Kukoamine A alleviates nephrolithiasis by inhibiting endogenous oxalate synthesis via the IL-6/JAK/STAT3/DAO signaling pathway.

BACKGROUND: The recurrent nature and socioeconomic burden of nephrolithiasis demand effective treatments. Delineating the crosstalk between inflammatory processes and the endogenous oxalate metabolism pathway, which underpins nephrolithiasis pathogenesis, is essential for advancing treatment strategies. PURPOSE: We aim to screen therapeutic Chinese herbal remedies and their bioactive constituents for kidney stone treatment using a fruit fly model, followed by efficacy and mechanism validation in a rodent nephrolithiasis model as well as in vitro human cell culture model. STUDY DESIGN AND METHODS: We developed a fruit fly model to screen for efficient traditional Chinese medicine herbs and their active compounds for kidney stone treatment. Candidate active compounds from efficient herbs were separated and identified by solid-phase chromatography coupled with LC-MS analysis. Fruit fly genetic tools were employed to manipulate the expression of related genes to explore the therapeutic mechanisms of the Lycii Cortex and kukoamine A (KuA). To confirm the therapeutic effects and mechanisms of KuA for mammalian nephrolithiasis, mouse model of glyoxylate-induced kidney stone and human renal tubular cells were used. The therapeutic role of kukoamine A in nephrolithiasis was evaluated by assessing tubular injury, crystal deposition, and adhesion. The level of expression and phosphorylation in cells and mice was assessed using RT-qPCR and western blot. RESULTS: Our findings indicate that Lycii Cortex potently inhibits calcium oxalate stone formation via activation of the JNK/Upd3/JAK/STAT signaling cascade, resulting in diminished endogenous oxalate synthesis by downregulating D-amino acid oxidase (DAO) gene expression, predominantly in fruit fly Malpighian tube stellate cells. KuA was identified as the principal bioactive constituent mediating these effects. Both mouse models and human cell assays confirmed KuA's efficacy in preventing calcium oxalate nephrolithiasis in mammals, through hepatic JAK/STAT3 pathway activation and upregulation of IL-6, culminating in reduced urinary crystal deposition. CONCLUSION: Our research underscores the potential of kukoamine A as a lead compound in treating nephrolithiasis and reveals the interplay between the IL-6/JAK/STAT3 inflammatory pathway and endogenous oxalate metabolism in nephrolithiasis pathogenesis. Additionally, it highlights the utility of the fruit fly model as a powerful tool for deciphering the therapeutic mechanisms of traditional Chinese herbs.

CXCR4-Targeted 68 Ga-Pentixafor PET/CT Imaging in Inflammatory Bowel Disease.

PURPOSE: To investigate the role of CXCR4-targeted 68 Ga-pentixafor PET/CT imaging in inflammatory bowel disease (IBD). METHODS: Five IBD patients and 12 control subjects performing 68 Ga-pentixafor PET/CT examinations were included. 68 Ga-pentixafor PET/CT imaging and endoscopic findings were recorded and compared. The semiquantitative parameters of 68 Ga-pentixafor uptake by the lesion segments in IBD patients and the normal intestines in the control were investigated. RESULTS: Among these 5 IBD patients, endoscopy successfully examined a total of 26 intestinal segments, with 13 segments showing endoscopic lesions. 68 Ga-pentixafor PET/CT was positive in all endoscopy-proven lesions (13/13). Additionally, 68 Ga-pentixafor PET/CT revealed the lesions in small intestines and colons that cannot be reached by endoscopy due to severe stenosis, and mesenteric lymphadenitis accompanied IBD. The SUV max of the lesion segments in IBD patients was significantly higher than that of the normal intestines in the control group (median, 3.15 [range, 1.61-6.26] vs 1.67 [1.18-2.29], P < 0.001). Moreover, the SUV max ratios of the lesion segments/liver or blood pool were higher when compared with the control (2.20 [1.13-3.26] vs 0.85 [0.54-1.20]; 1.66 [0.94-2.95] vs 0.67 [0.52-1.04]; P ≤ 0.001). CONCLUSIONS: 68 Ga-pentixafor PET/CT can be a potentially valuable tool to assess the active intestinal lesions of IBD with high sensitivity. Moreover, this noninvasive approach does not require fasting or bowel preparation, offering good tolerance and safety.

Self-Referenced Au Nanoparticles-Coated Glass Wafers for In Situ SERS Monitoring of Cell Secretion.

