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Purpose A same-day PET imaging agent capable of measuring PD-L1 status in tumors is an important tool for optimizing PD-1 and PD-L1 treatments. Herein we describe the discovery and evaluation of a novel, fluorine-18 labeled macrocyclic peptide-based PET ligand for imaging PD-L1. Methods [ 18 F]BMS-986229 was synthesized via copper mediated click-chemistry to yield a PD-L1 PET ligand with picomolar affinity and was tested as an in-vivo tool for assessing PD-L1 expression. Results Autoradiography showed an 8:1 binding ratio in L2987 (PD-L1 (+)) vs. HT-29 (PD-L1 (-)) tumor tissues, with >90% specific binding. Specific radioligand binding (>90%) was observed in human non-small-cell lung cancer (NSCLC) and cynomolgus monkey spleen tissues. Images of PD-L1 (+) tissues in primates were characterized by high signal-to-noise, with low background signal in non-expressing tissues. PET imaging enabled clear visualization of PD-L1 expression in a murine model in vivo, with 5-fold higher uptake in L2987 (PD-L1 (+)) than in control HT-29 (PD-L1 (-)) tumors. Moreover, this imaging agent was used to measure target engagement of PD-L1 inhibitors (peptide or mAb), in PD-L1 (+) tumors as high as 97%. Conclusion A novel 18 F-labeled macrocyclic peptide radioligand was developed for PET imaging of PD-L1 expressing tissues that demonstrated several advantages within a nonhuman primate model when compared directly to adnectin- or mAb-based ligands. Clinical studies are currently evaluating [ 18 F]BMS-986229 to measure PD-L1 expression in tumors.

The microPET Focus is the latest generation microPET system dedicated to high-resolution animal imaging and incorporates several changes to enhance its performance. This study evaluated the basic performance of the scanner and compared it with the Primate (P4) and Rodent (R4) models. The system consists of 168 lutetium oxyorthosilicate (LSO) detectors arranged in 4 contiguous rings, with a 25.8-cm diameter and a 7.6-cm axial length. Each detector consists of a 12 x 12 LSO crystal array of 1.51 x 1.51 x 10.00 mm3 elements. The scintillation light is transmitted to position-sensitive photomultiplier tubes via optical fiber bundles. The system was evaluated for its energy and spatial resolutions, sensitivity, and noise equivalent counting rate. Phantoms and animals of varying sizes were scanned to evaluate its imaging capability. The energy resolution averages 18.5% for the entire system. Reconstructed image resolution is 1.3-mm full width at half maximum (FWHM) at the center of field of view (CFOV) and remains under 2 mm FWHM within the central 5-cm-diameter FOV in all 3 dimensions. The absolute sensitivity of the system is 3.4% at the CFOV for an energy window of 250-750 keV and a timing window of 10 ns. The noise equivalent counting-rate performance reaches 645 kcps for a mouse-size phantom using 250- to 750-keV and 6-ns settings. Emission images of a micro-Derenzo phantom demonstrate the improvement in image resolution compared with previous models. Animal studies exhibit the capability of the system in studying disease models using mouse, rat, and nonhuman primates. The Focus has significantly improved performance over the previous models in all areas evaluated. This system represents the state-of-the-art scintillator-based animal PET scanner currently available and is expected to advance the potential of small animal PET.

Recent developments have established molecular imaging of mouse models with small-animal PET and bioluminescence imaging (BLI) as an important tool in cancer research. One of the disadvantages of these imaging modalities is the lack of anatomic information. We combined small-animal PET and BLI technology with small-animal CT to obtain fusion images with both molecular and anatomic information. We used small-animal PET/CT and BLI to detect xenografts of different cell lines and metastases of a melanoma cell line (A375M-3F) that had been transduced with a lentiviral vector containing a trimodality imaging reporter gene encoding a fusion protein with Renilla luciferase, monomeric red fluorescent protein, and a mutant herpes simplex virus type 1 thymidine kinase. Validation studies in mouse xenograft models showed a good coregistration of images from both PET and CT. Melanoma metastases were detected by 18F-FDG PET, 9-[4-(18)F-fluoro-3-(hydroxymethyl)butyl]guanine (18F-FHBG) PET, CT, and BLI and confirmed by ex vivo assays of Renilla luciferase and mutant thymidine kinase expression. 18F-FHBG PET/CT allowed detection and localization of lesions that were not seen on CT because of poor contrast resolution and were not seen on 18F-FDG PET because of higher background uptake relative to 18F-FHBG. The combination of 18F-FHBG PET, small-animal CT, and BLI allows a sensitive and improved quantification of tumor burden in mice. This technique is potentially useful for the study of the biologic determinants of metastasis and for the evaluation of novel cancer treatments.

