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Traditionally, immunotherapy agent selection and treatment strategies are guided by biopsy-based histological information. However, biopsies are limited in that they are invasive, provide static information regarding the tumor immune microenvironment, and only sample a small part of one tumor site. The tumor microenvironment is dynamic and heterogenous. As a result, the immune milieu at one site may be distinct from other metastatic sites. These factors make identifying which patients are likely to respond to different immunotherapies and which harbor intrinsic resistance mechanisms difficult to identify based on a biopsy alone. As such, there is significant interest in alternative methodologies that better characterize the tumor immune microenvironment and monitor immunotherapy response. PET imaging potentially offers a non-invasive way to characterize the tumor immune microenvironment at the primary tumor and metastases and allow for longitudinal characterization. Herein, we review pre-clinically and clinically tested T cell-targeted PET radiopharmaceuticals, as T cells have been the dominant immunotherapy target, and their utility in both evaluating response to immunotherapy and in understanding the systemic immune response to treatment with immunotherapeutics.

B7-H3 ( CD276 ) has two isoforms (2Ig and 4Ig), no confirmed cognate receptor, and physiological functions that remain elusive. While differentially expressed on many solid tumors correlating with poor survival, mechanisms of how B7-H3 signals in cis (tumor cell) versus in trans (immune cell co-regulator) to elicit pro-tumorigenic phenotypes remain poorly defined. Herein, we characterized a tumorigenic and signaling role for tumor cell-expressed 4Ig-B7-H3, the dominant human isoform, in gynecological cancers that could be abrogated upon CRISPR/Cas9 knockout of B7-H3; tumorigenesis was rescued upon re-expression of 4Ig-B7-H3. Size exclusion chromatography revealed dimerization states for the extracellular domains of both human 4Ig- and murine 2Ig-B7-H3. mEGFP lifetimes of expressed 4Ig-B7-H3-mEGFP fusions determined by FRET-FLIM assays confirmed close-proximity interactions of 4Ig-B7-H3 and identified two distinct homo-FRET lifetime populations, consistent with monomeric and homo-dimer interactions. In live cells, bioluminescence imaging of 4Ig-B7-H3-mediated split luciferase complementation showed dimerization of 4Ig-B7-H3. To separate basal from dimer state activities in the absence of a known receptor, C-terminus (cytosolic) chemically-induced dimerization of 4Ig-B7-H3 increased tumor cell proliferation and cell activation signaling pathways (AKT, Jak/STAT, HIF1α, NF-κβ) significantly above basal expression of 4Ig-B7-H3 alone. These results revealed a new, dimerization-dependent intrinsic tumorigenic signaling role for 4Ig-B7-H3, likely acting in cis , and provide a therapeutically-actionable target for intervention of B7-H3-dependent tumorigenesis. The 4Ig isoform of B7-H3, an immune modulatory protein expressed in tumors, resides in dimeric states with enhanced dimerization-dependent intrinsic signaling and tumorigenic activities, providing a therapeutically-actionable target for intervention.

Radioligand therapy (RLT) is an emerging oncologic strategy that uses molecularly targeted therapeutic radioisotopes to reduce tumor burden and improve survival in patients with advanced cancers. Expanding RLT to new targets and understanding its systemic immune effects could enhance its clinical impact. B7-H3 is an attractive target due to its high differential expression in solid tumors compared to normal tissues. However, the presence of two isoforms, 4Ig-B7-H3 (tumor-associated) and 2Ig-B7-H3 (soluble decoy), poses challenges for selective targeting, especially in the context of RLT. A novel IgG2a monoclonal antibody (MIL33B) was developed with high affinity for 4Ig-B7-H3 (72 picomolar) and 8- to 18-fold selectivity over soluble 2Ig-B7-H3. Target specificity was assessed using live-cell fluorescence microscopy with AF594-labeled MIL33B. tumor binding was evaluated by PET-CT imaging with Zr-labeled MIL33B in murine xenograft (HeLa cervical) and syngeneic tumor models (4T1 breast, B16F10 melanoma, CT26 colorectal) expressing human 4Ig-B7-H3. Therapeutic efficacy was tested using Y-labeled MIL33B (100 μCi) in an established CT26 colorectal tumor model. Immunologic effects were analyzed to assess CD8+ T-cell activation and immune memory. MIL33B demonstrated strong membranous localization using live cell fluorescence microscopy. PET-CT imaging with Zr-labeled MIL33B confirmed robust tumor-selective binding . A single systemic dose of Y-MIL33B achieved 53% long-term survival in a 4Ig-B7-H3-dependent manner in an otherwise fatal CT26 colorectal syngeneic tumor model. Immunologic analysis revealed that Y-MIL33B RLT acted as an immune priming event, engaging CD8+ T-cell activation and inducing immunological memory. MIL33B enables selective targeting of 4Ig-B7-H3 for beta-emitting RLT, overcoming challenges posed by soluble isoforms. These findings support further investigation of MIL33B as a systemic therapeutic with immune-priming potential, either alone or in combination strategies for cancer treatment.