Surface-enhanced Raman spectroscopy (SERS) is a powerful technique for discrimination of bimolecules in complex systems. However, its practical applications face challenges such as complicated manufacturing procedures and limited scalability of SERS substrates, as well as poor reproducibility during detection which compromises the reliability of SERS-based analysis. In this study, we developed a convenient method for simultaneous fabrication of massive SERS substrates with an internal standard to eliminate the substrate-to-substrate differences. We first synthesized Au@CN@Au nanoparticles (NPs) which contain embedded internal standard molecules with a single characteristic peak in the Raman-silent region, and then deposited the NPs on 6 mm glass wafers in a 96-well plate simply by centrifugation for 3 min. The one-time obtained 96 SERS substrates have excellent intrasubstrate uniformity and intersubstrate repeatability for SERS detection by using the internal standard (relative standard deviation = 10.47%), and were able to detect both charged and neutral molecules (crystal violet and triphenylphosphine) at a concentration of 10-9 M. Importantly, cells can be directly cultured on glass wafers in the 96-well plate, enabling real time monitoring of the secretes and metabolism change in response to external stimulation. We found that the release of nucleic acids, amino acids and lipids by MDA-MB-231 cells significantly increased under hypoxic conditions. Overall, our approach enables fast and large-scale production of Au@CN@Au NPs-coated glass wafers as SERS substrates, which are homogeneous and highly sensitive for monitoring trace changes of biomolecules.

LATS1 inhibitor and zinc supplement synergistically ameliorates contrast-induced acute kidney injury: Induction of Metallothionein-1 and suppression of tubular ferroptosis.

Contrast-induced acute kidney injury (CI-AKI) is a prevalent cause of renal dysfunction among hospitalized patients, yet the precise pathogenesis and effective therapeutic strategies remain elusive. In this study, we investigated the role of tubular ferroptosis in both experimental CI-AKI models and in primary tubular epithelial cells (PTECs) treated with ioversol. Using whole exome sequencing, we identified metallothioneins (MTs) as being among the most significantly downregulated genes following ioversol exposure. Our findings reveal that overexpression of Mt1 mitigates, whereas suppression of Mt-1 exacerbates, ioversol-induced tubular ferroptosis. Interestingly, the level of MTF1 (metal regulatory transcription factor 1), a principal regulator of Mt1, was found to increase in response to ioversol treatment. We further elucidated that ioversol activates LATS1 (Large tumor suppressor homolog 1), a kinase that promotes the phosphorylation and nuclear translocation of MTF1, thereby inhibiting its transcriptional activity for Mt1. Both genetic and pharmacological inhibition of LATS1 reversed the ioversol-induced suppression of Mt-1. From a therapeutic perspective, the LATS1 inhibitor TDI-011536, in combination with zinc acetate, was administered to a rodent model of CI-AKI. Our data indicate that this combination synergistically upregulates Mt1 expression and provides protection against contrast media-induced tubular ferroptosis. In summary, our study demonstrates that the reduction of Mt-1 contributes to tubular ferroptosis associated with CI-AKI. We show that contrast media activate LATS1, which in turn suppresses the transcriptional activity of MTF1 for Mt1. Herein, the combination of zinc acetate and a LATS1 inhibitor emerges as a potential therapeutic approach for the treatment of CI-AKI.

Neoadjuvant sintilimab plus chemotherapy in EGFR-mutant NSCLC: Phase 2 trial interim results (NEOTIDE/CTONG2104).

The clinical efficacy of neoadjuvant immunotherapy plus chemotherapy remains elusive in localized epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Here, we report interim results of a Simon's two-stage design, phase 2 trial using neoadjuvant sintilimab with carboplatin and nab-paclitaxel in resectable EGFR-mutant NSCLC. All 18 patients undergo radical surgery, with one patient experiencing surgery delay. Fourteen patients exhibit confirmed radiological response, with 44% achieving major pathological response (MPR) and no pathological complete response (pCR). Similar genomic alterations are observed before and after treatment without influencing the efficacy of subsequent EGFR-tyrosine kinase inhibitors (TKIs) in vitro. Infiltration and T cell receptor (TCR) clonal expansion of CCR8+ regulatory T (Treg)hi/CXCL13+ exhausted T (Tex)lo cells define a subtype of EGFR-mutant NSCLC highly resistant to immunotherapy, with the phenotype potentially serving as a promising signature to predict immunotherapy efficacy. Informed circulating tumor DNA (ctDNA) detection in EGFR-mutant NSCLC could help identify patients nonresponsive to neoadjuvant immunochemotherapy. These findings provide supportive data for the utilization of neoadjuvant immunochemotherapy and insight into immune resistance in EGFR-mutant NSCLC.