A same-day PET imaging agent capable of measuring PD-L1 status in tumors is an important tool for optimizing PD-1 and PD-L1 treatments. Herein we describe the discovery and evaluation of a novel, fluorine-18 labeled macrocyclic peptide-based PET ligand for imaging PD-L1.PURPOSEA same-day PET imaging agent capable of measuring PD-L1 status in tumors is an important tool for optimizing PD-1 and PD-L1 treatments. Herein we describe the discovery and evaluation of a novel, fluorine-18 labeled macrocyclic peptide-based PET ligand for imaging PD-L1.[18F]BMS-986229 was synthesized via copper mediated click-chemistry to yield a PD-L1 PET ligand with picomolar affinity and was tested as an in-vivo tool for assessing PD-L1 expression.METHODS[18F]BMS-986229 was synthesized via copper mediated click-chemistry to yield a PD-L1 PET ligand with picomolar affinity and was tested as an in-vivo tool for assessing PD-L1 expression.Autoradiography showed an 8:1 binding ratio in L2987 (PD-L1 (+)) vs. HT-29 (PD-L1 (-)) tumor tissues, with >90% specific binding. Specific radioligand binding (>90%) was observed in human non-small-cell lung cancer (NSCLC) and cynomolgus monkey spleen tissues. Images of PD-L1 (+) tissues in primates were characterized by high signal-to-noise, with low background signal in non-expressing tissues. PET imaging enabled clear visualization of PD-L1 expression in a murine model in vivo, with 5-fold higher uptake in L2987 (PD-L1 (+)) than in control HT-29 (PD-L1 (-)) tumors. Moreover, this imaging agent was used to measure target engagement of PD-L1 inhibitors (peptide or mAb), in PD-L1 (+) tumors as high as 97%.RESULTSAutoradiography showed an 8:1 binding ratio in L2987 (PD-L1 (+)) vs. HT-29 (PD-L1 (-)) tumor tissues, with >90% specific binding. Specific radioligand binding (>90%) was observed in human non-small-cell lung cancer (NSCLC) and cynomolgus monkey spleen tissues. Images of PD-L1 (+) tissues in primates were characterized by high signal-to-noise, with low background signal in non-expressing tissues. PET imaging enabled clear visualization of PD-L1 expression in a murine model in vivo, with 5-fold higher uptake in L2987 (PD-L1 (+)) than in control HT-29 (PD-L1 (-)) tumors. Moreover, this imaging agent was used to measure target engagement of PD-L1 inhibitors (peptide or mAb), in PD-L1 (+) tumors as high as 97%.A novel 18F-labeled macrocyclic peptide radioligand was developed for PET imaging of PD-L1 expressing tissues that demonstrated several advantages within a nonhuman primate model when compared directly to adnectin- or mAb-based ligands. Clinical studies are currently evaluating [18F]BMS-986229 to measure PD-L1 expression in tumors.CONCLUSIONA novel 18F-labeled macrocyclic peptide radioligand was developed for PET imaging of PD-L1 expressing tissues that demonstrated several advantages within a nonhuman primate model when compared directly to adnectin- or mAb-based ligands. Clinical studies are currently evaluating [18F]BMS-986229 to measure PD-L1 expression in tumors.

The structure of urban environments is known to alter local climate, in part due to changes in land cover. A growing subset of research focuses specifically on the UHI in terms of land surface temperature by using data from remote sensing platforms. Past research has established a clear relationship between land surface temperature and the proportional area of land covers, but less research has specifically examined the effects of the spatial patterns of these covers. This research considers the rapidly growing City of Phoenix, Arizona in the United States. To better understand how landscape structure affects local climate, we explored the relationship between land surface temperature and spatial pattern for three different land uses: mesic residential, xeric residential, and industrial/commercial. We used high-resolution (2.4 m) land cover data and an ASTER temperature product to examine 90 randomly selected sample sites of 240 square-meters. We (1) quantify several landscape-level and class-level landscape metrics for the sample sites, (2) measure the Pearson correlation coefficients between land surface temperature and each landscape metric, (3) conduct an analysis of variance among the three land uses, and (4) model the determinants of land surface temperature using ordinary least squares linear regression. The Pearson’s correlation coefficients reveal significant relationships between several measures of spatial configuration and LST, but these relationships differ among the land uses. The ANOVA confirmed that mean land surface temperature and spatial patterns differed among the three land uses. Although a relationship was apparent between surface temperatures and spatial pattern, the results of the linear regression indicate that proportional land cover of grass and impervious surfaces alone best explains temperature in mesic residential areas. In contrast, temperatures in industrial/commercial areas are explained by changes in the configuration of grass and impervious surfaces.

Antibodies to PD-1 protein and to one of its ligands, PD-L1, have shown antitumor activity. Unleashing T cells from inhibitory signals may be a strategy to treat cancers. Autoimmune side effects from anti–PD-L1 antibody seem less severe than those from anti–CTLA-4 antibody. Passive cancer immunotherapy that uses tumor-targeted monoclonal antibodies has achieved broad therapeutic efficacy. 1 However, T-cell directed immunotherapy has been less successful. 2 Despite the large number of tumor antigens induced by genetic and epigenetic changes found in all cancers, tumors resist immune attack by inducing tolerance among tumor-specific T cells and by expressing ligands that engage inhibitory receptors and dampen T-cell functions within the tumor microenvironment. 3 Preclinical and clinical data show that antibody blockade of these immune checkpoints can significantly enhance antitumor immunity. 4 Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), an inhibitory receptor that down-modulates the initial stages of T-cell activation, was the . . .

