Recent uclapharm items

Bioorthogonal Click Chemistry-Enabled Enrichment of Extracellular Vesicles for Integrated Molecular and Functional Liquid Biopsy

Fri, 22 May 2026 00:00:00 +0000

ConspectusExtracellular vesicles (EVs) are lipid bilayer-enclosed nanoparticles released by virtually all cells, carrying protected lipids, nucleic acids, proteins, and active enzymes that faithfully reflect the physiological and pathological states of their cellular origins. Tumor- and neuron-derived EVs are abundantly present in peripheral blood, even at early disease stages, and thus represent highly attractive substrates for liquid biopsy. However, the clinical translation of EV-based diagnostics has been constrained by a central challenge: the inability to selectively enrich disease-relevant EVs from a vast background of normal EVs with sufficient specificity, efficiency, and compatibility for seamless integration with downstream molecular and functional analyses. Conventional physical isolation approaches generate heterogeneous EV mixtures that dilute disease-specific signals, whereas traditional immunoaffinity capture often suffers from nonspecific interactions and low...

Therapeutic efficacy of dendritic cell vaccination in a novel syngeneic mouse model of diffuse hemispheric glioma, H3 G34-mutant

Wed, 22 Apr 2026 00:00:00 +0000

PurposeThe prognosis for pediatric high-grade gliomas associated with mutations in the H3-3A gene is very poor. To investigate whether tumor lysate-pulsed dendritic cells (DC) together with checkpoint blockade might be a potential treatment modality for diffuse hemispheric glioma H3 G34-mutant (DHG), we have developed a novel syngeneic mouse model.MethodsWe used the RCAS/tv-A system to target the expression of H3G34R and PDGFβ and knock out p53 in neural progenitors in C57BL/6 neonatal mice. Three independent cell lines were obtained that expressed transcripts associated with oligodendrocyte and interneuron lineages. Lethal tumor developed following intracranial injection.ResultsTwo cycles of DC vaccination with PD-1 blockade decreased tumor burden and increased survival. In treatment resistant tumors we found higher expression of several genes involved in remodeling the extracellular matrix compared with tumors from untreated animals, suggesting a causal link to resistance to...

Noninvasive Assessment of Protease Activity in Osteosarcoma via Click Chemistry‐Mediated Enrichment of Extracellular Vesicles (Adv. Funct. Mater. 41/2025)

Wed, 8 Apr 2026 00:00:00 +0000

Liquid Biopsy In their Research Article (10.1002/adfm.202422469), Junseok Lee, Steven John Jonas, Shaohua Lu, Yazhen Zhu, Hsian‐Rong Tseng, and co‐workers present a novel osteosarcoma extracellular vesicle matrix metalloproteinase activity assay (OS EV MMP activity assay) for noninvasive and real‐time monitoring of disease progression and treatment response in pediatric osteosarcoma. By combining click chemistry‐enabled tumor EV enrichment with FRET‐based protease activity profiling, the assay quantitatively evaluates six specific EV surface marker/MMP combinations. This minimally invasive platform enables early detection of metastasis and longitudinal disease monitoring, offering a powerful tool to improve clinical management of osteosarcoma.

Detection of Extracellular Vesicles with Colocalized Surface Markers via a Capture–Release–Capture Strategy for Treatment Monitoring in Ewing Sarcoma

Wed, 8 Apr 2026 00:00:00 +0000

Ewing Sarcoma (ES) is a rare but aggressive malignancy of bone tissue in adolescents and young adults, where early detection of progression and real-time treatment monitoring remain unmet clinical needs. Tumor extracellular vesicles (EVs) carry surface markers and nucleic acid cargo that can serve as minimally invasive biomarkers, but single-marker EV assays often lack specificity, and colocalized-marker approaches may suffer from low sensitivity. Here, we report the ES EV Capture-Release-Capture (CaReCa) assay, a two-step enrichment strategy that combines desthiobiotin (DTB)-mediated capture/release of CD99⁺ EVs with click chemistry-mediated recapture of CD99⁺/B7-H3⁺ EVs, introducing molecular specificity to suppress background signals. To overcome limited yield from EVs with colocalized markers, we incorporated RT-digital PCR quantification of encapsulated ACTB mRNA, a stable housekeeping transcript, as a sensitive proxy for EV abundance. Using...