11C-CFT PET brain imaging in Parkinson's disease using a total-body PET/CT scanner.

PURPOSE: This study aimed to evaluate the feasibility of 11C-CFT PET brain imaging in Parkinson's Disease using a total-body PET/CT scanner and explore the optimal scan duration to guide the clinical practice. METHODS: Thirty-two patients with Parkinson's disease (PD) performing 11C-CFT PET/CT brain imaging using a total-body PET/CT scanner were retrospectively enrolled. The PET data acquired over a period of 900 s were reconstructed into groups of different durations: 900-s, 720-s, 600-s, 480-s, 300-s, 180-s, 120-s, 60-s, and 30-s (G900 to G30). The subjective image quality analysis was performed using 5-point scales. Semi-quantitative measurements were analyzed by SUVmean and dopamine transporter (DAT) binding of key brain regions implicated in PD, including the caudate nucleus and putamen. The full-time images (G900) were served as reference. RESULTS: The overall G900, G720, and G600 image quality scores were 5.0 ± 0.0, 5.0 ± 0.0, and 4.9 ± 0.3 points, respectively, and there was no significant difference among these groups (P > 0.05). A significant decrease in these scores at durations shorter than 600 s was observed when compared to G900 images (P < 0.05). However, all G300 image quality was clinically acceptable (≥ 3 points). As the scan duration reduced, the SUVmean and DAT binding of caudate nucleus and putamen decreased progressively, while there were no statistically significant variations in the SUVmean of the background among the different groups. Moreover, the changes in the lesion DAT binding (ΔDAT-binding) between the full-time reference G900 image and other reconstructed group G720 to G30 images generally increased along with the reduced scan time. CONCLUSION: Sufficient image quality and lesion conspicuity could be achieved at 600-s scan duration for 11C-CFT PET brain imaging in PD assessment using a total-body PET/CT scanner, while the image quality of G300 was acceptable to meet clinical diagnosis, contributing to improve patient compliance and throughput of PET brain imaging.

"Triple-Punch" Strategy Exosome-Mimetic Nanovesicles for Triple Negative Breast Cancer Therapy.

Triple-negative breast cancer (TNBC) is the most malignant breast cancer, with high rates of relapse and metastasis. Because of the nonspecific targeting of chemotherapy and insurmountable aggressiveness, TNBC therapy lacks an effective strategy. Exosomes have been reported as an efficient drug delivery system (DDS). CD82 is a tumor metastasis inhibitory molecule that is enriched in exosomes. Aptamer AS1411 specifically targets TNBC cells due to its high expression of nucleolin. We generated a "triple-punch" cell membrane-derived exosome-mimetic nanovesicle system that integrated with CD82 overexpression, AS1411 conjugation, and doxorubicin (DOX) delivery. CD82 enrichment effectively inhibits the migration of TNBC cells. AS1411 conjugation specifically targets TNBC cells. DOX loading effectively inhibits proliferation and induces apoptosis of TNBC cells. Our results demonstrate a system of exosome-mimetic nanovesicles with "triple-punch" that may facilitate TNBC therapeutics.

Implications of Sarcopenia and Glucometabolism Parameters of Muscle Derived From Baseline and End-of-Treatment 18F-FDG PET/CT in Diffuse Large B-Cell Lymphoma.

