Molecular Imaging and Biology最新文献

Introduction: The adenosine monophosphate-activated protein kinase (AMPK) induces glucose uptake by increasing the expression of glucose transporter 4 (GLUT4), and [¹⁸F]Fluorodeoxyglucose (FDG) is readily transported into tissues with high GLUT4 expression. Thus, positron emission tomography with FDG (FDG-PET) could serve as an important pharmacodynamic readout of AMPK activation. In this study, the impact of treatment with the pan-AMPK activator MK-8722 on FDG uptake was evaluated in rats and Rhesus monkeys.

Methods: Rats were evaluated with FDG-PET following intravenous (IV) or oral (PO) administration of MK-8722. Rhesus monkeys were orally dosed and evaluated with FDG-PET. FDG uptake was measured in skeletal and cardiac muscle, and the incorporation rate was calculated using the Patlak graphical method.

Results: In rats, the highest IV dose of MK-8722 (5 mg/kg) and both PO doses (4 mg/kg and 10 mg/kg) given 4 h prior to FDG-PET resulted in a significant increase in forelimb skeletal muscle FDG uptake (p < 0.01). In Rhesus monkeys, chronic oral administration of 10 mg/kg MK-8722 QD resulted in significantly higher FDG uptake in bicep skeletal muscle than vehicle treatment after 2 and 4 weeks of treatment (p < 0.01), but no difference was observed after 5 weeks of drug washout (p > 0.05). FDG uptake in cardiac muscle was significantly reduced with MK-8722 treatment in rats, but no significant changes in cardiac muscle FDG uptake were measured in Rhesus monkey.

Conclusions: FDG-PET can be used as a pharmacodynamic readout for systemic pharmacological activation of AMPK for preclinical studies and potentially be extended to study humans.

Background: CD38 is an excellent biomarker and therapeutic target for multiple myeloma due to its high expression on cancerous cells in comparison to healthy cells.

Purpose: We aimed to adapt Isatuximab as a PET imaging agent to detect CD38 positive multiple myeloma.

Methods: In vitro studies confirmed the specificity of [⁸⁹Zr]Zr-DFO-Isatuximab in CD38 + OPM-2 and MM.1S cells. Upregulation of CD38 was performed using pomalidomide and ricolinostat. Athymic nude mice were implanted with OPM-2 tumors and PET/CT images were collected 24 h, 3d, and 7d post-injection. Dosimetry data was collected from male and female mice and calculated using OLINDA. Three productions of [⁸⁹Zr]Zr-DFO-Isatuximab were produced using GMP techniques and validated for use in the clinic.

Results: Upregulation of CD38 was observed in vitro in CD38 + cells when treated with either pomalidomide or ricolinostat. In vivo evaluation of [⁸⁹Zr]Zr-DFO-Isatuximab showed high selectivity in OPM-2 xenografts. Blocking with an excess of unlabeled Isatuximab reduced the tumor accumulation of [⁸⁹Zr]Zr-DFO-Isatuximab by 45.5-48.5% confirming the in vivo specificity of this radiotracer. Dosimetry calculations were performed and showed an estimated effective dose of 0.359 mSv/MBq in females and 0.327 mSv/MBq in males. Three clinical grade [⁸⁹Zr]Zr-DFO-Isatuximab doses using good manufacturing practices were synthesized which passed all quality control requirements and were stable up to 6 h, thus validating this compound for use in future clinical trials.

Conclusion: [⁸⁹Zr]Zr-DFO-Isatuximab showed high specificity to CD38 positive cells, had estimated effective doses comparable to other clinically relevant ⁸⁹Zr-labeled antibodies, and can be prepared using GMP practices for clinical use.