Vaccine therapy for pediatric high-grade glioma: current landscape, challenges, and future directions

Mon, 16 Feb 2026 00:00:00 +0000

BackgroundPediatric high-grade gliomas (pHGG) are among the most aggressive childhood brain tumors, with limited treatment options and poor prognosis. Vaccine-based immunotherapy offers a promising strategy by leveraging tumor-specific or associated antigens to stimulate durable anti-tumor immune responses with minimal toxicity.DiscussionThis review outlines the scientific rationale for vaccine therapies in pHGG, detailing key targets such as glioma-associated antigens (EphA2, IL-13Rα2, survivin), driver mutation–derived neoantigens (H3.3K27M, TP53, IDH1), and viral antigens (CMV pp65). We evaluate current vaccine platforms, including peptide vaccines, dendritic cell vaccines, mRNA-based vaccines, and neoantigen-personalized approaches, highlighting early-phase clinical trial results that demonstrate safety and immunogenicity. Despite encouraging preliminary data, several challenges hinder clinical translation, including the distinct immune environment in the central nervous system,...

Tumor Extracellular Vesicle Digital Scoring Assays for Cancer Detection and Monitoring

Wed, 14 Jan 2026 00:00:00 +0000

Tumor-derived extracellular vesicles (EVs) have emerged as promising targets for liquid biopsy, enabling noninvasive mRNA profiling to support cancer detection, staging, and treatment monitoring. This Review highlights the development and clinical translation of EV Digital Scoring Assays, an innovative class of two-step liquid biopsy platforms integrating click chemistry-mediated tumor EV enrichment (via EV Click Beads or EV Click Chips) with reverse transcription digital PCR (RT-dPCR) for absolute quantification of tumor mRNA. These assays have demonstrated clinical utility across multiple solid tumors: identifying oncogenic alterations in pancreatic ductal adenocarcinoma and Ewing sarcoma, detecting early stage hepatocellular carcinoma in at-risk cirrhotic patients, differentiating localized from metastatic prostate cancer, and monitoring treatment response in hepatocellular carcinoma. We also examine emerging technologies and parallel efforts from other groups, including microfluidic...

Feasibility of different meningioma delineation approaches on [18F]SiTATE PET/CT imaging

Wed, 3 Dec 2025 00:00:00 +0000

BackgroundSomatostatin receptor (SSTR)-targeted PET is valuable for meningioma imaging due to high SSTR expression. [18F]SiTATE, a novel tracer, is not only promising for imaging neuroendocrine tumors but also for meningiomas. Standardized delineation methods on [18F]SiTATE PET are lacking. This study correlates CT-based volumes with PET-based delineation approaches to identify a threshold for standardized [18F]SiTATE PET volume assessment.MethodsPatients with well-delineated, extraosseous meningioma on CT (≥ 1mL) who underwent [18F]SiTATE PET/CT were included. Volumes were assessed on contrast-enhanced CT and correlated with PET-based delineation approaches: (I) fixed SUV threshold, (II) isocontour thresholding relative to SUVmax (SUV%), and thresholds relative to (III) bone marrow (SUVBM), (IV) parotid gland (SUVparotis) and (V) pituitary gland (SUVsella).Results19 meningiomas in 17 PET/CT scans (16 patients) were included. A fixed SUV of 4.0 (r = 0.783, p < 0.001) showed...

Liquid Biopsy of Circulating Tumor Cells and DNA in the Context of PSMA Radiopharmaceutical Therapy.

Fri, 14 Nov 2025 00:00:00 +0000

Liquid Biopsy of Circulating Tumor Cells and DNA in the Context of PSMA Radiopharmaceutical Therapy.

Association Between the PRIMARY Score at Staging Prostate-specific Membrane Antigen Positron Emission Tomography and Overall Survival Among Patients with Newly Diagnosed Prostate Cancer: Findings from the International, Multicenter PROMISE Registry

Wed, 5 Nov 2025 00:00:00 +0000

The PRIMARY score was implemented in Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) version 2 to improve accuracy for the diagnosis of clinically significant prostate cancer using prostate-specific membrane antigen (PSMA) positron emission tomography (PET). We reviewed overall survival (OS) for patients who underwent PSMA PET for initial staging to evaluate the prognostic value of PRIMARY in a large, international, multicenter cohort. The cohort comprised 1889 patients who underwent PSMA PET for initial staging of prostate cancer at investigator sites across Europe and Australia between 2012 and 2021. Hazard ratios (HRs) with 95% confidence interval (CI) were calculated for PRIMARY scores to identify predictors of OS. Complete-case head-to-head comparisons were conducted for Prostate Imaging-Reporting and Data System (PI-RADS) versus PRIMARY scores, and cT stage versus PRIMARY scores. We present preliminary findings up to January 31, 2025, when 231 deaths...