OBJECTIVE: We previously found that the incidence of sarcopenia increased with declining glucose metabolism of muscle in patients with treatment-naïve diffuse large B-cell lymphoma (DLBCL). This study aimed to investigate the relationship between sarcopenia and muscle glucometabolism using 18F-FDG PET/CT at baseline and end-of-treatment, analyze the changes in these parameters through treatment, and assess their prognostic values. MATERIALS AND METHODS: The records of 103 patients with DLBCL (median 54 years [range, 21-76]; male:female, 50:53) were retrospectively reviewed. Skeletal muscle area at the third lumbar vertebral (L3) level was measured, and skeletal muscle index (SMI) was calculated to determine sarcopenia, defined as SMI < 44.77 cm²/m² and < 32.50 cm²/m² for male and female, respectively. Glucometabolic parameters of the psoas major muscle, including maximum standardized uptake value (SUVmax) and mean standardized uptake value (SUVmean), were measured at L3 as well. Their changes across treatment were also calculated as ΔSMI, ΔSUVmax, and ΔSUVmean; Δbody mass index was also calculated. Associations between SMI and the metabolic parameters were analyzed, and their associations with progression-free survival (PFS) and overall survival (OS) were identified. RESULTS: The incidence of sarcopenia was 29.1% and 36.9% before and after treatment, respectively. SMI (P = 0.004) was lower, and sarcopenia was more frequent (P = 0.011) at end-of-treatment than at baseline. The SUVmax and SUVmean of muscle were lower (P < 0.001) in sarcopenia than in non-sarcopenia at both baseline and end-of-treatment. ΔSMI was positively correlated with ΔSUVmax of muscle (P = 0.022). Multivariable Cox regression analysis showed that sarcopenia at end-of-treatment was independently negatively associated with PFS (adjusted hazard ratio [95% confidence interval], 2.469 [1.022-5.965]), while sarcopenia at baseline was independently negatively associated with OS (5.051 [1.453-17.562]). CONCLUSION: Sarcopenic patients had lower muscle glucometabolism, and the muscular and metabolic changes across treatment were positively correlated. Sarcopenia at baseline and end-of-treatment was negatively associated with the prognosis of DLBCL.

Four-Color SERS Monitoring of Size-dependent Nanoparticle Delivery in the Same Tumor.

The physicochemical properties of nanoparticles (NPs) significantly influence their deposition at the disease site, ultimately impacting the overall therapeutic efficacy; however, precisely assessing the effects of various factors on NP accumulation within a single cell/tumor tissue is challenging due to the lack of appropriate labeling techniques. Surface-enhanced Raman spectroscopy (SERS) tag is a powerful encoding method that has recently been intensively employed for immunodetection of biomarkers. Herein, we introduce a multiplexed SERS tracking approach for systematic investigation of size-dependent accumulation and distribution of NPs within the same tumor. Four-sized (34, 60, 108, and 147 nm) NPs encoded with different SERS "colors" were fabricated, mixed, and incubated with monolayer tumor cells, multicellular tumor spheroids, or injected into mouse models bearing xenograft solid tumors in a single dose. Multicolor SERS detection of the specimens revealed that NP accumulation in tumor cells, tumor spheroids, and solid tumors was in the order of 34 nm > 60 nm > 108 nm > 147 nm, 60 nm > 34 nm > 108 nm > 147 nm, and 34 nm > 147 nm > 108 nm > 60 nm, respectively. Inductively coupled plasma mass spectroscopy determination performed in parallel samples were in alignment with the four-color SERS probing results, demonstrating the effectiveness of this multiplexed evaluation assay. Furthermore, in combination with fluorescence labeling of specific biomolecules, this method can be applied for the colocalization of different NPs in various pathological structures and provide additional information for analysis of the possible mechanisms.

2, 2-dimethylthiazolidine hydrochloride protects against experimental contrast-induced acute kidney injury via inhibition of tubular ferroptosis.

Contrast-induced acute kidney injury (CI-AKI) has become the third leading cause of AKI acquired in hospital, lacking of effective interventions. In the study, we identified the renal beneficial role of 2, 2-dimethylthiazolidine hydrochloride (DMTD), a safer compound which is readily hydrolyzed to cysteamine, in the rodent model of CI-AKI. Our data showed that administration of DMTD attenuated the impaired renal function and tubular injury induced by the contrast agent. Levels of MDA, 4-hydroxynonenal, ferrous iron and morphological signs showed that contrast agent induced ferroptosis, which could be inhibited in the DMTD group. In vitro, DMTD suppressed ferroptosis induced by ioversol in the cultured tubular cells. Treatment of DMTD upregulated glutathione (GSH) and glutathione peroxidase 4 (GPX4). Moreover, we found that DMTD promoted the ubiquitin-mediated proteasomal degradation of Keap1, and thus increased the activity of nuclear factor erythroid 2-related factor 2 (Nrf2). Mechanistically, increase of the ubiquitylation degradation of Keap1 mediates the upregulated effect of DMTD on Nrf2. Consequently, activated Nrf2/Slc7a11 results in the increase of GSH and GPX4, and therefore leads to the inhibition of ferroptosis. Herein, we imply DMTD as a potential therapeutic agent for the treatment of CI-AKI.

