The Complementary Role of 68Ga-FAPI-04 PET/CT in a Case of Neuroblastoma.

ABSTRACT: As a common and highly aggressive malignancy of childhood, more than half of neuroblastomas are metastatic at the time of presentation. Herein, we reported 68Ga-FAPI-04 and 18F-FDG PET/CT findings in a 13-year-old girl with undifferentiated neuroblastoma. FAPI PET/CT showed intense uptake in the bone and bone marrow metastases. The primary lesions presented with low FAPI uptake but moderate FDG uptake. Above findings suggested the potential of FAPI PET/CT in the imaging evaluation of neuroblastoma.

Fluorine-18 fluorodeoxyglucose uptake change in liver, mediastinal blood pool, and lymphoid cell-rich organs during programmed cell death-1 immunotherapy in lymphoma.

PURPOSE: The aim of this study was to evaluate metabolism change in reference organs (liver and mediastinum) and lymphoid cell-rich organs (spleen and bone marrow) during programmed cell death-1 immunotherapy in relapsed or refractory lymphoma patients. METHODS: A total of 66 patients with baseline and serial monitoring fluorodeoxyglucose (FDG) PET/computed tomography scans were retrospectively enrolled. Mean standardized uptake value (SUV) and maximum SUV of evaluated organs were obtained by two reviewers, and their association with tumor burden and clinical response were evaluated. Immune-related adverse events detected by FDG PET/computed tomography were also recorded. RESULTS: The SUV values of reference organs and lymphoid cell-rich organs did not change significantly during the immunotherapy process. The intersubject variability of these values ranged from 13.0 to 28.5%. Meanwhile, metabolism of reference organs was affected by neither the tumor burden nor clinical response. SUV change of lymphoid cell-rich organs was associated with clinical response to immunotherapy. Responders showed decreased metabolism, while nonresponders showed a reverse trend (spleen SUV max : -0.30 ±â€…0.47 vs. 0.18 ±â€…0.39, P  = 0.001, spleen SUV mean : -0.24 ±â€…0.39 vs. 0.14 ±â€…0.31, P  = 0.001; and bone marrow SUV max : -0.14 ±â€…0.37 vs. 0.07 ±â€…0.46, P  = 0.042, respectively). The influence of immune-related adverse events on the SUV change in evaluated organs was not significant. CONCLUSION: During programmed cell death-1 immunotherapy, metabolism change of reference organs is influenced neither by tumor burden nor by clinical response, while FDG uptake change of lymphoid cell-rich organs is significantly associated with clinical response.

Gastric Fundus Splenosis Mimicking Malignancy on FDG PET/CT.

ABSTRACT: A 17-year-old man presented with dull pain in the left upper abdomen for 1 month. Initial CT and gastroscopy revealed a mass in the gastric fundas, protruding into the lumen. Based on findings of a fine-needle biopsy, an inflammatory myofibroblastic tumor was suspected. Subsequent PET/CT showed increased FDG uptake in the gastric fundas as well as hepatogastric ligament, para-aortic region. Eventually, he underwent surgical resection, and histopathologic findings confirmed the diagnosis of splenosis.

Spatiotemporal transformable nano-assembly for on-demand drug delivery to enhance anti-tumor immunotherapy.

Induction of tumor cell senescence has become a promising strategy for anti-tumor immunotherapy, but fibrotic matrix severely blocks senescence inducers penetration and immune cells infiltration. Herein, we designed a cancer-associated fibroblasts (CAFs) triggered structure-transformable nano-assembly (HSD-P@V), which can directionally deliver valsartan (Val, CAFs regulator) and doxorubicin (DOX, senescence inducer) to the specific targets. In detail, DOX is conjugated with hyaluronic acid (HA) via diselenide bonds (Se-Se) to form HSD micelles, while CAFs-sensitive peptide is grafted onto the HSD to form a hydrophilic polymer, which is coated on Val nanocrystals (VNs) surface for improving the stability and achieving responsive release. Once arriving at tumor microenvironment and touching CAFs, HSD-P@V disintegrates into VNs and HSD micelles due to sensitive peptide detachment. VNs can degrade the extracellular matrix, leading to the enhanced penetration of HSD. HSD targets tumor cells, releases DOX to induce senescence, and recruits effector immune cells. Furthermore, senescent cells are cleared by the recruited immune cells to finish the integrated anti-tumor therapy. In vitro and in vivo results show that the nano-assembly remarkably inhibits tumor growth as well as lung metastasis, and extends tumor-bearing mice survival. This work provides a promising paradigm of programmed delivering multi-site nanomedicine for cancer immunotherapy.