B7-H3 (CD276), a member of the B7-family of immune checkpoint proteins, has been shown to have immunological and non-immunological effects promoting tumorigenesis [1, 2] and expression correlates with poor prognosis for many solid tumors, including cervical, ovarian and breast cancers [3-6]. We recently identified a tumor-cell autochthonous tumorigenic role for dimerization of the 4Ig isoform of B7-H3 (4Ig-B7-H3) [7], where 4Ig-B7-H3 dimerization activated tumor-intrinsic cellular proliferation and tumorigenesis pathways, providing a novel opportunity for therapeutic intervention. Herein, a live cell split-luciferase complementation strategy was used to visualize 4Ig-B7-H3 homodimerization in a high-throughput small molecule screen (HTS) to identify modulators of this protein-protein interaction (PPI). Notably, the HTS identified several compounds that converged on lipid metabolism (including HMG-CoA reductase inhibitors, also known as statins) as significant inhibitors of 4Ig-B7-H3 dimerization (p < 0.01). and murine studies provided evidence that statin-mediated disruption of 4Ig-B7-H3 dimerization was associated with anti-tumor effects. Statin-mediated anti-cancer efficacy was selective for B7-H3-expressing tumors and retrospective analysis of clinical tumor specimens supported the hypothesis that concurrent statin use enhanced clinical outcomes for patients in a B7-H3 restricted manner. Thus, disruption of 4Ig-B7-H3 dimerization provides an unanticipated molecular mechanism linking statin use in cancer therapy and prevention with immune checkpoint.

Radioligand therapy (RLT), a re-emerging oncologic strategy using molecularly-targeted therapeutic radioisotopes, clinically reduces tumor burden and enhances survival for select patients with otherwise unresponsive advanced prostate cancer and neuroendocrine tumors. Developing new approaches to next generation targets and a better understanding of systemic immune effects could broaden the impact of RLT. Aside from contributions to immune checkpoint, B7-H3 (CD276) is an attractive oncologic target because of its widespread and high differential expression across a variety of solid tumors compared to normal tissues. However, B7-H3 has two isoforms: a 4Ig-B7-H3 isoform, the dominant transmembrane protein expressed on tumors and tumor immune microenvironments (TIME), and a 2Ig-B7-H3 isoform, a soluble ectodomain protein, representing a circulating, and in the context of RLT, significant shed (decoy) antigen. To enhance tumor-specific binding and circumvent confounding soluble 2Ig-B7-H3, a novel IgG2a monoclonal antibody (MIL33B) was generated with high affinity for 4Ig-B7-H3 (72 picomolar) and 8- to 18-fold selectivity over soluble 2Ig-B7-H3. Live cell fluorescence microscopy using AF594-labeled MIL33B demonstrated strong membranous localization and target specificity. PET-CT imaging with 89Zr-labeled MIL33B confirmed robust tumor-selective target binding in vivo in murine xenograft (HeLa cervical) and syngeneic tumor models (4T1 breast, B16F10 melanoma, and CT26 colorectal) expressing human 4Ig-B7-H3. As a single dose beta-emitting systemic RLT therapeutic, 90Y-labeled MIL33B (100 μCi) produced 53% long-term survival in a 4Ig-B7-H3-dependent manner in an otherwise fatal established CT26 colorectal tumor model. Immunologic analysis showed that 90Y-MIL33B RLT functioned as an immune priming event, engaging downstream CD8+ T-cell activation and inducing immunological memory in vivo, thus illustrating the potential of systemic beta-RLT to target both primary and metastatic sites. Thus, MIL33B showcases a strategy to selectively target 4Ig-B7-H3 for beta-RLT, warranting further investigation as an immune priming tactic alone or in combination for cancer therapy.Competing Interest StatementThe University of Texas MD Anderson Cancer Center has filed a patent application on compounds and methods described in this report (S.T.G., F.P. and D.P.W., inventors). The technology is licensed in part to Radiopharm Ventures, LLC. The remaining authors have no conflicts of interest.

Telomeres are engaged in a host of cellular functions, and their length is regulated by multiple genes. Telomere shortening, in the course of somatic cell replication, ultimately leads to replicative senescence. In humans, rare mutations in genes that regulate telomere length have been identified in monogenic diseases such as dyskeratosis congenita and idiopathic pulmonary fibrosis, which are associated with shortened leukocyte telomere length (LTL) and increased risk for aplastic anemia. Shortened LTL is observed in a host of aging-related complex genetic diseases and is associated with diminished survival in the elderly. We report results of a genome-wide association study of LTL in a consortium of four observational studies (n = 3,417 participants with LTL and genome-wide genotyping). SNPs in the regions of the oligonucleotide/oligosaccharide-binding folds containing one gene (OBFC1; rs4387287; P = 3.9 x 10⁻⁹) and chemokine (C-X-C motif) receptor 4 gene (CXCR4; rs4452212; P = 2.9 x 10⁻⁸) were associated with LTL at a genome-wide significance level (P < 5 x 10⁻⁸). We attempted replication of the top SNPs at these loci through de novo genotyping of 1,893 additional individuals and in silico lookup in another observational study (n = 2,876), and we confirmed the association findings for OBFC1 but not CXCR4. In addition, we confirmed the telomerase RNA component (TERC) as a gene associated with LTL (P = 1.1 x 10⁻⁵). The identification of OBFC1 through genome-wide association as a locus for interindividual variation in LTL in the general population advances the understanding of telomere biology in humans and may provide insights into aging-related disorders linked to altered LTL dynamics.