Role of body composition and metabolic parameters extracted from baseline 18F-FDG PET/CT in patients with diffuse large B-cell lymphoma.

This study aimed to clarify the clinical and prognostic role of body composition and metabolic parameters extracted from baseline 18F-FDG PET/CT in patients with diffuse large B-cell lymphoma (DLBCL). We retrospectively collected the clinicopathological and 18F-FDG PET/CT parameters of 181 DLBCL patients. The indexes of skeletal muscle, subcutaneous adipose tissue, and visceral adipose tissue were calculated using the area measured at the 3rd lumbar level normalized for height. Additionally, the metabolic activity of corresponding muscle and adipose tissue, and maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of all lesions were measured. Survival endpoints included progression-free survival (PFS) and overall survival (OS). We identified 75 (41.4%) patients with low skeletal muscle index (sarcopenia), presenting risk factors including male, high ß2-microglobulin, low BMI, high visceral adipose tissue index, low SUVmax of skeletal muscle, and high SUVmax of visceral adipose tissue. Male, low BMI, low visceral adipose tissue index, and high SUVmax of subcutaneous adipose tissue were risk factors for low subcutaneous adipose tissue index diagnosed in 105 (58.0%) patients. In total, 132 (79.2%) patients represented low visceral adipose tissue index, associated with younger age, B symptoms, and low BMI. Eastern Cooperative Oncology Group (ECOG) status, sarcopenia, and visceral adipose tissue index were found independently predictive of PFS and OS, while ß2-microglobulin was independently predictive of OS. In conclusion, body composition indexes were correlated with both clinical characteristics and 18F-FDG PET/CT metabolic parameters, significantly impacting survival, such that sarcopenia and high visceral adipose tissue index were powerful predictors of poor DLBCL outcomes.

18 F-fluorodeoxyglucose PET/computed tomography metabolic parameters and sarcopenia in pancreatic cancer.

OBJECTIVE: This study aimed to investigate the association between 18 F-fluorodeoxyglucose ( 18 F-FDG) PET/computed tomography (CT) and clinicopathological characteristics and sarcopenia in patients with pancreatic cancer and to determine their prognostic roles. METHODS: Clinicopathological factors and 18 F-FDG PET/CT metabolic parameters of maximum standard uptake value, metabolic tumor volume, and total lesion glycolysis of the primary tumor (SUVmax_P, MTV_P, and TLG_P) and of whole-body lesions (MTV_T and TLG_T) were retrospectively reviewed in 113 pretreatment patients with pancreatic cancer. Sarcopenia was defined based on skeletal muscle index (SMI) calculated at the third lumbar vertebra (L3), and SUVmax of the psoas major muscle (SUVmax_M) was measured at L3 as well. The primary endpoint used was the overall survival (OS). RESULTS: Among 113 patients, 49 patients (43.4%) were diagnosed with sarcopenia. Compared with nonsarcopenia, sarcopenia more frequently occurred in the older population ( P  = 0.027), males ( P  = 0.014), and lower BMI ( P  < 0.001), and displayed lower SUVmax_M ( P  = 0.011). Age, sex, BMI, and SUVmax_M were independently predictive of sarcopenia. Multivariate Cox regression analysis revealed that tumor stage ( P  = 0.010) and TLG_T ( P  < 0.001) were independently predictive of OS. CONCLUSION: Sarcopenia increased with declining SUVmax_M in pancreatic cancer. Compared with SMI, SUVmax_M offers a more straightforward prediction of sarcopenia, thus a promising measurement to be incorporated into the diagnostic algorithm. Tumor stage and TLG_T, but not sarcopenia, were independent prognostic factors of pancreatic cancer.

Ultrasensitive iodide detection in biofluids based on hot electron-induced reduction of p-Nitrothiophenol on Au@Ag core-shell nanoparticles.