FAP Expression in Renal Tumors Assessed by [68Ga]Ga-FAPI-46 PET Imaging and FAP Immunohistochemistry: A Case Series of Six Patients from the Prospective Exploratory Trial NCT04147494.

Wed, 5 Nov 2025 00:00:00 +0000

Fibroblast activation protein (FAP) has been proposed as a pan-tumor target for PET imaging using FAP-targeted tracers. Here, we explore the potential value of FAP PET in renal tumors. Methods: Six patients with renal tumors (4 with clear cell renal cell carcinoma, 1 with papillary renal cell carcinoma, and 1 with renal oncocytoma) who were included in a prospective imaging study (NCT04147494) underwent [⁶⁸Ga]Ga-FAPI-46 PET before nephrectomy. FAP PET radiotracer uptake and FAP expression by immunohistochemistry were assessed in the tumors and surrounding renal parenchyma. Results: Tumoral FAP radiotracer uptake was highest in clear cell renal cell carcinoma (median SUV_max, 3.1; range, 2.5-5.3), followed by renal oncocytoma (SUV_max, 1.9) and papillary renal cell carcinoma (SUV_max, 1.1). The FAP PET signal strongly correlated with FAP expression by immunohistochemistry (SUV_max; r = 0.93; P = 0.007)....

Prostate Cancer Imaging Beyond PSMA: Applications of GRPR, AR, and Amino Acid Tracers

Sun, 2 Nov 2025 00:00:00 +0000

Prostate-specific membrane antigen (PSMA) targeting agents have been the cornerstone of advanced prostate cancer (PCa) management in theranostics due to their high sensitivity for detecting and treating metastatic disease. However, approximately one-third of metastatic castration-resistant PCa (mCRPC) lesions may exhibit low or absent PSMA expression due to tumor heterogeneity, prior androgen deprivation therapy, or loss of androgen receptor expression, subsequently altering their response to PSMA-targeted therapy. The molecular and biological mechanisms underlying PSMA downregulation remain elusive but may include neuroendocrine differentiation or epithelial-to-mesenchymal transition (EMT). This review addresses this knowledge gap by examining recent preclinical and clinical evidence on novel radiotracers with the potential to provide alternative strategies beyond PSMA for imaging and treating PCa. The diagnostic performance and therapeutic potential of three emerging radiotracer...

Lentiviral vectors for hematopoietic stem cell gene therapy restore α-globin expression in α-thalassemia red blood cells

Thu, 9 Oct 2025 00:00:00 +0000

Alpha thalassemia major (ATM) is an inherited blood disorder caused by the absence of all four α-globin genes (HBA2/1), resulting in severe anemia and lifelong transfusion dependence. While allogeneic hematopoietic stem cell transplantation (HSCT) offers a potential cure, donor availability remains limited. We present a gene therapy approach for autologous HSCT using lentiviral vectors (LVs) to deliver HBA2 under the regulation of optimized β-globin locus control region (LCR) enhancers, restoring α-globin expression in red blood cells. The best-performing LVs, erythroid vector-alpha (EV-α) and EV-α-UV, achieved up to 100% transduction efficiency in human hematopoietic stem and progenitor cells (HSPCs), optimal vector copy numbers, and safe integration profiles. ATM-derived HSPCs from three donors treated with these LVs yielded α/β-globin mRNA and chain ratios within the therapeutic range (∼0.5+), and restored hemoglobin levels by 50%-100%. These findings establish the safety and...

SSTR PET/CT for skull base low-grade meningioma: a critical tool for accurate gross tumor volume delineation in radiotherapy?

Wed, 8 Oct 2025 00:00:00 +0000

BackgroundPrecise delineation of gross tumor volume (GTV) is fundamental for effective radiation therapy in low-grade skull base meningiomas. Magnetic resonance imaging (MRI) serves as the primary imaging tool but may not fully represent tumor extent. This study investigates the additional value of incorporating Somatostatin receptor (SSTR)-directed PET/CT in radiation therapy planning.MethodsA retrospective analysis was conducted with four experienced radiation oncologists contouring GTVs for skull base meningiomas using MRI alone (GTV_MRI), PET/CT alone (GTV_PET/CT), and both modalities combined (GTV_ALL). Consensus ground truth volumes were generated for each modality through a STAPLE algorithm. Agreement between modalities, excluding observer variability, was assessed using statistical metrics including Dice Similarity Coefficient (DSC), Jaccard Index (JCI), Hausdorff distance (HD95), Geographical Miss Index (GMI), sensitivity, and kappa statistics.ResultsThe study included...