Background High dose vasopressors portend poor outcome in vasodilatory shock. We aimed to evaluate the impact of baseline vasopressor dose on outcomes in patients treated with angiotensin II (AT II). Methods Exploratory post-hoc analysis of the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) trial data. The ATHOS-3 trial randomized 321 patients with vasodilatory shock, who remained hypotensive (mean arterial pressure of 55–70 mmHg) despite receiving standard of care vasopressor support at a norepinephrine-equivalent dose (NED) > 0.2 µg/kg/min, to receive AT II or placebo, both in addition to standard of care vasopressors. Patients were grouped into low (≤ 0.25 µg/kg/min; n = 104) or high (> 0.25 µg/kg/min; n = 217) NED at the time of study drug initiation. The primary outcome was the difference in 28-day survival between the AT II and placebo subgroups in those with a baseline NED ≤ 0.25 µg/kg/min at the time of study drug initiation. Results Of 321 patients, the median baseline NED in the low-NED subgroup was similar in the AT II (n = 56) and placebo (n = 48) groups (median of each arm 0.21 µg/kg/min, p  = 0.45). In the high-NED subgroup, the median baseline NEDs were also similar (0.47 µg/kg/min AT II group, n = 107 vs. 0.45 µg/kg/min placebo group, n = 110, p  = 0.75). After adjusting for severity of illness, those randomized to AT II in the low-NED subgroup were half as likely to die at 28-days compared to placebo (HR 0.509; 95% CI 0.274–0.945, p  = 0.03). No differences in 28-day survival between AT II and placebo groups were found in the high-NED subgroup (HR 0.933; 95% CI 0.644–1.350, p  = 0.71). Serious adverse events were less frequent in the low-NED AT II subgroup compared to the placebo low-NED subgroup, though differences were not statistically significant, and were comparable in the high-NED subgroups. Conclusions This exploratory post-hoc analysis of phase 3 clinical trial data suggests a potential benefit of AT II introduction at lower doses of other vasopressor agents. These data may inform design of a prospective trial. Trial registration : The ATHOS-3 trial was registered in the clinicaltrials.gov repository (no. NCT02338843). Registered 14 January 2015.

Identifying host genes essential for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has the potential to reveal novel drug targets and further our understanding of Coronavirus Disease 2019 (COVID-19). We previously performed a genome-wide CRISPR/Cas9 screen to identify proviral host factors for highly pathogenic human coronaviruses. Few host factors were required by diverse coronaviruses across multiple cell types, but DYRK1A was one such exception. Although its role in coronavirus infection was previously undescribed, DYRK1A encodes D ual Specificity T y rosine Phosphorylation R egulated K inase 1A and is known to regulate cell proliferation and neuronal development. Here, we demonstrate that DYRK1A regulates ACE2 and DPP4 transcription independent of its catalytic kinase function to support SARS-CoV, SARS-CoV-2, and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) entry. We show that DYRK1A promotes DNA accessibility at the ACE2 promoter and a putative distal enhancer, facilitating transcription and gene expression. Finally, we validate that the proviral activity of DYRK1A is conserved across species using cells of nonhuman primate and human origin. In summary, we report that DYRK1A is a novel regulator of ACE2 and DPP4 expression that may dictate susceptibility to multiple highly pathogenic human coronaviruses.

In October 2024, twelve primates from 4 species died of sepsis at the Hong Kong Zoological and Botanical Gardens. Postmortem examinations and microbiological analyses confirmed Burkholderia pseudomallei infection. Phylogenetic analysis revealed a clonal sequence type 46 strain with minimal variation, signifying a single source. This outbreak highlights melioidosis risk in zoo settings.

PhD-trained scientists are essential contributors to the workforce in diverse employment sectors that include academia, industry, government, and nonprofit organizations. Hence, best practices for training the future biomedical workforce are of national concern. Complementing coursework and laboratory research training, many institutions now offer professional training that enables career exploration and develops a broad set of skills critical to various career paths. The National Institutes of Health (NIH) funded academic institutions to design innovative programming to enable this professional development through a mechanism known as Broadening Experiences in Scientific Training (BEST). Programming at the NIH BEST awardee institutions included career panels, skill-building workshops, job search workshops, site visits, and internships. Because doctoral training is lengthy and requires focused attention on dissertation research, an initial concern was that students participating in additional complementary training activities might exhibit an increased time to degree or diminished research productivity. Metrics were analyzed from 10 NIH BEST awardee institutions to address this concern, using time to degree and publication records as measures of efficiency and productivity. Comparing doctoral students who participated to those who did not, results revealed that across these diverse academic institutions, there were no differences in time to degree or manuscript output. Our findings support the policy that doctoral students should participate in career and professional development opportunities that are intended to prepare them for a variety of diverse and important careers in the workforce.