Surveillance of iodine intake is important because either inadequate or excessive amount of iodine may lead to thyroid malfunctions. Herein, we report a method for fast iodide quantification based on a plasmonic hot electron-driven chemical reaction, which occurs on Au@Ag core-shell nanoparticles (NPs) coated with p-nitrothiophenol (PNTP) molecules. Upon resonant light illumination, hot electron-hole pairs are generated in the NPs. The hot holes capture iodide ions (I-) and form AgI which decomposes under light; while the hot electrons are shifted to the electron orbital (LUMO) of PNTP and trigger its reduction to p-aminothiophenol (PATP). By measuring characteristic surface-enhanced Raman spectroscopic (SERS) peaks of PNTP and PATP, the concentration of I- in water can be quantitatively determined, with a linear response in the 0.5-20 µM range and a detection limit of 0.30 µM. The Au@Ag nanosensor was then applied for I- detection in various biofluids including urine, serum and saliva, exhibiting superior detection sensitivity and high selectivity. This sensing assay requires a small sample volume of ∼10 µL and completes the entire detection process in ∼2 min, and therefore holds significant potential for application in point-of-care settings.

PDIA4 confers resistance to ferroptosis via induction of ATF4/SLC7A11 in renal cell carcinoma.

The prognosis of renal cell carcinoma (RCC) remains poor due to metastases and resistance to chemotherapy. Salinomycin (Sal) exhibits the potential of antitumor, while the underlying mechanism is not completely clear. Here, we found that Sal induced ferroptosis in RCCs and identified Protein Disulfide Isomerase Family A Member 4 (PDIA4) as a mediator of Sal's effect on ferroptosis. Sal suppressed PDIA4 by increasing its autophagic degradation. Downregulation of PDIA4 increased the sensitivity to ferroptosis, while ectopic overexpression of PDIA4 conferred ferroptosis resistance to RCCs. Our data showed that downregulation of PDIA4 suppressed activating transcription factor 4 (ATF4) and its downstream protein SLC7A11 (solute carrier family 7 member 11), thereby aggravating ferroptosis. In vivo, the administration of Sal promoted ferroptosis and suppressed tumor progress in the xenograft mouse model of RCC. Bioinformatical analyses based on clinical tumor samples and database indicated a positive correlation exists between PDIA4 and PERK/ATF4/SLC7A11 signaling pathway, as well as the malignant prognosis of RCCs. Together, our findings reveal that PDIA4 promotes ferroptosis resistance in RCCs. Treatment of Sal sensitizes RCC to ferroptosis via suppressing PDIA4, suggesting the potential therapeutical application in RCCs.

Usefulness of 18 F-FDG PET/computed tomography metabolic parameters in predicting sarcopenia and prognosis of treatment-naive patients with non-small cell lung cancer.

PURPOSE: Sarcopenia tremendously impacts the quality of life but remains debatable in prognostication in treatment-naive patients with non-small cell lung cancer (NSCLC). Hence, this study aimed to find a clinically feasible approach using 18 F-FDG PET/computed tomography (CT) imaging parameters and clinical characteristics to predict sarcopenia and determine independent prognostic factors. METHODS: Clinical characteristics and 18 F-FDG PET/CT metabolic parameters, including maximum standard uptake value, metabolic tumor volume, and total lesion glycolysis of primary tumor (SUVmax_P, MTV_P, and TLG_P) and combination of whole-body lesions (MTV_C and TLG_C) were collected in 344 treatment-naive patients with NSCLC. Skeletal muscle index at the third lumbar vertebra was calculated to determine sarcopenia. SUVmax of the psoas major muscle (SUVmax_M) was measured at the third lumbar vertebra as well. The diagnostic endpoint is the probability of sarcopenia, and the survival endpoints include progression-free survival (PFS) and overall survival (OS). RESULTS: Among 344 patients with NSCLC there were 271 patients with adenocarcinoma and 73 with squamous cell carcinoma (SCC). One hundred forty-seven patients (42.7%) were diagnosed with sarcopenia. Higher age, male, lower BMI, SCC, and lower SUVmax_M were correlated with a higher incidence of sarcopenia ( P < 0.05), while age, sex and SUVmax_M were independently predictive of sarcopenia. Multivariate Cox-regression analysis revealed that BMI, advanced stage and TLG_C were independent predictors of PFS and OS, while sex was independently predictive of OS. CONCLUSIONS: The incidence of sarcopenia increased with declining SUVmax of muscle. BMI, tumor stage, and TLG_C, but not sarcopenia, were found independently predictive of both PFS and OS.

KDM6B regulates M2 polarization of macrophages by modulating the stability of nuclear ß-catenin.