[18F]SiTATE PET for PRRT selection and monitoring metastatic tumors of the adrenal medulla and extra-adrenal paraganglia

Wed, 8 Oct 2025 00:00:00 +0000

PurposeIn somatostatin receptor (SSTR)-expressing tumors, theranostics with SSTR-directed imaging and therapy showed promising results regarding disease control. This study evaluated the use of PET imaging with [18F]SiTATE in pheochromocytoma and paraganglioma (PPGL) patients, focusing on eligibility for peptide radioreceptor therapy (PRRT) and therapy monitoring.MethodsFive patients with metastatic paraganglioma (n = 3) or pheochromocytoma (n = 2) were included. Eligibility for PRRT was assessed by [18F]SiTATE applying the Krenning score and baseline SUVmax. Treatment response was analyzed by RECIST 1.1 criteria, total tumor volume (PET-based TTV), and Chromogranin A (CgA).ResultsAt baseline, all patients showed high lesional uptake, with the highest in the bone (mean SUVmax 41.4 ± 87.3) and a high Krenning Score of 3–4, Suggestive for PRRT eligibility. At the follow up, 2.5 months after completion of PRRT, all patients presented with stable disease (RECIST 1.1) and decreasing...

Randomized Phase 2 Trial of an Extended and Flexible Dosing Schedule of 177Lu-PSMA Molecular Radiotherapy in Patients with Metastatic Castration-Resistant Prostate Cancer (FLEX-MRT): Study Protocol

Wed, 10 Sep 2025 00:00:00 +0000

[¹⁷⁷Lu]Lu-PSMA-617 radiopharmaceutical therapy has been approved for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) using a fixed dosing schedule of once every 6 wk for up to a total of 6 doses. We hypothesized that patients may benefit from a flexible and extended dosing schedule, up to 12 doses with potential "treatment holiday" periods. Objective: The objective of this study is to determine the 2-y survival rate of patients with mCRPC treated with an extended and flexible dosing schedule of [¹⁷⁷Lu]Lu-PSMA-617 therapy in comparison to patients treated with the standard fixed dosing schedule of a maximum of 6 treatment cycles once every 6 wk. Study Design: The FLEX-MRT trial is an investigator-initiated prospective phase 2, parallel group, randomized, controlled, open-label, single-center trial in men with mCRPC to determine the efficacy of a flexible and extended dosing schedule of [¹⁷⁷Lu]Lu-PSMA-617...

Comparing neuromodulation targets to reduce cigarette craving and withdrawal: a randomized clinical trial

Sat, 30 Aug 2025 00:00:00 +0000

Cigarette smoking remains the leading preventable cause of death, emphasizing the need for new therapeutics, such as repetitive transcranial magnetic stimulation (TMS). We tested the hypothesis that TMS to three targets would reduce cigarette craving and withdrawal by modulating connectivity within and between three canonical networks in a randomized clinical trial (ClinicalTrials.gov: NCT03827265). Participants (N = 72; DSM-5 tobacco use disorder, ≥1 year of daily smoking) received one session of TMS to hubs of canonical resting-state networks: the dorsolateral prefrontal cortex (dlPFC), superior frontal gyrus (SFG), posterior parietal cortex (PPC), and area v5 (control). Self-reports (craving, withdrawal, and negative affect) and resting-state functional connectivity were measured before and after stimulation. SFG stimulation significantly reduced craving (95% CI, 0.0476–7.9559) and withdrawal (95% CI, 0.9225–8.1063) versus control, with larger effects in men (D = 0.59) than...

Saturated lipid stress attenuates mitochondrial genome synthesis in human cells

Wed, 27 Aug 2025 00:00:00 +0000

Fatty acids are trafficked between organelles to support membrane biogenesis and act as signaling molecules to rewire cellular metabolism in response to starvation, overnutrition, and environmental cues. Mitochondria are key cellular energy converters that harbor their own multi-copy genome critical to metabolic control. In homeostasis, mitochondrial DNA (mtDNA) synthesis is coupled to mitochondrial membrane expansion and division at sites of contact with the endoplasmic reticulum (ER). Here, we provide evidence from cultured hepatocytes that mtDNA synthesis and lipid droplet biogenesis occur at spatially and functionally distinct ER-mitochondria membrane contact sites. We find that, during saturated lipid stress, cells pause mtDNA synthesis and mitochondrial network expansion secondary to rerouted fatty acid trafficking through the ER and lipid droplet biogenesis, coincident with a defect in soluble protein import to the ER lumen. The relative composition of fatty acid pools...

