decreased in 8 of 17 ankles. The total MOCART score showed a significant improvement from 6 months to 1 year postoperatively (P = .05). All skeletally immature children who underwent microfracture for OLTs in this study were able to return to sports activity and showed improvements in clinical scores and MRI parameters. Microfracture may be considered an effective first-line treatment for OLTs <10 mm in diameter in skeletally immature athletes. Level IV, retrospective case-control study.

In situ three-dimensional visualization of Bursaphelenchus xylophilus inoculated in Pinus thunbergii using X-ray micro-computed tomography

Pine wilt disease, a devastating infectious disease of pine trees, is caused by the pinewood nematode, Bursaphelenchus xylophilus. It is important to understand the spatial dispersal processes of B. xylophilus within host-tree tissues to assess its pathogenic mechanism. However, this is not feasible with conventional microscopy-imaging techniques. In this study, we showed that X-ray micro-computed tomography (micro-CT) imaging can be a powerful tool for visualizing infected nematodes within host-tree tissues. We visualized 161 nematodes and 11 eggs within a Pinus thunbergii stem section, 47.3 mm3 in volume, using an appropriate segmentation of the micro-CT images. Quantitative measurements of the segmented region corresponding to the nematodes allowed for the calculation of the longitudinal length and a-value, which were similar to previous morphological descriptions of B. xylophilus. The technique adopted in this study can aid in understanding the behavior of and obtaining quantitative information on B. xylophilus within tree tissues.

Abstract A078: Response and resistance to KRAS inhibition in PDAC mouse models

Abstract Pancreatic ductal adenocarcinoma (PDAC), among the most lethal cancers with a 5-year survival rate of 11%, is a KRAS-driven disease. Studies have shown that a single glycine (G) to aspartic acid (D) substitution on codon 12 of KRAS protein (known as KRASG12D mutation) appears in 41% of all PDAC cases, highlighting the necessity of targeting KRASG12D as a therapeutic approach. MRTX1133, a recently developed potent, non-covalent, direct, and selective KRASG12D small molecule inhibitor demonstrates a high-affinity interaction with KRASG12D. Previous studies have shown striking efficacy of MRTX1133 on growth inhibition of mouse/human PDAC tumor cells carrying KRASG12D mutation in various in vivo and in vitro models, during short-term treatment. Here in our study, we investigated the efficacy of continuous long-term treatment with MRTX1133 in two different PDAC mouse models: KPC (a genetically engineered mouse model harboring a KRASG12D mutation) and its syngeneic orthotopic model. In both models, tumor sizes were detected by ultrasound imaging and after reaching 100-300 mm3 in volume, mice were enrolled in either MRTX1133 or vehicle treatment (30mg/kg, IP, BID). Tumor sizes were monitored by ultrasound regularly and the treatment continued until mice reached clinical endpoint. At endpoint, mice were sacrificed, and tumors were harvested for a series of downstream experiments. Our results showed that while, in both models, vehicle treated tumors grew aggressively and mice reached endpoint in average 6 days post treatment, drug treated tumors regressed rapidly and survival rate increased significantly to as late as 222 days post treatment in KPC model. However, in both models, drug treated tumors ultimately relapsed, developed resistance to the drug, and resulted in death. Further analysis of KPC mice ultrasound images evidenced that the relapsed tumors occurred at the same sites of the primary tumors. This suggests the possibility of relapsed tumors arising from the regrowth of the dormant residual cells from the primary tumors. Re-implantation of the resistant tumors either in the flank or pancreata of the new wildtype mice resulted in the formation of drug-resistant tumors in hosts. In addition, histopathology analysis of the tumor sections demonstrated a significant increase in the ratio of invasive PDAC to PanIN areas in the drug resistant tumors. Furthermore, multiplex immunofluorescence of both MRTX1133 resistant and vehicle treated tumors from KPC mice demonstrated co-expression of markers representing basal-like and classical PDAC subtypes. Moreover, flow cytometry analysis indicated an increase in the myeloid population of the resistant tumors comparing to the vehicle treated group. In the future directions, through applying a broad range of cellular and molecular experiments we will characterize the kinetics of KRAS inhibitor drug resistance and define possible combination therapy startegies to overcome drug resistance mechanisms. Citation Format: Laleh Abbassi, Jullien Dilly, Annan Yang, Giselle Uribe, Branden Parent, Connor Hennessey, Kevin Kapner, Alexander Jordan, Shatavisha Dasgupta, Micaela Morgado, Taimour Baslan, Li Qiang, Peter Winter, Seema Chugh, Alex Shalek, Ben Stanger, Srivastan Raghavan, Scott Lowe, Brian Wolpin, Stephanie Dougan, Jonathan Nowak, Andrew Aguirre. Response and resistance to KRAS inhibition in PDAC mouse models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A078.

