177Lu-FAP-2286 Therapy in a Patient With Metastatic Rhabdoid Meningioma.

ABSTRACT: Rhabdoid meningioma is a rare subtype of meningioma and has a poor prognosis. Herein, we reported a patient of rhabdoid meningioma with multiple liver, pancreas, and bone metastases, who received 177Lu-FAP-2286 therapy. After 1 treatment cycle, 68Ga-FAP-2286 PET/CT revealed partial remission of the lesions.

High Affinity and FAP-Targeted Radiotracers: A Potential Design Strategy to Improve the Pharmacokinetics and Tumor Uptake for FAP Inhibitors.

Fibroblast activation protein (FAP) is overexpressed in cancer-associated fibroblasts, making it an attractive target for both imaging and therapy of malignancy. This study presents a range of novel FAP inhibitors derived from amino derivatives of UAMC1110, incorporating polyethylene glycol and bulky groups containing bifunctional DOTA chelators. The compounds labeled with gallium-68 were developed and characterized to study biodistribution properties and tumor-targeting performance in nude mice bearing U87MG tumor xenografts. Several tracers of interest were screened due to the advantages in imaging and tumor-specific uptake. Positron emission tomography scans revealed that polyethylene glycol-modified 68Ga-3-3 had a rapid penetration within the neoplastic tissue and excellent tumor-to-background contrast. In a comparative biodistribution study, naphthalene-modified 68Ga-6-3 exhibited more significant tumor uptake (∼50% ID/g, 1 h p.i.) than 68Ga-3-3 and 10-fold higher than 68Ga-FAPI-04 under the same conditions. Remarkably, 68Ga-8-1, combining the two structural design strategies, obtains superior imaging performance.

Comparison of 68 Ga-FAPI-04 and fluorine-18-fluorodeoxyglucose PET/computed tomography in the detection of ovarian malignancies.

BACKGROUND: Currently, fluorine-18-fluorodeoxyglucose ( 18 F-FDG) is the most frequently used diagnostical radiotracer for PET/computed tomography (PET/CT) in ovarian malignancies. However, 18 F-FDG has some limitations. The fibroblast activation protein inhibitor (FAPI) previously demonstrated highly promising results in studies on various tumor entities and 68 Ga-labeled FAPI presents a promising alternative to 18 F-FDG. This study aimed to compare the performance of 68 Ga-FAPI and 18 F-FDG PET/CT for imaging of ovarian malignancies. METHODS: A total of 27 patients were included in this retrospective study conducted at the Affiliated Hospital of Southwest Medical University between June 2020 and February 2022. The 18 F-FDG and 68 Ga-FAPI uptakes of tumors, lymph nodes, and distant metastases were quantified using the maximum standardized uptake values, and the tumor-to-background ratios were also evaluated and calculated by using the Wilcoxon signed-rank test. RESULTS: Twenty-one patients with suspected ( n = 11) and previously treated ovarian malignancies ( n = 10) were in statistical analysis finally. For detecting tumors, 68 Ga-FAPI PET/CT was more sensitive than 18 F-FDG PET/CT [14 of 14 (100%) vs. 11 of 14 (78%)], lymph node metastases [75 of 75 (100%) vs. 60 of 75 (80%)] and superior to 18 F-FDG PET/CT in terms of the peritoneal and pleural metastases [9 of 9 (100%) vs. 5 of 9 (56%)]. For four of the newly diagnosed patients ( n = 11), 68 Ga-FAPI PET/CT upstaged the clinical stage compared to 18 F-FDG PET/CT. CONCLUSION: 68 Ga-FAPI PET/CT has superior potential in the detection of ovarian cancers, especially in peritoneal carcinomatosis. 68 Ga-FAPI PET/CT may be a promising supplement for staging and follow-up of ovarian malignancies.

Advances on Cell Autophagy and Its Potential Regulatory Factors in Renal Ischemia-Reperfusion Injury.

Ischemia-reperfusion injury is a major reason for acute kidney injury and various kidney diseases. Autophagy plays an important role during renal ischemia-reperfusion injury (RIRI), but it remains controversial whether autophagy contributes to cell survival or ischemia-reperfusion-induced cell death. In the review, we summarized the function of autophagy in the progression of acute ischemic kidney injury, as well as its related molecular mechanisms. While analyzing the opposite roles of autophagy in RIRI, it was concluded that the protective or detrimental function of autophagy was depending on the timing and amount of the activation of cell autophagy. We also summarized the regulatory agents, including active compounds, proteins, or microRNAs (miRNAs), which regulated the cell autophagy during renal acute ischemic kidney injury process. This explained why the opposite conclusion occurred when cell autophagy was studied in the RIRI models from different researchers. Therefore, the article provided a hypothesis to control cell autophagy at the appropriate timing and intensity so as to alleviate renal injury and sustain cell survival of the renal cell.

Bavachin Protects Human Aortic Smooth Muscle Cells Against ß-Glycerophosphate-Mediated Vascular Calcification and Apoptosis via Activation of mTOR-Dependent Autophagy and Suppression of ß-Catenin Signaling.