FDG PET/CT may replace bone marrow biopsy for the evaluation of bone marrow involvement in selected mature T- and natural killer-cell lymphomas: A meta-analysis.

PURPOSE: To systematically determine the role of FDG PET/CT for the diagnosis of bone marrow involvement in mature T- and natural killer (NK)-cell lymphomas. METHODS: The PubMed, Embase and Cochrane Library databases were searched to identify eligible studies. Data extraction and quality assessment were independently conducted. Then, pooled diagnostic performance with the 95 % confidence interval (CI) was calculated and further analyzed based on different interpretation criteria, tumor type and stage. RESULTS: Fifteen studies were eventually included for quantitative analysis. Overall, the methodological quality of included studies was acceptable. For detecting bone marrow involvement, FDG PET/CT achieved a poor sensitivity of 0.62 (95 % CI, 0.48-0.71) and a reasonable specificity of 0.92 (95 % CI, 0.87-0.96). Similar performance was observed for the specific type of extranodal NK/T-cell lymphoma (ENKTCL). In early-stage patients revealed by PET/CT, extremely small proportion (2/777) showed positive bone marrow biopsy, especially for the specific type of ENKTCL, whereas in advanced-stage patients, the specificity of FDG PET/CT dropped to 0.77 (95 % CI, 0.72-0.82). Regarding the interpretation, both diffuse and focal increased uptake patterns as positivity may result in increased sensitivity but decreased specificity compared with focal pattern alone as positivity. CONCLUSIONS: FDG PET/CT demonstrated excellent negative predictive value for detecting marrow involvement in early-stage patients with mature T- and NK-cell lymphomas, especially the ENKTCL. Conversely, FDG PET/CT showed poor performance for the diagnosis of bone marrow involvement in advanced-stage patients.

Eosinophilic Cystitis Mimicking Malignancy on FDG PET/CT.

ABSTRACT: A 64-year-old man had progressive dysuria and nocturia for 1 month. Initial MRI and CT revealed localized thickening of the bladder wall with significant enhancement. Meanwhile, the lesion showed intense FDG accumulation on the delayed PET/CT. Taken together, a malignancy was suspected. However, the pathologic findings confirmed the diagnosis of eosinophilic cystitis.

Uptake, accumulation and metabolism of UV-320 in vegetables and its impact on growth and quality.

UV-320 is classified as a Substance of Very High Concern (SVHC) by the European Chemicals Agency and has attracted significant attention due to its presence in the environment. Understanding the uptake, translocation and metabolic patterns of UV-320 in vegetables is essential for assessing their ability to bioaccumulate and potential risks to human health. In this study, we investigated the uptake and translocation of UV-320 in lettuce and radish by hydroponic experiments. The results showed that the root concentration factors (Croot/Csolution, RCF) of lettuce and radish were in the range of 47.9 to 464 mL/g and 194 to 787 mL/g, respectively. The transfer factors (Cshoot/Croot, TF) were observed to be 0.001-0.012 for lettuce and 0.02-0.05 for radish. Additionally, non-targeted screening identified twelve phase I and one phase II metabolites of UV-320 in vegetables, which were confirmed based on their molecular formulas and structures. The metabolic pathways involving oxidation, ketonylation and deamination were proposed in vegetables. Also, we have observed that UV-320 inhibits the growth of vegetables. Meanwhile, we evaluated the health risk of UV-320 in lettuce and radish and found that the consumption of lettuce is relatively safe, while the consumption of radish has a risk of HQ >1 for both adults and children, which should be seriously considered. This study provides valuable insights into the behavior and ecological risks of UV-320 in the environment.

SeMet alleviates LPS-induced eggshell gland necroptosis mediated inflammation by regulating the Keap1/Nrf2/HO-1 pathway.