Sarcopenia, characterized by the progressive loss of skeletal muscle mass and function, remains a formidable challenge in aging populations. This review synthesizes current knowledge on its multifactorial pathogenesis, including mitochondrial dysfunction, oxidative stress, chronic inflammation, apoptosis, and satellite cell impairment. Neuromuscular alterations such as motor unit Remodeling and neuromuscular junction degeneration further exacerbate functional decline. Diagnostic approaches, ranging from DXA, CT, MRI, and ultrasound imaging to functional assessments like handgrip strength and gait speed, exhibit variability that complicates standardization. Therapeutic strategies are equally versatile. Resistance-based exercise and targeted nutritional support remain first-line, but late-phase trials of myostatin-neutralising antibodies (e.g., LY2495655, bimagrumab) and oral selective androgen-receptor modulators (SARMs; e.g., enobosarm, GSK2881078) now show dose-dependent gains in appendicular lean mass and preliminary functional benefits, signalling that combination regimens integrating lifestyle and drug therapy are imminent. Integration of these approaches with personalized medicine paradigms and AI-driven diagnostic tools holds promise for improved outcomes. This review also outlines critical research areas including mechanistic studies, diagnostic standardization, and translational gaps between preclinical models and clinical application. Addressing these challenges requires an interdisciplinary strategy that encompasses molecular, clinical, and public health perspectives to mitigate the personal and societal impacts of sarcopenia. Future efforts must focus on harmonizing diagnostic criteria, refining therapeutic regimens, and leveraging emerging technologies to develop targeted interventions that preserve muscle function and enhance quality of life in the aging population.

Background: Pafolacianine (Cytalux^®) represents the first FDA-approved tumor-specific fluorescence imaging agent, demonstrating efficacy in ovarian cancer through folate receptor-α (FR-α) targeting. Given the need for improved intraoperative margin assessment in head and neck squamous cell carcinoma (HNSCC), where positive surgical margins occur in 10-30% of cases, we investigated the potential utility of pafolacianine for fluorescence-guided surgery in HNSCC models.

Objective: To evaluate the feasibility of visualizing HNSCC using pafolacianine in vitro, in vivo, and clinical tissue analysis, with comparison to fluorescence-guided surgery agents that have been successful in patients.

Methods: HNSCC cell lines (FaDu, UMSCC47) were treated with escalating concentrations of pafolacianine (0-500 nM) and assessed for binding at 1 and 24 h. Nude mice bearing HNSCC xenografts (FaDu, UMSCC47) received intraperitoneal injection of pafolacianine (10 nmol) with fluorescence imaging at multiple timepoints. Immunohistochemistry analysis of patient samples (n = 8 tumor, n = 8 normal) evaluated FR-α and FR-β expression. Panitumumab-IRDye800CW served as a positive control for comparison.

Results: In vitro analysis demonstrated minimal pafolacianine binding across all HNSCC cell lines, with fluorescence intensities similar to or lower than the FR-α-negative A549 control cell line. In vivo imaging revealed poor tumor localization with mean fluorescence intensity (MFI) of 7.39 (FaDu) and 6.97 (UMSCC47), substantially lower than non-target tissues including skin. Immunohistochemistry analysis showed no statistically significant difference in FR-α expression between tumor and normal tissue (p > 0.05). For comparison, panitumumab-IRDye800CW demonstrated robust tumor targeting with MFI of 32.14 (FaDu) and 14.98 (UMSCC47).

Conclusions: This study demonstrates that pafolacianine exhibits limited utility for fluorescence-guided surgery in HNSCC due to insufficient FR-α expression and poor tumor-to-background contrast. These negative findings provide crucial evidence against the clinical translation of pafolacianine for HNSCC applications and highlight the importance of target expression validation in precision medicine approaches.

Clinical relevance: Negative studies such as this are essential for evidence-based clinical decision-making, preventing unnecessary resource allocation and potential patient exposure to ineffective interventions. These findings inform the broader fluorescence-guided surgery field and support continued investigation of alternative targeting strategies for HNSCC.

Background: Increased amino acid transport in gliomas allows imaging of metabolically active tumor volume by PET. Tryptophan analog PET radiotracers can provide additional information by tracking tumoral metabolism via the upregulated immunosuppressive tryptophan-kynurenine pathway. We tested the recently developed tryptophan analog PET tracer [¹⁸F]-fluoro-ethyl-L-tryptophan ([¹⁸F]FETrp) for detecting post-treatment glioblastoma while using a non-invasive approach to generate parametric tryptophan metabolic maps and comparing them with static tracer uptake maps and contrast-enhanced MRI.

Methods: Five patients (age: 22-67 years) with previously treated glioblastoma underwent [¹⁸F]FETrp PET/CT imaging. A dynamic acquisition protocol sampled the brain and blood pool non-invasively using the FlowMotion Multiparametric PET software (Siemens Healthineers). Parametric brain images of the unidirectional uptake rate constant (K_i), characterizing irreversible tryptophan trapping and the volume of distribution (V_D) were fused with static uptake (SUV) maps and contrast-enhanced brain MRI. Voxels with elevated K_i, V_D, and SUV were defined, and their spatial associations with contrast-enhanced volumes were characterized by their % volume overlap and the distance between their centroids.