Kinematic Evolution of a Large Paraglacial Landslide in the Barry Arm Fjord of Alaska

AbstractOur warming climate is adversely affecting cryospheric landscapes via glacial retreat, permafrost degradation, and associated slope destabilization. In Prince William Sound, Alaska, the rapid retreat of Barry Glacier has destabilized the slopes flanking the glacier, resulting in numerous landslides. The largest of these landslides (∼500 Mm3 in volume) is more than 2 km wide and has the potential to generate a tsunami that could affect nearby recreationists, marine traffic, infrastructure, natural and cultural resources, and the community of Whittier, located 60 km from the landslide. Here, we combine landslide structural and kinematic element mapping with data acquired from bi‐yearly airborne lidar, multi‐week satellite‐based synthetic aperture radar (SAR), sub‐hourly ground‐based SAR, and seismic monitoring from 2020 to 2022 to characterize this landslide and examine its evolution. While some methods serve as a snapshot in time that is a culmination of events, others emphasize the ever‐evolving nature of the landslide and associated hazards. Four major kinematic elements define the overall structure of the landslide, which vary in deformation type and rate, from creep (5 mm per day over several months) to episodic movement (2 m in 30 days) and landslide‐wide to localized events. In some areas of the landslide, short‐term deformation deviates from structures formed by cumulative movement, implying structural and kinematic evolution associated with glacier retreat. These insights are important for assessing landslide hazards and hazard evolution for large, slow‐moving bedrock landslides in actively deglaciating environments.

A miniaturized CPW-fed CSRR-loaded quad-port MIMO antenna for 5.5/6.5 GHz wireless applications

Abstract For forthcoming wireless applications, a small and highly decoupled complementary split ring resonators (CSRR)–loaded co-planar waveguide (CPW)–fed antenna for dual-band applications is investigated. The low-profile antenna consists of a CSRR-loaded rectangular radiating element with a truncated bottom, giving a wideband performance over the frequency ranges of 5.28–5.52 GHz and 6–7.2 GHz. The antenna has been printed on a widely used FR4 substrate measuring 7.5 × 10.5 × 1.6 mm3 in volume. This research’s suggested antenna is turned into a 4 × 4 multi input multi output (MIMO) construction using a 25 × 25 mm2 printed circuit board. Individual antennas were isolated by nearly 20 dB without using a decoupling device. The antenna has been built, and the measured and simulated results correspond well. Computing envelope correlation coefficient (ECC), channel capacity (CC), and channel capacity loss (CCL) further validates the antenna’s performance (−). The antenna has an overall gain of around 2.54 dBi and a radiation efficiency of approximately 89% throughout the relevant spectral range, which is much better for wireless applications. The suggested antenna’s omnidirectional emission pattern makes it a potential contender for future wireless and cellular applications.

Quantitative 3D assessment of the lung cancer microenvironment using multi-resolution open-top light-sheet microscopy.

2616 Background: Non-small cell lung cancer (NSCLC) tissue is a valuable resource for diagnosis, treatment planning, and drug development. Current 2D histopathological techniques introduce under-sampling error (i.e., a single 5 µm section represents 0.5% of a 1 mm thick biopsy), interobserver variability, and failure to capture the biology contained within the entire tissue sample. We have developed a suite of technologies to stain, chemically clarify, image, visualize, and analyze entire, intact lung tissue samples. Herein, we present analysis methods for comprehensive 3D assessment of intact NSCLC tissue. Methods: Human NSCLC tissue, stored frozen in optimal cutting temperature (OCT) compound, was fixed in 4% paraformaldehyde, stained with nuclear (TOPRO-3) and general protein (Eosin) fluorescent dyes, and optically cleared using a modified iDISCO protocol with ethyl cinnamate as the refractive index matching solution. Twenty tissue samples measuring 1-5 mm3 in volume were imaged at 2 µm/pixel resolution with a hybrid open-top light-sheet microscope. Smaller regions of interest (ROIs) with interesting pathologic features were re-imaged at higher resolution, 0.17 µm/pixel. Visualization and analysis was performed using Aivia software, custom spatial analysis software and python scripts. Results: All NSCLC tissue samples were successfully imaged in 3D at both low and high resolution. Computational approaches, such as machine learning, were used to segment and classify tumor cells and lymphocytes within the high resolution ROIs. In one example we quantified a 0.0045 mm3 ROI containing 1x109 voxels. We segmented 1,474 unique objects, and classified 683 (46%) of the objects as lymphocytes and 309 (20%) of the cells as tumor cells. We found that on average the lymphocytes were within 12 µm of the nearest tumor cell. Additionally the tissue was broken into separate lymphocyte dense (58% of volume) and tumor dense regions (42% of volume). Further analysis is in progress to quantify more features, such as tertiary lymphoid structures, stromal cells, and fibrosis over the full 20 sample dataset. Conclusions: We successfully implemented 3D machine learning analysis pipelines using images from intact NSCLC tissue samples measuring up to 5 mm3. The imaging was performed using our custom hybrid open-top light-sheet microscope. This novel method enables us to identify and quantify key histological features such as tumor cells and lymphocytes within the tumor microenvironment. In addition, machine learning driven algorithms clustered cells into distinct tissue regions in 3D which enables a more precise assessment of disease state and heterogeneity. Further investigation is ongoing to link these results to patient outcomes.