Exposure to lipopolysaccharide (LPS) can lead to inflammation in a variety of tissues and organs. Selenium (Se) plays a crucial role in mitigating inflammatory damage. Compared with inorganic selenium, organic selenium, such as selenomethionine (SeMet), has the advantages of a higher absorption rate and lower toxicity in animals. This study examined the protective effects of SeMet on eggshell gland tissue damage caused by LPS. Hy-Line Brown laying hens were chosen as the experimental animals and were randomly assigned to four groups: control group (C), lipopolysaccharide group (LPS), SeMet group (Se), and SeMet + lipopolysaccharide group (Se + LPS). H&E staining and transmission electron microscope were performed to observe the pathological changes of eggshell glands, oxidative stress related indicators were measured using relevant kits, qRT‒PCR and western blotting were used to evaluate the mRNA and protein levels of the Nrf2 pathway, necroptosis, and inflammation related indicators. The results showed that LPS treatment increased the content of malondialdehyde (MDA), decreased the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX), and decreased the content of glutathione (GSH). LPS increased the levels of Keap1, RIPK1, RIPK3, MLKL, TNF-α, COX-2, and NF-κB, while decreasing the levels of HO-1, NQO1, Nrf2, and Caspase-8. However, SeMet treatment effectively reversed the changes of the above indicators, indicating that SeMet alleviates eggshell gland cell necroptosis-mediated inflammation induced by LPS via regulating the Keap1/Nrf2/HO-1 pathway. This study elucidated the mechanism by which SeMet alleviates LPS-induced eggshell gland tissue damage in Hy-Line Brown laying hens and provided a new direction for expanding the application of SeMet in the feeding and production of laying hens.

Essential oil from Fructus Alpiniae zerumbet ameliorates vascular endothelial cell senescence in diabetes by regulating PPAR-γ signalling: A 4D label-free quantitative proteomics and network pharmacology study.

ETHNOPHARMACOLOGICAL RELEVANCE: Vascular endothelial cell senescence is associated with cardiovascular complications in diabetes. Essential oil from Fructus Alpiniae zerumbet (Pers.) B.L.Burtt & R.M.Sm. (EOFAZ) has potentially beneficial and promising diabetes-related vascular endothelial cell senescence-mitigating effects; however, the underlying molecular mechanisms remain unclear. AIM OF THE STUDY: To investigate the molecular effects of EOFAZ on vascular endothelial cell senescence in diabetes. MATERIALS AND METHODS: A diabetes mouse model was developed using a high-fat and high-glucose diet (HFD) combined with intraperitoneal injection of low-dose streptozotocin (STZ, 30 mg/kg) and oral treatment with EOFAZ. 4D label-free quantitative proteomics, network pharmacology, and molecular docking techniques were employed to explore the molecular mechanisms via which EOFAZ alleviates diabetes-related vascular endothelial cell senescence. A human aortic endothelial cells (HAECs) senescence model was developed using high palmitic acid and high glucose (PA/HG) concentrations in vitro. Western blotting, immunofluorescence, SA-ß-galactosidase staining, cell cycle, reactive oxygen species (ROS), cell migration, and enzyme linked immunosorbent assays were performed to determine the protective role of EOFAZ against vascular endothelial cell senescence in diabetes. Moreover, the PPAR-γ agonist rosiglitazone, inhibitor GW9662, and siRNA were used to verify the underlying mechanism by which EOFAZ combats vascular endothelial cell senescence in diabetes. RESULTS: EOFAZ treatment ameliorated abnormal lipid metabolism, vascular histopathological damage, and vascular endothelial aging in diabetic mice. Proteomics and network pharmacology analysis revealed that the differentially expressed proteins (DEPs) and drug-disease targets were associated with the peroxisome proliferator-activated receptor gamma (PPAR-γ) signalling pathway, a key player in vascular endothelial cell senescence. Molecular docking indicated that the small-molecule compounds in EOFAZ had a high affinity for the PPAR-γ protein. Western blotting and immunofluorescence analyses confirmed the significance of DEPs and the involvement of the PPAR-γ signalling pathway. In vitro, EOFAZ and rosiglitazone treatment reversed the effects of PA/HG on the number of senescent endothelial cells, expression of senescence-related proteins, the proportion of cells in the G0/G1 phase, ROS levels, cell migration rate, and expression of pro-inflammatory factors. The protective effects of EOFAZ against vascular endothelial cell senescence in diabetes were aborted following treatment with GW9662 or PPAR-γ siRNA. CONCLUSIONS: EOFAZ ameliorates vascular endothelial cell senescence in diabetes by activating PPAR-γ signalling. The results of the present study highlight the potential beneficial and promising therapeutic effects of EOFAZ and provide a basis for its clinical application in diabetes-related vascular endothelial cell senescence.