Validation of SUV thresholds in [¹⁸F]SiTATE PET/CT for accurate meningioma segmentation

Wed, 13 Aug 2025 00:00:00 +0000

PurposeSomatostatin receptor (SSTR)-targeted PET/CT provides valuable clinical insights beyond standard imaging in meningioma patients. Due to its excellent diagnostic capabilities and favorable logistics, the 18F-labeled SSTR-targeting peptide SiTATE is increasingly in demand. We aimed to validate a recently proposed standard uptake value (SUV) threshold for accurate meningioma delineation in a clinically diverse patient cohort, including complex anatomical locations and lesions with prior surgical intervention.MethodsConsecutive patients with known or suspected meningioma who underwent [18F]SiTATE PET/CT and contrast enhanced cerebral MRI were included. Lesions were semi-automatically segmented on PET images using an individualized minimal SUV (SUVmin) within a manually defined volume of interest. Correlative CT and MRI images were used to refine segmentations for each lesion, identifying the optimal lesion-specific SUVmin to accurately capture the true volume of the meningioma....

Ubiquitin C-terminal hydrolase L1 is a regulator of tumor growth and metastasis in double-negative prostate cancer.

Wed, 13 Aug 2025 00:00:00 +0000

Prostate cancer is the second leading cause of cancer-related deaths among men worldwide. With heavy androgen deprivation therapies, prostate cancer may shift to androgen receptor negative and neuroendocrine negative subtype of castration resistant prostate cancer, defined as double-negative prostate cancer. Double-negative prostate cancer is associated with poor prognosis and disease mortality. The molecular mechanisms underlying the emergence of double-negative prostate cancer remain poorly understood. Here, we demonstrate that Ubiquitin C-Terminal Hydrolase L1 (UCH-L1), is negatively correlated with androgen receptor levels in prostate cancer patients. UCH-L1 plays a functional role in tumorigenesis and metastasis in double-negative prostate cancer. Knock-down of UCH-L1 decreases double-negative prostate cancer colony formation in vitro and tumor growth in vivo. Moreover, decrease of UCH-L1 significantly delays cell migration in vitro and spontaneous metastasis...

Intratumoral vidutolimod as monotherapy or in combination with pembrolizumab in patients with programmed cell death 1 blockade–resistant melanoma: Final analysis from a phase 1b study

Fri, 8 Aug 2025 00:00:00 +0000

BACKGROUND: New treatment options are needed for patients with metastatic anti-programmed cell death 1 (PD-1)-resistant melanoma. The final analysis of a phase 1b study evaluating the Toll-like receptor 9 agonist vidutolimod is reported here. METHODS: This two-part, open-label, multicenter, phase 1b study in adults with metastatic/unresectable anti-PD-1-resistant melanoma evaluated the safety and clinical activity of intratumoral vidutolimod plus systemic pembrolizumab (part 1) or vidutolimod alone (part 2). Two vidutolimod formulations were evaluated with different concentrations of polysorbate (PS20-A, 0.005%-0.01% polysorbate 20; PS20-B, 0.00167% polysorbate 20). Key end points were safety and investigator-assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors, version 1.1). RESULTS: A total of 159 patients were treated in part 1 (PS20-A, n = 98; PS20-B, n = 61), and 40 patients were treated in part 2. Any-grade treatment-emergent...

Defining STING–sterol interactions with chemoproteomics

Fri, 8 Aug 2025 00:00:00 +0000

Stimulator of interferon genes (STING) is an intracellular pattern recognition receptor that plays a key role in responding to cytosolic DNA and cyclic dinucleotides. STING activity is tightly regulated to avoid aberrant STING activity, excessive type I IFN responses, and resultant autoinflammatory disease. As such understanding the molecular events regulating STING activity is critical. Recent work has revealed cellular cholesterol metabolism also functions to modulate STING activity, although the molecular events linking cholesterol homeostasis with STING remain incompletely understood. Here we pair genetic and chemoproteomic approaches to inform the mechanisms governing cholesterol modulation of STING activity. Using gain- and loss-of-function systems, we find that markedly increasing SCAP-SREBP2 processing and resultant cholesterol synthesis has little impact on STING activity. In contrast, we find that genetic deletion of Srebf2 increased basal and ligand inducible...

Application of the American Thyroid Association Risk Assessment in Patients with Differentiated Thyroid Carcinoma in a German Population