Vascular calcification is a major complication of cardiovascular disease and chronic renal failure. Autophagy help to maintain a stable internal and external environment that is important for modulating arteriosclerosis, but its pathogenic mechanism is far from clear. Here, we aimed to identify the bioactive compounds from traditional Chinese medicines (TCM) that exhibit an anti-arteriosclerosis effect. In ß-glycerophosphate (ß-GP)-stimulated human aortic smooth muscle cells (HASMCs), the calcium level was increased and the expression of the calcification-related proteins OPG, OPN, Runx2, and BMP2 were all up-regulated, followed by autophagy induction and apoptosis. Meanwhile, we further revealed that ß-GP induced apoptosis of human osteoblasts and promoted differentiation of osteoblasts through Wnt/ß-catenin signaling. Bavachin, a natural compound from Psoralea corylifolia, dose-dependently reduced the level of intracellular calcium and the expression of calcification-related proteins OPG, OPN, Runx2 and BMP2, thus inhibiting cell apoptosis. In addition, bavachin increased LC3-II and beclin1 expression, along with intracellular LC3-II puncta formation, which autophagy induction is Atg7-dependent and is regulated by suppression of mTOR signaling. Furthermore, addition of autophagy inhibitor, wortmannin (WM) attenuated the inhibitory effect of bavachin on ß-GP-induced calcification and apoptosis in HASMCs. Collectively, the present study revealed that bavachin protects HASMCs against apoptosis and calcification by activation of the Atg7/mTOR-autophagy pathway and suppression of the ß-catenin signaling, our findings provide a potential clinical application for bavachin in the therapy of cardiovascular disease.

Detection of protein targets with a single binding epitope using DNA-templated photo-crosslinking and strand displacement.

DNA-based probes are powerful analytical tools for protein detection and analysis. Target-induced DNA assembly is a widely used strategy to transduce target-ligand binding to detectable signals. However, most of the existing methods based on DNA assembly require two or more binding sites on the target protein. Here we report a novel detection method suitable for protein targets with just a single binding site. This method is based on target-induced probe assembly, DNA-templated photo-crosslinking, and DNA-mediated toehold strand displacement to form a tri-probe complex that is specific for target protein.

Burkitt Lymphoma Presented as Acute Lower Back Pain and Revealed by 18F-NaF PET/CT.

A 15-year-old man with acute lower back pain for 7 days underwent F-NaF PET/CT to determine the cause of his symptoms. The PET images revealed irregularly increased F activity in the L1 vertebral body without definite sclerotic changes on CT. However, the corresponding CT images revealed an adjacent paravertebral mass extending into the vertebral foramen without elevated activity on PET. A diagnosis of Burkitt lymphoma was made after pathological examination.

Affinity purification in target identification: the specificity challenge.

Since phenotype-based screening directly evaluates capability of small molecules for modulating biology in actual biological systems, it has become an important discover modality in modern pharmaceutical sciences. However, in order to fully elucidate the molecular mechanism underlying the bioactivity of small molecules, identification of their biological targets is an indispensable step. Among the many target identification strategies developed during the past several decades, affinity purification remains to be one of the most important and powerful approaches, as it can directly reveal the physical interactions between small molecules and their biomolecular targets. However, due to the complexity of the proteome and the diversity of small molecule-protein interactions, affinity purification faces the specificity challenge: how to identify the true specific targets from the non-specific background? Focusing on this challenge, in this review, we briefly introduce the history and background of affinity purification, and then we discussed the major technological developments aiming to address this challenge. We have summarized these approaches in two categories: noise reduction and comparative distinction. This review also highlights the importance of choosing an integrated approach combining multiple methods to achieving success in target identification.

Novel encoding methods for DNA-templated chemical libraries.

Among various types of DNA-encoded chemical libraries, DNA-templated library takes advantage of the sequence-specificity of DNA hybridization, enabling not only highly effective DNA-templated chemical reactions, but also high fidelity in library encoding. This brief review summarizes recent advances that have been made on the encoding strategies for DNA-templated libraries, and it also highlights their respective advantages and limitations for the preparation of DNA-encoded libraries.

Photoaffinity labeling of transcription factors by DNA-templated crosslinking.

Characterization of transcription factor-DNA interaction is of high importance in elucidating the molecular mechanisms of gene transcriptions. DNA-based affinity probes were developed to capture and identify transcription factors by covalent crosslinking; however, the requirement of a crosslinker on the affinity probe remains a disadvantage, as the crosslinker itself often interferes with the protein-DNA interactions. We report a dual-probe method able to capture DNA-binding transcription factors with unmodified protein-binding sites in scenarios where conventional probes have failed. We have also shown the method's converse application in selecting specific transcription factor-binding DNA sequences from a probe library and its extension to studying proteins recognizing epigenetic marks. This study may provide a new tool for exploring DNA-binding proteins in biology.

Design, preparation, and selection of DNA-encoded dynamic libraries.

We report a method for the preparation and selection of DNA-encoded dynamic libraries (DEDLs). The library is composed of two sets of DNA-linked small molecules that are under dynamic exchange through DNA hybridization. Addition of the protein target shifted the equilibrium, favouring the assembly of high affinity bivalent binders. Notably, we introduced a novel locking mechanism to stop the dynamic exchange and "freeze" the equilibrium, thereby enabling downstream hit isolation and decoding by PCR amplification and DNA sequencing. Our DEDL approach has circumvented the limitation of library size and realized the analysis and selection of large dynamic libraries. In addition, this method also eliminates the requirement for modified and immobilized target proteins.