Examination of embolisms in maple and birch saplings utilising microCT

We demonstrate the application of synchrotron x-ray microtomography (microCT) to non-invasively examine the internal structure of a maple and birch sapling. We show that, through the use of standard image analysis techniques, embolised vessels can be extracted from reconstructed slices of the stem. By combining these thresholded images with connectivity analysis, we map out the embolisms within the sapling in three dimensions and evaluate the size distribution, showing that large embolisms over 0.005mm3 in volume compose the majority of the saplings' total embolised volume. Finally we evaluate the radial distribution of embolisms, showing that in maple fewer embolisms are present towards the cambium, while birch has a more uniform distribution.

Morphological characterization of lode gold in the auriferous quartz veins at M’Popo mine, Angola, by computed tomography and optical microscopy

ABSTRACT Auriferous vein samples of the Angolan M’Popo deposit were characterized by a combination of 2D microscopy and 3D computed tomography (CT) in order to visualize and assess the gold distribution and gold morphology in in situ high-grade gold ore. The 0.1–2.4 m wide hydrothermal quartz veins in the Mesoproterozoic M’Popo granitic complex are composed mainly of quartz and pyrite, minor other sulfides and (visible) gold. The favourable X-ray attenuation/density contrast within this mineral assemblage allows delineation of the gold particle fraction so that gold particles of <0.01–19.95 mm³ in volume have been identified. Statistical analysis reveals that the bulk (∼99.98%) of all gold particles belong to the smallest volume classes (≤0.02 mm²) while large particles (>0.5 mm³) are few. The contrast between rounded, compact smaller particles and branched larger ones is clearly expressed in the CT reconstructions while transitions between these reflect a likely continuum in gold mineralization.

Abstract P3-07-03: Anti-tumor activity of a liposomal formulation of Eribulin compared with the same dose of Eribulin in patient-derived breast cancer xenografts