Accumulating evidences suggest that the epigenetic regulation plays a pivotal role in establishing phenotype and function of tumor associated macrophages (TAMs). KDM6B is an epigenetic enzyme responsible for the H3K27me3 and reported to influence macrophage polarization. However, the underlying mechanism remains to be determined. Here, we demonstrated that inhibition of KDM6B in TAMs increased M2 polarization induced by coculture of breast cancer cells. Furthermore, we identified that KDM6B downregulation activated ß-catenin/c-Myc signaling, and thus promoted the M2-like phenotype. KDM6B accelerated the intranuclear ubiquitination degradation of ß-catenin, which depended on its demethylase activity. Therapeutically, our data showed that activated vitamin D analog paricalcitol upregulated the expression of KDM6B and decreased the M2 polarization, consequently protected against tumor progress in the xenograft mouse model of breast cancer. Taken together, our data reveal that epigenetic regulator KDM6B prevents M2 polarization via promoting the intranuclear degradation of ß-catenin. Active vitamin D analog induces KDM6B and suppresses tumor progress, suggesting a novel therapeutic potential of epigenetic modulation for the tumor treatment.

18F-FDG PET/CT and contrast-enhanced CT in the diagnosis of Castleman disease.

OBJECTIVE: Castleman disease (CD) is a rare group of lymphoproliferative disorders, which is easily confused with lymphoma or other solid tumors. Hence, this study aimed to investigate the diagnostic role of 18F-FDG PET/CT and contrast-enhanced CT (CECT) in patients with CD. METHODS: Clinicopathological characteristics, and 18F-FDG PET/CT and CECT findings and parameters were retrospectively reviewed in 32 patients with CD. RESULTS: These 32 patients (12 males, 20 females; median age, 41 years) consisted of 17 unicentric CD (UCD) patients and 15 multicentric CD (MCD) patients. Compared with MCD, UCD had a higher prevalence in female (82.4% vs. 40.0%) and hyaline vascular subtype (94.1% vs. 40.0%) (P < 0.05). FDG uptake was avid in all cases, including moderate uptake in 7 cases and intense uptake in 25 cases. The median SUVmax, SUVmean, MLV, and TLG of all cases were 4.4 (range, 1.4-23.6), 2.7 (range, 1.1-15.2), 26.6 (range, 4.8-393.0), and 78.8 (range, 9.4-1545.6), respectively. The lesions of 29 cases showed homogeneous enhancement, and marked enhancement was observed in 27 cases. 18F-FDG PET/CT corrected 6.3% CECT diagnoses, while CECT corrected 37.5% PET/CT diagnosis. The accuracy of combined PET/CT and CECT was superior to PET/CT or CECT alone (78.1%, 31.3%, and 62.5%). Besides, higher SUVmax and SUVmean were found in male subjects, MCD, and plasma cell subtype (P < 0.05), while higher MLV and TLG were observed in larger lesion size and volume (P < 0.05). CONCLUSION: Castleman disease most commonly appears as marked and homogeneous enhancement meanwhile with moderate or intense FDG uptake. 18F-FDG PET/CT combined with CECT was the effectively diagnostic modality for CD. The glucose metabolism of CD was associated with gender, clinical classification, histopathological classification, and lesion size and volume.

Invasive mucinous adenocarcinoma of the lung: clinicopathological features, 18F-FDG PET/CT findings, and survival outcomes.

OBJECTIVE: Invasive mucinous adenocarcinoma (IMA) is a rare subtype of lung adenocarcinoma. This study aimed to retrospectively evaluate the clinicopathological features, 18F-FDG PET/CT findings, and prognosis of IMA of the lung, as well as to investigate the associations among these variables, to improve the management of such patients. METHODS: Clinicopathological and 18F-FDG PET/CT characteristics of 72 patients with pathologically confirmed IMA of the lung were retrospectively collected and investigated, and their predictive efficacy on progression-free survival (PFS) was evaluated. RESULTS: The median age of the enrolled 72 patients was 61 years (range, 26-79 years), and the male-to-female ratio was 1:1.25. According to the radiological morphology of IMA, solidary nodule/mass type (n = 59, 81.9%) was the most common, followed by GGO type (n = 8, 11.1%) and pneumonia type (n = 5, 6.9%). Lobulated or spiculated margin and pleural traction were the most common radiological signs. The median SUVmax of IMA lesions was 3.0, ranging from 0.5 to 23.1. Higher SUVmax was observed in IMA with non-GGO type, clinical symptom, advanced stage, lobulated margin, pleural traction or spread through air spaces (STAS) (P < 0.05). Moreover, higher SUVmax was related to larger tumor size in non-pneumonia-type IMA (r = 0.708, P < 0.001). The median PFS was 21.3 months, and the 12-, 24- and 36-month PFS rates were 89.8%, 83.3% and 75.5%, respectively. A poorer PFS was significantly associated with SUVmax ≥ 3, advanced stage and STAS. CONCLUSION: 18F-FDG PET/CT combined with clinicopathological characteristics can aid the diagnosis and prognostic evaluation of lung IMA, which could provide guidance for the appropriate management of such patients.