Development of mitochondrial gene-editing strategies and their potential applications in mitochondrial hereditary diseases: a review.

Mitochondrial DNA (mtDNA) is a critical genome contained within the mitochondria of eukaryotic cells, with many copies present in each mitochondrion. Mutations in mtDNA often are inherited and can lead to severe health problems, including various inherited diseases and premature aging. The lack of efficient repair mechanisms and the susceptibility of mtDNA to damage exacerbate the threat to human health. Heteroplasmy, the presence of different mtDNA genotypes within a single cell, increases the complexity of these diseases and requires an effective editing method for correction. Recently, gene-editing techniques, including programmable nucleases such as restriction endonuclease, zinc finger nuclease, transcription activator-like effector nuclease, clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats-associated 9 and base editors, have provided new tools for editing mtDNA in mammalian cells. Base editors are particularly promising because of their high efficiency and precision in correcting mtDNA mutations. In this review, we discuss the application of these techniques in mitochondrial gene editing and their limitations. We also explore the potential of base editors for mtDNA modification and discuss the opportunities and challenges associated with their application in mitochondrial gene editing. In conclusion, this review highlights the advancements, limitations and opportunities in current mitochondrial gene-editing technologies and approaches. Our insights aim to stimulate the development of new editing strategies that can ultimately alleviate the adverse effects of mitochondrial hereditary diseases.

Enterovesical Fistula in a Lymphoma Patient Revealed by FDG PET/CT With an Oral Contrast Agents.

ABSTRACT: A 60-year-old man with colonic diffuse large B-cell lymphoma was referred for FDG PET/CT for initial staging. He was suspected of enterovesical fistula. After oral administration, large amounts of contrast agents accumulated in the bowel lumen and leaked into the bladder through a well-marked fistulous tract. Corresponding to the fistula, a linear pattern of FDG uptake extended from the bladder into the colonic lumen, and the measured SUV max inside the lesion was as high as that of the urinary bladder. Cystography confirmed the presence of the enterovesical fistula.

Efficacy Analysis of Neoadjuvant versus Adjuvant Cisplatin-Paclitaxel Regimens for Initial Treatment of FIGO Stages IB3 and IIA2 Cervical Cancer.

BACKGROUND Large cancer lesions are often challenging to treat with surgical intervention alone. Neoadjuvant chemotherapy is frequently used for FIGO stage IB3 and IIA2 cervical cancers to optimize the outcomes of radical surgeries. This study aimed to compare the effectiveness of neoadjuvant chemotherapy, followed by adjuvant chemotherapy and radiotherapy, if necessary, with the traditional approach of adjuvant chemotherapy and radiotherapy after radical hysterectomy in treatment-naïve patients with cervical cancer of specified stages. MATERIAL AND METHODS A total of 245 female patients were administered either 70 to 85 mg/m² cisplatin and 165 to 175 mg/m² paclitaxel every 21 days (2 cycles) prior to radical hysterectomy, followed by adjuvant chemotherapy and radiotherapy if needed (neoadjuvant therapy, NT cohort, n=105), or received adjuvant chemotherapy and radiotherapy after radical hysterectomy adjuvant therapy, AT cohort, n=140). RESULTS In the NT cohort, 76% of patients responded to neoadjuvant chemotherapy, while 24% did not. Adverse operative, intraoperative, and postoperative outcomes were significantly more common among the non-responders (P<0.05). After 5 years, 91% of responders and 72% of non-responders survived without recurrence (P=0.0372), and 3% of responders and 28% of non-responders had died (P=0.0005). CONCLUSIONS The resistance to neoadjuvant chemotherapy is a poor prognostic factor. Neoadjuvant chemotherapy followed by radical hysterectomy and adjuvant chemotherapy/radiotherapy appears to be advantageous for cervical cancer patients who respond well to neoadjuvant chemotherapy.