Abstract Backgrounds: A liposomal formulation of Eribulin, E7389-LF may allow increased access to tumor tissues and has been under development for breast cancer. In a phase 1, expansion cohort as a late line treatment, objective response rate was observed to be 35.7% (Her2-negative breast cancer), and 42.9% for hormone receptor-positive (HR+ve) patients (Masuda, European Journal of Cancer, 2022). However, survival benefit and its mode of action of E7389-LF remains unclear, although E7389-LF seems more effective than Eribulin in clinic. Methods: PDX#1 is a breast cancer patient-derived xenograft (PDX) from a patient with triple negative breast cancer who later received Eribulin for 7 cycles until progression in lung metastases. PDX#2 is also a breast cancer PDX from paclitaxel-resistant HR+ve/HER2-ve breast cancer, respectively. These two PDXs were provided by the National Cancer Center J-PDX library, Japan, and were bred in NOD/Shi-scid, IL-2Rγnull (NOG) mice and observed until the onset of a mammary tumor approximately 180 and 240 mm3 in volume (Day 0). PDX tumors were randomized and monitored with tumor growth measurements. Each group received either saline, 0.34mg/kg, or 0.67 mg/kg (clinically relevant dose of E7389-LF, estimated) of Eribulin or E7389-LF at Day 0 and 7 (Experiment 1). For short-term experiments, 9 PDX#1 or 12 PDX#2 tumors were removed one week after an injection of saline, 0.67 mg/kg of Eribulin, or 0.67 mg/kg of E7389-LF (n=3/group for PDX#1, n=4/group for PDX#2), and tumors were immunohistochemically stained with anti-CD31 antibody, an endothelial cell marker, to investigate microvessel density and RNA sequencing was additionally performed (Experiment 2). Results: Table 1 summarizes the results. In Experiment 1, both E7389-LF and Eribulin showed significant antitumor activity compared with saline in a dose-dependent manner with respect to tumor growth inhibition and survival benefit, extension of tumor doubling time (earlier day with relative tumor volume &amp;gt;200%), in PDX#1 and #2. Tumor shrinkage was seen in PDX#1, and E7389-LF at 0.34 mg/kg, or 0.67 mg/kg were more potent than the same doses of Eribulin at Day 21 in both PDXs (p &amp;lt; 0.05). E7389-LF at 0.67 mg/kg also showed relative tumor growth inhibition compared with the same dose of Eribulin in PDX#2 (p &amp;lt; 0.05). As for survival, PDX#1 with E7389-LF at 0.67 mg/kg demonstrated significantly longer survival (p=0.03) than Eribulin at 0.67 mg/kg, while PDX#2 with E7389-LF at 0.67 mg/kg did not (p=0.10). In Experiment 2, microvessel density increased in PDX#1 after receiving eribulin and E7389-LF compared with untreated ones, with a significant difference for E7389-LF (p=0.006), and showed an increasing tendency over Eribulin (p=0.06), while microvessel density in PDX#2 did not differ between groups. Conclusions: Pre-clinical data demonstrates that E7389-LF is more potent than the same dose of Eribulin in patient-derived breast cancer xenografts. Survival benefit was observed in a PDX with a tumor shrinkage and an increase in microvessel density. Table 1. Summary of the findings. p&amp;lt;0.05 vs Saline (at the indicated time point for tumor volume), *: p&amp;lt;0.05 E7389-LF vs Eribulin (at Day 21 for tumor volume) Citation Format: Maki Tanioka, Taro Semba, Tatsunori Shimoi, Yuki Niwa, Kan Yonemori. Anti-tumor activity of a liposomal formulation of Eribulin compared with the same dose of Eribulin in patient-derived breast cancer xenografts [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-03.

Effect of contact force on pulsed field ablation lesions in porcine cardiac tissue.

Contact force has been used to titrate lesion formation for radiofrequency ablation. Pulsed field ablation (PFA) is a field-based ablation technology for which limited evidence on the impact of contact force on lesion size is available. Porcine hearts (n = 6) were perfused using a modified Langendorff set-up. A prototype focal PFA catheter attached to a force gauge was held perpendicular to the epicardium and lowered until contact was made. Contact force was recorded during each PFA delivery. Matured lesions were cross-sectioned, stained, and the lesion dimensions measured. A total of 82 lesions were evaluated with contact forces between 1.3and 48.6 g. Mean lesion depth was 4.8 ± 0.9 mm (standard deviation), mean lesion width was 9.1 ± 1.3 mm, and mean lesion volume was 217.0 ± 96.6 mm3 . Linear regression curves showed an increase of only 0.01 mm in depth (depth = 0.01 × contact force + 4.41, R2 = 0.05), 0.03 mm in width (width = 0.03 × contact force + 8.26, R2 = 0.13) for each additional gramof contact force, and 2.20 mm3 in volume (volume = 2.20 × contact force + 162, R2 = 0.10). Increasing contact force using a bipolar, biphasic focal PFA system has minimal effects on acute lesion dimensions in an isolated porcine heart model and achieving tissue contact is more important than the force with which that contact is made.

Accuracy of Various Methods to Estimate Volume and Weight of Symmetrical and Non-Symmetrical Fruits using Computer Vision

Many researchers have used images to measure the volume and weight of fruits so that the measurement can be done remotely and non-contact. There are various methods for fruit volume estimation based on images, i.e., Basic Shape, Solid of Revolution, Conical Frustum, and Regression. The weight estimation generally uses Regression. This study analyzed the accuracy of these methods. Tests were done by taking images of symmetrical fruits (represented by tangerines) and non-symmetrical fruits (represented by strawberries). The images were processed using segmentation in saturation color space to get binary images. The Regression method used Diameter, Projection Area, and Perimeter as features that were extracted from the binary images. For symmetrical fruits, the best accuracy was obtained with the Linear Regression based on Diameter (LDD), which gave the highest R2 (0.96 for volume and 0.93 for weight) and the lowest RMSE (5.7 mm3 for volume and 5.3 gram for volume). For non-symmetrical fruits, the highest accuracy for non-symmetric fruits was given by the Linear Regression based on Diameter (LRD) and Linear Regression based on Area (LRA) with an R2 of 0.8 for volume and weight. The RMSE for LRD and LRA for strawberries was 3.3 mm3 for volume and 1.4 grams for weight.

In Vivo Prediction of Kidney Stone Fragility Using Radiomics-Based Regression Models.