Results: A substantial spatial volume overlap was observed between MRI contrast-enhancing regions and elevated static [¹⁸F]FETrp uptake and V_D. In contrast, the overlap between contrast-enhancing regions and elevated K_i metabolic volumes was low (0-16%), with high K_i areas extending deeper into non-enhancing brain (7-33 mm centroid distance). These non-enhancing high K_i areas showed new contrast-enhancement on follow-up MRI, consistent with tumor progression.

Conclusions: Areas of high tryptophan metabolism detected by [¹⁸F]FETrp PET-derived parametric (K_i) maps extend outside the contrast-enhancing glioblastoma mass in adjacent non-enhancing brain regions that can be missed or underestimated by static uptake images. Consequently, [¹⁸F]FETrp PET metabolic maps have the potential for enhanced detection of non-enhancing glioma infiltration for improved radiation or surgical treatment planning.

Purpose: Despite advancements in colorectal cancer (CRC) therapy, surgery remains the only curative option. Incomplete resection resulting in tumor cell positive surgical margins occurs in ~ 7% of CRC surgeries and is associated with recurrence and poor prognosis. Fluorescence-guided surgery (FGS) enhances tumor detection and enables real-time identification of tumor margins. Claudins, a large family of tight junction proteins, are being explored as cancer biomarkers and therapeutic targets due to their presence on the cell surface, tissue-specific expression, and selective upregulation in carcinomas. Claudin-1 (CLDN1) is overexpressed in CRC and associated with therapy resistance and metastasis, making it a promising target for fluorescence-based tumor detection.

Procedures: CLDN1 expression in CRC was analyzed using the Cancer Genome Atlas Colorectal Adenocarcinoma (TCGA-COAD) dataset. To enable in vivo tumor detection, a CLDN1 monoclonal antibody was conjugated to a near-infrared fluorescent dye (CLDN1-IR800). Sensitivity, specificity, and tumor-to-background ratio were tested in vitro and in vivo using CRC cell lines, patient-derived organoids, and an orthotopic, syngeneic model of CRC metastasis.

Results: This study demonstrates that CLDN1 is upregulated in 100% of CRC tumors compared to patient-matched normal adjacent colon in the TCGA-COAD dataset, with an average 40-fold increase in expression. CLDN1-IR800 showed specific binding and strong fluorescence in CLDN1-expressing CRC cells, with minimal signal in non-expressing cells or IgG-IR800 controls. In vivo, CLDN1-IR800 produced a significantly higher tumor-to-background ratio in CLDN1-expressing CRC cell line and patient-derived organoid xenografts compared to CLDN1-negative tumors or IgG-IR800-injected mice. Necropsy revealed significantly higher fluorescence in tumors than in other organs. In an orthotopic syngeneic mouse model, both primary and metastatic lesions were detectable. Ex vivo imaging confirmed signal in a panel of patient-derived organoids.

Conclusions: These findings demonstrate CLDN1's potential as a target for tumor detection and FGS in CRC.

Purpose: We aimed to compare the diagnostic performance of [⁶⁸Ga]Ga-FAPI-04 PET/CT, [¹⁸F]F-FDG PET/CT, enterography and intestinal ultrasound (IUS) in detecting inflamed segments in patients with Crohn's disease (CD), as well as in identifying CD-related complications.

Methods: This prospective study enrolled 16 patients with CD. Each patient underwent [⁶⁸Ga]Ga-FAPI-04 PET/CT, [¹⁸F]F-FDG PET/CT, enterography, and IUS within 14 days. Using endoscopic results as the reference standard, we assessed the diagnostic accuracy and agreement across these imaging modalities for detecting segmental lesions in the proximal upper gastrointestinal (GI) tract and ileocolon. Their performance in identifying CD-associated complications and mesenteric changes was also evaluated.