Potential therapies targeting nuclear metabolic regulation in cancer.

The interplay between genetic alterations and metabolic dysregulation is increasingly recognized as a pivotal axis in cancer pathogenesis. Both elements are mutually reinforcing, thereby expediting the ontogeny and progression of malignant neoplasms. Intriguingly, recent findings have highlighted the translocation of metabolites and metabolic enzymes from the cytoplasm into the nuclear compartment, where they appear to be intimately associated with tumor cell proliferation. Despite these advancements, significant gaps persist in our understanding of their specific roles within the nuclear milieu, their modulatory effects on gene transcription and cellular proliferation, and the intricacies of their coordination with the genomic landscape. In this comprehensive review, we endeavor to elucidate the regulatory landscape of metabolic signaling within the nuclear domain, namely nuclear metabolic signaling involving metabolites and metabolic enzymes. We explore the roles and molecular mechanisms through which metabolic flux and enzymatic activity impact critical nuclear processes, including epigenetic modulation, DNA damage repair, and gene expression regulation. In conclusion, we underscore the paramount significance of nuclear metabolic signaling in cancer biology and enumerate potential therapeutic targets, associated pharmacological interventions, and implications for clinical applications. Importantly, these emergent findings not only augment our conceptual understanding of tumoral metabolism but also herald the potential for innovative therapeutic paradigms targeting the metabolism-genome transcriptional axis.

Effects of somatostatin analogs on uptake of radiolabeled somatostatin analogs on imaging: a systematic review and meta-analysis.

Background: The imaging of somatostatin receptors (SSTRs) plays a significant role in imaging neuroendocrine tumors (NETs). However, there has been no clear definition on whether it is necessary to withdraw somatostatin analogs (SSAs) before SSTRs imaging. We aimed to assess whether nonradioactive SSAs affect the uptake of radiolabeled SSAs on imaging for NETs patients. Methods: The databases of PubMed, Embase, and Web of Science (WoS) were searched until March 12, 2022 to identify eligible studies. Maximum standardized uptake values (SUVmax) in tumor and normal tissues were extracted, pooled, and compared before and after SSAs treatment. The change of tumor-to-background/liver ratio was also described. The quality of each study was assessed using the revised Quality Assessment of Diagnostic Accuracy Studies-2 tool. Results: A total of 9 articles involving 285 patients were included and 5 studies using Gallium-68-labeled [1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid]-D-Phe1-Tyr3-Thr8-octreotide (68Ga-DOTATATE) were used for pooled evaluation. We found a significantly decreased SUVmax in the liver (9.56±2.47 vs. 7.62±2.12, P=0.001) and spleen (25.74±7.14 vs. 20.39±6.07, P=0.006) after SSAs treatment whereas no significant differences were observed in the uptake of thyroid, adrenal, and pituitary gland. For either primary tumor sites or metastases, the SUVmax did not change significantly before and after SSAs treatment. The tumor-to-liver/background ratio increased following SSAs therapy. High heterogeneity was observed across the studies, mainly due to inherent diversity of study design, sample size, and scanning technique. Conclusions: Based on current evidence, long-acting SSAs therapy before imaging has no effect on the uptake of radiolabeled SSAs at tumor primary sites and metastatic lesions, but results in a significant reduction of uptake in the liver and spleen. These findings may implicate the unnecessary discontinuation of SSAs before radiolabeled SSAs imaging.

Acquired resistance to KRAS G12C small-molecule inhibitors via genetic/nongenetic mechanisms in lung cancer.

Inherent or acquired resistance to sotorasib poses a substantialt challenge for NSCLC treatment. Here, we demonstrate that acquired resistance to sotorasib in isogenic cells correlated with increased expression of integrin ß4 (ITGB4), a component of the focal adhesion complex. Silencing ITGB4 in tolerant cells improved sotorasib sensitivity, while overexpressing ITGB4 enhanced tolerance to sotorasib by supporting AKT-mTOR bypass signaling. Chronic treatment with sotorasib induced WNT expression and activated the WNT/ß-catenin signaling pathway. Thus, silencing both ITGB4 and ß-catenin significantly improved sotorasib sensitivity in tolerant, acquired, and inherently resistant cells. In addition, the proteasome inhibitor carfilzomib (CFZ) exhibited synergism with sotorasib by down-regulating ITGB4 and ß-catenin expression. Furthermore, adagrasib phenocopies the combination effect of sotorasib and CFZ by suppressing KRAS activity and inhibiting cell cycle progression in inherently resistant cells. Overall, our findings unveil previously unrecognized nongenetic mechanisms underlying resistance to sotorasib and propose a promising treatment strategy to overcome resistance.