Introduction: The surgical technique for urinary stone removal is partly influenced by its fragility, as prognosticated by the clinician. This feasibility study aims to develop a linear regression model from CT-based radiomic markers to predict kidney stone comminution time in vivo with two ultrasonic lithotrites. Materials and Methods: Patients identified by urologists at our institution as eligible candidates for percutaneous nephrolithotomy were prospectively enrolled. The active engagement time of the lithotrite in breaking the stone during surgery denoted the comminution time of each stone. The comminution rate was computed as the stone volume disintegrated per minute. Stones were grouped into three fragility classes (fragile, moderate, hard), based on inverse of the comminution rates with respect to the mean. Multivariable linear regression models were trained with radiomic features extracted from clinical CT images to predict comminution times in vivo. The model with the least root mean squared error (RMSE) on comminution times and the fewest misclassification of fragility was finally selected. Results: Twenty-eight patients with 31 stones in total were included in this study. Stones in the cohort averaged 1557 (±2472) mm3 in volume and 5.3 (±7.4) minutes in comminution time. Ten stones had nonmoderate fragility. Linear regression of stone volume alone predicted comminution time with an RMSE of 6.8 minutes and missed all 10 stones with nonmoderate fragility. A fragility model that included stone volume, internal morphology, shape-based radiomics, and device type improved RMSE to below 3.3 minutes and correctly classified 20/21 moderate and 6/10 nonmoderate stones. Conclusions: CT metrics-based fragility models may provide information to surgeons regarding kidney stone fragility and facilitate the selection of stone removal procedures.

Synergistic effect of Laves phase evolution and porosity defects in nuclear-grade FeCrAl alloy laser welded joints: Experiments and crystal plasticity modeling

The Fukushima Daiichi nuclear accident in Japan in 2011 created a strong push for the exploration of advanced accident-tolerant fuel materials. For this purpose, FeCrAl-based alloys are a promising class of materials. However, no study has been conducted on the Laves phase evolution in the weld, which is proved to be directly related to weld softening based on the observations in this study. Moreover, the failure mechanism after laser welding remains unknown. In this study, laser welded nuclear-grade FeCrAl alloys were investigated through experiments and crystal plasticity modeling. The maximum ultimate tensile strength and elongation of the welds were 652 MPa (strength coefficient of ∼70.7%) and 9.7%, respectively. Obvious softening was observed in the laser-welded FeCrAl alloy joints. The re-precipitated nanoscale Fe2(Nb,Mo) Laves-phase particles in the fusion zone (FZ) were smaller than 200 nm, whereas the particles in the heat-affected zone (HAZ) were coarsened over 1.6 μm owing to Ostwald ripening. The bipolar size distribution of the Laves phase was the intrinsic reason for the weld softening. In addition, porosity defects were detected in the FZ and fusion line. Most of them were less than 4 × 10−5 mm3 in volume and were distributed left-of-center or right-of-center instead of in the exact center of the FZ. The in situ mechanical response confirmed that pore-induced stress concentration triggered off crack initiation and propagation, leading to the weld failure. Therefore, enhancing the precipitation of Laves phase with concurrent elimination of the porosity defects can serve as a promising strategy to achieve high-strength FeCrAl alloy joints. The fundamental discoveries in this study can facilitate the application of laser welding in joining the nuclear-grade FeCrAl-based alloys.

Precision of &lt;em&gt;In Vivo&lt;/em&gt; Quantitative Tooth Wear Measurement Using Intra-Oral Scans

Quantitative wear measurement is of increasing interest for measuring tooth wear progression. However, most research on quantitative wear measurement has focused on simulated wear or scanned gypsum casts. A 3D Wear Analysis (3DWA) protocol has been developed that analyzes tooth wear in vivo through intra-oral scanners available to dental clinicians. This study investigated the precision of the 3DWA protocol for measuring wear through maximum height loss (mm) and volume change (mm3). Observational prospective wear data from 55 patients were analyzed after 0-1-, 0-3-, and 0-5-year intervals to determine rates of wear, and convenience samples were chosen to test the protocol's precision on dentitions scanned twice in one sitting and its intra- and inter-rater precision on scans with 0-3- and 0-5-year intervals. Scans were made using intra-oral scanners (IOS) and superimposed using 3D measurement software. T-tests were performed to determine the structural and random error, and trimmed ranges were calculated to interpret the error. For protocol precision, the mean difference was 0.015 mm (-0.002; 0.032, p = 0.076) for height and -0.111 mm3 (-0.250; 0.023, p = 0.101) for volume. The duplicate measurement error was 0.062 mm for height and 0.268 mm3 for volume. The height measurements were precise enough to measure wear after intervals of 0-3 or 0-5 years; however, volume measurements were susceptible to procedural error and operator sensitivity. The 3DWA protocol is precise enough to adequately measure tooth height loss after intervals of a minimum of 3 years or in patients with severe wear progression, but it is not suited to measuring volumetric changes.