Results: [⁶⁸Ga]Ga-FAPI-04 PET/CT exhibited high sensitivity (73.3%, 95% CI: 0.610-0.829), specificity (97.8%, 95% CI: 0.887-0.996) and accuracy (84.0%, 95% CI: 0.758-0.897) for detecting segmental lesions in the terminal ileum and colon. These performance metrics were comparable to those of enterography, [¹⁸F]F-FDG PET/CT and IUS (all P > 0.05), with nearly perfect diagnostic agreement observed among these imaging modalities (all κ > 0.81; all P < 0.001). In the upper GI tract and proximal small intestine, its sensitivity (53.8%, 95% CI:0.291-0.768), specificity (92.1%, 95% CI:0.792-0.973) and accuracy (82.4%, 95% CI:0.697-0.904) were similar to [¹⁸F]F-FDG PET/CT and enterography, with good diagnostic agreement (both κ = 0.73; P < 0.001). However, its resolution was suboptimal for detecting mild lesions. Notably, [⁶⁸Ga]Ga-FAPI-04 PET/CT outperformed other imaging methods in detection rate and sensitivity for identifying CD-associated complications and mesenteric changes.

Conclusion: [⁶⁸Ga]Ga-FAPI-04 PET/CT may sever as a one-step, non-invasive diagnostic option for CD patients.

Purpose: Wound healing process in lung injury involves the activation of the mitogen-activated protein kinase (MAPK) pathway. In this study, we investigated the role of the MAPK pathway in wound healing in a murine model of emphysema using hyperpolarized ¹²⁹Xe (HP ¹²⁹Xe) magnetic resonance imaging (MRI).

Procedures: Porcine pancreatic elastase was administered intratracheally to 25 mice to induce lung injury. Temporal changes in pulmonary gas exchange function were monitored using HP ¹²⁹Xe MRI, revealing a significant decline in function one day after elastase administration. Treatments with ethyl pyruvate (EP) and nicorandil (Nic), which upregulate and downregulate the MAPK pathway, respectively, were initiated in 12 and 7 of the 25 mice, respectively, and continued for 20 days. Over the 21-day period, HP ¹²⁹Xe MRI was performed to monitor the disease progression and treatment efficacy through changes in the metrics of gas exchange and fractional ventilation.

Results: HP ¹²⁹Xe MRI showed that EP significantly improved gas exchange function 14 days after elastase administration, whereas Nic did not show any improvement. Ventilatory function also improved in the EP group, but not in the Nic group, 14 days after elastase administration. Histological analysis showed that EP repaired tissue damage to a level similar to that observed in healthy mice, whereas Nic did not.

Conclusions: In the present study, we provide some insight into the role of the MAPK pathway in wound healing in elastase-induced lung injury, as assessed using the HP ¹²⁹Xe MRI protocol.

Purpose: Early detection and intervention in lung adenocarcinoma (LUAD) are critical for improving patient prognosis. This study explores the role of basic leucine zipper and W2 domains 1 (BZW1, BZAP45) in regulating malignant cellular behavior and glycolytic metabolism in LUAD.

Procedures: Bioinformatics and clinical information analysis was conducted to study BZW1 expression and its relationship with prognosis, glycolysis-related genes expression and PET/CT parameters of 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) in LUAD. BZW1 was knocked out in A549 cell line and verified. In vitro and in vivo studies were performed to analyze BZW1's impact on malignant behaviors and glycolysis. Non-targeted mass spectrometry analyzed xenograft tumor metabolites and potential biomarkers.

Results: Bioinformatic analyses identified BZW1 as a pivotal gene driving LUAD progression. The retrospective analysis revealed that BZW1 expression is elevated in LUAD tissues and is significantly correlated with clinical tumor parameters and metabolic parameters obtained from [¹⁸F]FDG PET/CT. In vitro assays demonstrated that BZW1 overexpression promotes LUAD cell proliferation, migration, and invasion. In vivo experiments with mouse xenograft models confirmed that BZW1 promotes tumor growth. Further analysis revealed that BZW1 may facilitate glycolysis and the Warburg effect by upregulating hypoxia inducible factor-1α (HIF-1α) and cellular Myelocytomatosis (c-Myc).

Conclusions: These findings highlighted the role of BZW1 in LUAD metabolism and may promote tumor progression through modulating of glycolytic pathways. In conclusion, BZW1 is significantly associated with LUAD malignancy and [¹⁸F]FDG PET/CT derived metabolic parameters. It could provide a potential molecular target for the diagnosis and treatment of LUAD, offering new insights into precision oncology.