Role of 18F-FDG PET/CT and sarcopenia in untreated non-small cell lung cancer with advanced stage.

BACKGROUND: Sarcopenia is essential in managing advanced stage (III-IV) non-small cell lung cancer (NSCLC) but is laborious to diagnose using currently available method. This study aimed to establish a simple approach to predict sarcopenia using 18F-FDG PET/CT parameters and clinical characteristics and determine their roles in prognostication in advanced stage NSCLC. METHODS: Untreated 202 NSCLC patients with stage III-IV were retrospectively reviewed. Sarcopenia was defined using the skeletal muscle index (SMI) measured at the third lumbar vertebra (L3). 18F-FDG PET/CT metabolic parameters of maximum standard uptake value, metabolic tumor volume, and total lesion glycolysis of the primary tumor (SUVmax_T, MTV_T, and TLG_T) and of whole-body lesions (MTV_WB and TLG_WB) were measured. Besides, SUVmax of the psoas major muscle (SUVmax_Muscle) was measured at the L3 level. The diagnostic endpoint was the probability of sarcopenia, and the survival endpoints included progression-free survival (PFS) and overall survival (OS). RESULTS: Among the enrolled 202 patients, 82 (40.6%) were diagnosed with sarcopenia. Higher age, male, lower BMI, and lower SUVmax_Muscle were correlated with a higher incidence of sarcopenia (P < 0.05), while age, sex, BMI, and SUVmax_Muscle were independently predictive of sarcopenia, and thus were utilized to construct a nomogram model. Multivariate Cox regression analysis revealed that sarcopenia score derived from the nomogram model, sarcopenia, stage, and TLG_WB were independently predictive of both PFS and OS. CONCLUSION: The incidence of sarcopenia increased with declining SUVmax_Muscle in advanced stage NSCLC. Our model using age, sex, BMI, and SUVmax_Muscle might be substituted for the complicated measurement of SMI. After adjustment by stage and TLG_WB, both sarcopenia score and sarcopenia were found to be independently predictive of PFS and OS.

18F-FDG PET/CT and clinicopathological characteristics of neurolymphomatosis in lymphoma patients.

OBJECTIVE: Neurolymphomatosis (NL) is a rare but serious manifestation defined as invasion of peripheral nervous system by malignant lymphocytes. Thus, this study investigated fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) and clinicopathological characteristics of NL in lymphoma patients. SUBJECTS AND METHODS: Clinicopathological and 18F-FDG PET/CT findings and treatment regimens were retrospectively investigated in 20 lymphoma patients with NL, and analyzed their correlation with progression-free survival (PFS) and overall survival (OS). RESULTS: These 20 lymphoma patients (11 males, 9 females; median age, 49 years) included 10 primary and 10 secondary NL patients. Non-Hodgkin's lymphoma (NHL) was noted in 19 patients, B-cell NHL was associated with 18 cases, and diffuse large B-cell lymphoma was the most common. Notably, 18 patients were aggressive lymphoma while 2 were indolent lymphoma. The affected neural structures included nerve roots (n=17), peripheral nerves (n=3), cranial nerves (n=3), and neural plexus (n=2). Fluorine-18-FDG was avid in all cases, and the median maximum standardized uptake value (SUVmax) of neural and all lesions was 12.2 (range, 3.3-25.6) and 15.0 (range, 4.4-34.2), respectively. The median PFS and OS of all patients were 9.3 and 14.3 months. The 12-month OS rate of 18 patients with aggressive lymphoma receiving intrathecal chemotherapy/autologous stem cell transplants (IT chem/ASCT) was significantly higher than who did not (64.8% vs 15.9%). CONCLUSION: The majority of NL occurred in patients with aggressive lymphoma, of which B-cell NHL were the predominant subtypes. Fluorine-18-FDG PET/CT imaging of NL was mainly characterized by intense glucose accumulation alongside peripheral nerves, and IT chem/ASCT was suggested to improve the outcomes of NL.