Precision of In Vivo Quantitative Tooth Wear Measurement using Intra-Oral Scans.

Quantitative wear measurement is of increasing interest for measuring tooth wear progression. However, most research on quantitative wear measurement has focused on simulated wear or scanned gypsum casts. A 3D Wear Analysis (3DWA) protocol has been developed that analyzes tooth wear in vivo through intra-oral scanners available to dental clinicians. This study investigated the precision of the 3DWA protocol for measuring wear through maximum height loss (mm) and volume change (mm3). Observational prospective wear data from 55 patients were analyzed after 0-1-, 0-3-, and 0-5-year intervals to determine rates of wear, and convenience samples were chosen to test the protocol's precision on dentitions scanned twice in one sitting and its intra- and inter-rater precision on scans with 0-3- and 0-5-year intervals. Scans were made using intra-oral scanners (IOS) and superimposed using 3D measurement software. T-tests were performed to determine the structural and random error, and trimmed ranges were calculated to interpret the error. For protocol precision, the mean difference was 0.015 mm (-0.002; 0.032, p = 0.076) for height and -0.111 mm3 (-0.250; 0.023, p = 0.101) for volume. The duplicate measurement error was 0.062 mm for height and 0.268 mm3 for volume. The height measurements were precise enough to measure wear after intervals of 0-3 or 0-5 years; however, volume measurements were susceptible to procedural error and operator sensitivity. The 3DWA protocol is precise enough to adequately measure tooth height loss after intervals of a minimum of 3 years or in patients with severe wear progression, but it is not suited to measuring volumetric changes.

Abstract 4165: Combined FGFR1 and PD-1 inhibition could enhance antitumor activity in lung cancer models

Abstract FGFR1 and PD-1 - mediated signals are involved in growth and survival of lung cancer and should be considered as targets for therapeutic approaches. Here, we report the potential efficacy of an anti-FGFR1 humanized antibody OM-RCA-01, either alone or in combination with an anti-PD-1 antibody. To assess the activity of OM-RCA-01 on FGF-mediated signaling, A549 human adenocarcinoma cells expressing FGFR1 were incubated and dosed with OM-RCA-01. Control cells were left untreated. Six hours after dosing, FGF2 was added at a concentration of 100 ng/ml. Cell growth was determined using Promega’s Cell Titer-Glo assay. Thirty-five NCr nu/nu female mice (10-12 weeks of age) were used for A549 xenotransplantation. Twenty animals with measurable tumors were pair matched and selected on day 7 after tumor inoculation. Intravenous OM-RCA-01 (30 mg/kg, N=10) or saline (Vehicle, N=10) were administered every 3 days starting on day 7 after tumor inoculation. To evaluate the efficacy of co-inhibition, patient explants (adenocarcinoma with PD-L1 expression &amp;gt;50%, DAKO 22C3) were obtained from surgical lung specimens, and PDX models were generated by implantation of PDX into humanized NSG mice (Jackson Laboratory, Sacramento, CA, USA) as previously described (Wang, FASEB J., 2018). Treatment with intravenous OM-RCA-01 (30 mg/kg) with pembrolizumab (10 mg/kg) or pembrolizumab alone (10 mg/kg) or saline (vehicle) every 3 days was started when the tumors reached 70 mm3 in volume. Measurements of tumor volume were performed by digital calipers every 3 days during 31 days in xenograft and PDX studies. In vitro study showed that FGF2 significantly increased proliferation of the human lung cancer cells (P&amp;lt;0.001). OM-RCA-01 exerted dose-dependent inhibitory effects on FGF-triggered lung cancer cell proliferation in comparison with control (P=0.01). IC50 was 9.69 mcg/mL. In the xenograft model, treatment resulted in median tumor volume of 1,048.5 mm3 and 2,174 mm3 at day 31 in the OM-RCA-01 and vehicle groups, respectively (P&amp;lt;0.0001). All tumors reached the volume endpoint of 2,000 mm3 to day 31 in vehicle group in comparison with study group where maximum size of tumor was 1,309 mm3. In the PDX study, the differences between groups were also statistically significant (all P&amp;lt;0.001). Median tumor volume was 97.1 mm3 in the combination group (N=7), 417.1 mm3 in the pembrolizumab only group (N=7), and 863.5 mm3 in the vehicle group (N=7). No group mean body weight losses or clinical manifestations of toxicity were observed in both groups. In conclusion, OM-RCA-01 antibody has potent antitumor activity against lung cancer in vitro and in vivo. Our findings also support that the co-inhibition of FGFR1 and immune checkpoints can enhance antitumor activity compared to anti-PD-1 antibody monotherapy. Citation Format: Ilya Tsimafeyeu, Jonathan Smith, Wei Yin, Alex Fanelli, Dmitry Khochenkov, Evgenia Stepanova. Combined FGFR1 and PD-1 inhibition could enhance antitumor activity in lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4165.