Astaxanthin attenuated cigarette smoke extract-induced apoptosis via decreasing oxidative DNA damage in airway epithelium.

Chronic obstructive pulmonary disease (COPD) is a lung inflammatory disease that is associated with environmental allergic component exposure. Cigarette smoke is an environmental toxicant that induces lung malfunction leading to various pulmonary diseases. Astaxanthin (AST) is a carotenoid that shows antioxidant and anti-inflammatory activities which might be a promising candidate for COPD therapy. In this study, we released that AST could attenuate cigarette smoke-induced DNA damage and apoptosis in vivo and in vitro. AST administration ameliorated cigarette smoke extract (CSE)-induced activation of Caspase-3 and apoptosis. Pretreated mice with AST significantly decrease CSE-induced DNA damage which shows lower nuclear γ-H2AX level. AST treatment also dramatically reduces the production of intracellular reactive oxygen species (ROS) by suppressing the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme 4 (NOX4) and dual oxidase 1 (DUOX1). Taken together, this study suggested that AST can decrease CSE-induced DNA damage and apoptosis by inhibiting NOX4/DUOX1 expression that promotes ROS generation. AST may be a potential protective agent against CSE-associated lung disease that is worth in-depth investigation.

Targeting ITGB4/SOX2-driven lung cancer stem cells using proteasome inhibitors.

This study investigates the role of integrin ß4 (ITGB4) and stemness-associated factor SOX2 in platinum resistance in lung squamous cell carcinoma (LUSC). The expression of SOX2 and ITGB4 is found to be high in all LUSC subtypes, but the impact of ITGB4 expression on overall patient survival varies by subtype. Cancer stem cells (CSCs) isolated from LUSC patients were found to be resistant to cisplatin, but knocking down ITGB4 or SOX2 sensitized them to cisplatin. Carfilzomib (CFZ) synergized with cisplatin and suppressed CSC growth by inhibiting ITGB4 and SOX2 expression. Additionally, CFZ was found to inhibit SOX2 expression epigenetically by inhibiting histone acetylation at the SOX2 promoter site. CFZ also suppressed the growth of SOX2-dependent small cell lung cancer cells in vitro and in vivo. The study highlights the unique function of CFZ as a transcriptional suppressor of SOX2, independent of its proteasome inhibitory function.

Magnetic Fluorescent Bead-Based Dual-Reporter Flow Analysis of PDL1-Vaxx Peptide Vaccine-Induced Antibody Blockade of the PD-1/PD-L1 Interaction.

The inhibition of checkpoint receptors (PD-1, PD-L1, and CTLA-4) with monoclonal antibodies has shown great benefit in clinical trials for treating cancer patients and has become a mainstay approach in modern cancer immunotherapy. However, only a subset of patients respond to checkpoint monoclonal antibody immunotherapy. Therefore, it is urgent to develop new therapeutic strategies against cancer. A novel B-cell peptide epitope PDL1 (programmed death ligand 1) cancer vaccine has been developed, with amino acids 130-147 linked to the MVF peptide ("promiscuous" T-cell measles virus fusion protein) via a GPSL linker. Preclinical testing has indicated that this PDL1 vaccine (PDL1-Vaxx) effectively stimulates highly immunogenic antibodies in animals. Animals immunized with PDL1-Vaxx show reduced tumor burden and extended survival rates in various animal cancer models. The mechanisms of action indicate that vaccine-elicited antibodies inhibit tumor cell proliferation, induce apoptosis, and block the PD-1/PD-L1 interaction. This manuscript introduces a magnetic bead-based assay that uses a dual-reporter flow analysis system to evaluate the PD-1/PD-L1 interaction and its blockade by the anti-PDL1 antibodies raised against the PDL1-Vaxx.