Aim: A detailed understanding of spatial genetic structure (SGS) and the factors driving contemporary patterns of gene flow and genetic diversity are fundamental for developing conservation and management plans for marine fisheries. We performed a detailed study of SGS and genetic diversity throughout the overharvested queen conch (Lobatus gigas) fishery. Caribbean countries were presented as major populations to examine transboundary patterns of population differentiation. Location: Nineteen locations in the greater Caribbean from Anguilla, the Bahamas, Belize, Caribbean Netherlands, Honduras, Jamaica, Mexico, Turks and Caicos, and the USA. Methods: We genotyped 643 individuals with nine microsatellites. Population genetic and multivariate analyses characterized SGS. We tested the alternate hypotheses: (1) SGS is randomly distributed in space or (2) pairwise genetic structure among sites is correlated with oceanic distance (IBOD). Results: Our study found that L. gigas does not form a single panmictic population in the greater Caribbean. Significant levels of genetic differentiation were identified between Caribbean countries (FCT = 0.011; p = .0001), within Caribbean countries (FSC = 0.003; p = .001), and among sites irrespective of geographic location (FST = 0.013; p = .0001). Gene flow across the greater Caribbean was constrained by oceanic distance (p = .0009; Mantel r = .40), which acted to isolate local populations. Main conclusions: Gene flow over the spatial scale of the entire Caribbean basin is constrained by oceanic distance, which may impede the natural recovery of overfished L. gigas populations. Our results suggest a careful blend of local and international management will be required to ensure long-term sustainability for the species.

Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency. We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants. Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1·9×10 −109 for rs2282679, in GC); 11q12 (p=2·1×10 −27 for rs12785878, near DHCR7); and 11p15 (p=3·3×10 −20 for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6·0×10 −10 for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2·47, 95% CI 2·20–2·78, p=2·3×10 −48) or lower than 50 nmol/L (1·92, 1·70–2·16, p=1·0×10 −26) compared with those in the lowest quartile. Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency. Full funding sources listed at end of paper (see Acknowledgments).

Recreational fishing is a pillar of the multibillion-dollar tourism sector in the Caribbean, supporting economic development and community livelihoods. However, as climate change drives increased habitat degradation, key recreational target species may experience declines. To effectively prioritize adaptation and mitigation efforts it is critical to project climate change impacts on recreational species and the communities that depend on them. We conducted a comprehensive climate vulnerability assessment (CVA) for three recreationally important tidal flats species in Belize and The Bahamas: bonefish ( Albula vulpes ), tarpon ( Megalops atlanticus ), and permit ( Trachinotus falcatus ). Species vulnerability was assessed by coupling 1) a research-based CVA to evaluate the sensitivity and exposure of species to climate impacts with 2) a participatory workshop involving 17 fishing guides, resource managers, and science and policy experts working in fisheries systems in Belize and/or The Bahamas. The workshop elicited local expert knowledge to resolve and contextualize CVA scoring and to identify strategies to increase climate resilience. According to the research-based CVA, key climate factors in the Caribbean are expected to see a ‘very high’ magnitude of change by 2050. All three species exhibit ‘very high’ vulnerability to these changes based on life history traits and reliance on nearshore habitats that are exposed to rapid temperature increases and storm damage. The expert stakeholder group confirmed a ‘very high’ magnitude of expected climate impacts in the Caribbean region, to which bonefish, the most valuable species, is likely to have a ‘very high’ vulnerability. However, stakeholders perceived tarpon and permit to be less vulnerable to these impacts than the CVA predicted, based on “on the water” observations of their habitat flexibility and resilience to disturbance. The group identified strategies at the individual, community, national, and international levels to enhance climate resilience in the recreational fishing sector. Our work highlights how participatory CVA processes can support a stronger understanding of species’ vulnerability while building capacity and collaboration to increase climate change readiness.

Women are consistently underrepresented in astrophysics yet are simultaneously subject to disproportionate attrition at every career stage. This disparity between demonstrated efficacy in job performance and ultimate career outcome was the primary motivation for the Picture an Astronomer series, which included both targeted public outreach to increase representation of women in astrophysics and high-level, solution-oriented discussions among professional astronomers. In March 2025, more than 200 astronomers came together in a hybrid-format symposium focused on the state of the field for female scientists, combining scientific exchange with discussions of policies and practices to strengthen retention of talent in the field. This white paper is the result of those discussions, offering a wide range of recommendations developed in the context of gendered attrition in astrophysics but which ultimately support a healthier climate for all scientists alike.