Abstract LB134: The rexinoid MSU-42011 enhances dendritic-T cell cross talk in a HER2 positive model of breast cancer

Abstract Breast cancer (BC) was considered an immunologically silent tumor, however recent findings suggest that immune cells present in the tumor microenvironment play important roles in tumor growth. Retinoid X receptors (RXRs) are a subclass of nuclear receptors that act as ligand-dependent transcription factors that regulate a variety of cellular processes including proliferation and differentiation. Rexinoids are synthetic molecules that bind and activate RXRs. Bexarotene (Targretin®) is the only rexinoid approved by the FDA and is used for the treatment of refractory cutaneous T-cell lymphoma. Other more potent rexinoids have been synthesized, such as LG100268 and LG101506, which will not be tested in clinical trials because of intellectual property issues. Because recent studies have suggested that RXRs are involved in immune regulation, we synthesized novel rexinoids and selected MSU-42011 as a lead compound. MMTV-neu mice with tumors approximately 32 mm3 in volume were treated with control diet or MSU-42011 (100 mg/kg diet) for 10 days. Rexinoid treatment significantly (p=0.0069) reduced tumor fold change normalized to initial volume from 8.33 in controls to 4.80 on treatment. Analysis of the tumor by flow cytometry showed no significant differences in the major immune populations, such as T cells, macrophages and dendritic cells. However, expression of PDL1 was increased in CD11c+, MHC-II+ dendritic cells (5484 vs 7140 MFI, p=0.0456), suggesting engaged dendritic cells in activating cytotoxic T cells. To further elucidate the cross talk between dendritic and T cells, cytokines associated with T cell recruitment and activation were analyzed by RT-PCR. Tumor treated with MSU42011 had a 38.5 fold increase in IL12a expression (p=0.011, n=4), and a 20.8 fold increase in CCL9 (p=ns, n=4), suggesting that dendritic cells are actively recruiting and activating T cells. The activation of cytotoxic T cells was confirmed by a 75.5 fold increase in interferon gamma (p=0.0026, n=4) and a decrease of FOXP3 expression (p=ns, n=4). To test if the effects seen in tumor reduction were dependent on the presence of T cells, CD4 and CD8 were depleted. Depletion of CD4 alone, but not CD8, reversed the tumor reduction induced by MSU-42011. These results show that RXR agonists can be used to modulate immune cell populations in the tumor microenvironment, specifically by recruiting and activating dendritic cells that then activate cytotoxic T cells. We thank the Breast Cancer Research Foundation for support of these studies. Citation Format: Ana Sofia Leal, Sarah Carapellucci, Karen T. Liby. The rexinoid MSU-42011 enhances dendritic-T cell cross talk in a HER2 positive model of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB134.

Abstract 2354: Downregulating the glutamine transporter, SLC1A5, significantly reduces cachexia in a PDAC xenograft

Abstract Cachexia occurs with high frequency and severity in pancreatic ductal adenocarcinoma (PDAC) patients [1]. Cachectic patients experience a wide range of symptoms affecting the function of organs such as muscle, liver, brain, and heart, causing significant morbidity [2]. In high-resolution 1H magnetic resonance spectroscopy (MRS) studies of extracts, we previously observed significant perturbation of glutamine in the brain and plasma of mice with a cachexia-inducing PDAC xenograft [3] that prompted us to evaluate the effects of modifying tumor glutamine metabolism on cachexia. We investigated tumors derived from cachexia-inducing Pa04C cells engineered to express shRNA against the glutamine transporter, SLC1A5, glutaminase (GLS) 1, and GLS 2. Patient-derived cachexia-inducing Pa04C cells were stably transduced with virions that expressed shRNA against GLS1 or GLS2 or SLC1A5. Pooled clones were obtained with puromycin selection. Empty vector (EV) cells were also established. Downregulation of target genes was confirmed with mRNA and protein expression characterization. The effects of gene knockdown on tumor growth and weight-loss were determined following subcutaneous inoculation of engineered cells or wild type cells in SCID mice. Longitudinal tumor growth, weights and percent weight changes were determined in 7 wild type (WT), 7 EV, 9 GLS1 downregulated, 9 GLS2 downregulated, and 9 SLC1A5 downregulated tumor bearing mice. Once tumors were ~500 mm3 in volume, tumors were harvested from euthanized mice, and snap frozen for molecular analysis. Protein and mRNA obtained from tumors was validated for downregulation of target genes. Efficient downregulation of SLC1A5, GLS1 and GLS2 mRNA and protein was confirmed in tumors. Downregulating SLC1A5 significantly reduced tumor growth. But, downregulating GLS1 or GLS2 did not reduce tumor growth and, in fact, GLS1 downregulated tumors grew significantly faster than WT or EV tumors. Importantly, for comparable tumor volumes, we found that body weight loss was markedly reduced in mice with SLC1A5 downregulated tumors. Although GLS1 downregulated tumors grew faster than WT tumors, weight loss was attenuated at comparable tumor volumes in these tumors although not to the same extent as in SLC1A5 downregulated tumors. These data highlight potential role of SLC1A5 in PDAC tumor treatment and in the treatment of PDAC-induced cachexia, and support targeting the glutamine/glutamate axis in PDAC to reduce or reverse cachexia.Supported by NIH R35 CA209960 and R01 CA193365. 1. Fearon KC, Baracos VE. Cachexia in pancreatic cancer: new treatment options and measures of success. 2010; 2. Inui A. Cancer anorexia-cachexia syndrome: current issues in research and management. CA Cancer J Clin. 2002; 3. Winnard PT, Jr., et al., Brain metabolites in cholinergic and glutamatergic pathways are altered by pancreatic cancer cachexia. J Cachexia Sarcopenia Muscle. 2020. Citation Format: Balaji Krishnamachary, Ishwarya Sivakumar, Yelena Mironchik, Raj Kumar Sharma, Santosh Kumar Bharti, Marie-France Penet, Paul Winnard, Flonne Wildes, Eibhlin Goggins, Anirban Maitra, Michael G. Goggins, Zaver M. Bhujwalla. Downregulating the glutamine transporter, SLC1A5, significantly reduces cachexia in a PDAC xenograft [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2354.

Morphometric analysis of fibrovascular pigment epithelial detachments treated with ranibizumab and aflibercept.

To assess fibrovascular pigment epithelial detachments (PED) and their response to two different anti-VEGF agents using optical coherence tomography (OCT) morphometric analysis. Seventy-three consecutive, treatment-naïve eyes with fibrovascular PED (>125 μm) treated with ranibizumab or aflibercept were retrospectively included. A custom-made software was used to manually segment and calculate PED maximum height, base area, volume and internal reflectivity at baseline, after three injections and 1 year. Visual acuity (VA) change was 2 ETDRS letters ± 7.6 after three injections and 3.2 ETDRS letters ± 10.3 at 1 year. There was no significant difference between VA changes amongst the two drugs. At 1 year, anti-VEGF treatment resulted in a mean reduction of 125 μm in maximum PED height, of 2.26 mm2 in base area and of 0.54 mm3 in volume with a corresponding increase in reflectivity. These changes were more prominent in the aflilbercept group. The observed PED and VA changes at year 1 were strongly correlated with their values at baseline and after three injections. Anti-VEGF treatment resulted in a reduction of all PED dimensions and a corresponding increase in optical reflectivity. Higher, larger and more hypo-reflective PEDs demonstrated a better anatomical response, especially with aflibercept, but this was not correlated with VA.

A novel antipodal tapered slot antenna integrated with half mode substrate integrated waveguide‐based bandpass filter for K and Ka band applications

AbstractIn this article, we present a novel half mode substrate integrated waveguide (HMSIW)‐based bandpass filter fed antipodal tapered slot antenna. We employ a novel feed consisting of three horizontal slots with two gaps arranged periodically on the top metal layer of HMSIW to obtain |S11|&lt;‐10 dB and |S21|≃0 dB over the passband from 21.6 to 40 GHz. We incorporate sinusoidal corrugations at the antenna outer edges along with ground plane slots. We control the operating bandwidth of the antenna over 21.6–40 GHz with |S11|&lt;‐10 dB using the proposed feed. The antenna offers gain of 10–12.44 dB and stable radiation pattern over the controlled band. The proposed antenna, 16 × 30.3 × 0.254 mm3 in volume, is fabricated and tested for validation. The measurement results show good agreement with simulations. The proposed antenna compares favorably with the state‐of‐the‐art. It is compact and exhibits stable gain and stable radiation pattern over the controlled bandwidth.