Polystyrene nanoplastics induce cardiotoxicity by upregulating HIPK2 and activating the P53 and TGF-ß1/Smad3 pathways.

Nanoplastics (NPs) pollution has become a global environmental problem, raising numerous health concerns. However, the cardiotoxicity of NPs exposure and the underlying mechanisms have been understudied to date. To address this issue, we comprehensively evaluated the cardiotoxicity of polystyrene nanoplastics (PS-NPs) in both healthy and pathological states. Briefly, mice were orally exposed to four different concentrations (0 mg/day, 0.1 mg/day, 0.5 mg/day, and 2.5 mg/day) of 100-nm PS-NPs for 6 weeks to assess their cardiotoxicity in a healthy state. Considering that individuals with underlying health conditions are more vulnerable to the adverse effects of pollution, we further investigated the cardiotoxic effects of PS-NPs on pathological states induced by isoprenaline. Results showed that PS-NPs induced cardiomyocyte apoptosis, cardiac fibrosis, and myocardial dysfunction in healthy mice and exacerbated cardiac remodeling in pathological states. RNA sequencing revealed that PS-NPs significantly upregulated homeodomain interacting protein kinase 2 (HIPK2) in the heart and activated the P53 and TGF-beta signaling pathways. Pharmacological inhibition of HIPK2 reduced P53 phosphorylation and inhibited the activation of the TGF-ß1/Smad3 pathway, which in turn decreased PS-NPs-induced cardiotoxicity. This study elucidated the potential mechanisms underlying PS-NPs-induced cardiotoxicity and underscored the importance of evaluating nanoplastics safety, particularly for individuals with pre-existing heart conditions.

Preparation of highly adsorptive biochar by sequential iron impregnation under refluxing and pyrolysis at low temperature for removal of tetracycline.

Iron-doping modification is a prevailing approach for improving adsorption capability of biochar with environmental friendliness, but usually requires high temperature and suffers from iron aggregation. Herein, a highly adsorptive biochar was manufactured via sequential disperse impregnation of iron by refluxing and pyrolysis at low temperature for eliminating tetracycline (TC) from aqueous solution. Iron oxides and hydroxides were impregnated and stably dispersed on the carbon matrix as pyrolyzed at 200 °C, meanwhile abundant oxygen and nitrogen functional groups were generated on surface. The iron-doped biochar exhibited up to 891.37 mg/g adsorption capacity at pH 5, and could be recycled with high adsorption capability. The adsorption of TC should be mostly contributed to the hydrogen bonding of N/O functional groups and the hydrogen bonding/coordination of iron oxides/hydroxides. This would provide a valuable guide for dispersedly doping iron and conserving functional groups on biochar, and a super iron-doped biochar was prepared with superior recyclability.

A novel 68Ga-labeled cyclic peptide molecular probe based on the computer-aided design for noninvasive imaging of PD-L1 expression in tumors.

Programmed death-ligand 1 (PD-L1) serves as a crucial biomarker for guiding the screening of cancer patients and the stratification of immunotherapy. However, due to the high heterogeneity of tumors, the current gold standard for detecting PD-L1 expression (immunohistochemistry) fails to comprehensively evaluate the overall PD-L1 expression levels in the body. Fortunately, the use of PD-L1 targeted radiotracers enables quantitative, real-time, and noninvasive assessment of PD-L1 expression levels and dynamics in tumors. Notably, analyzing the binding mode between the precursor and the target protein to find linker binding sites that do not affect the activity of the target molecule can greatly enhance the successful development of molecular probes. This study introduced a groundbreaking cyclic peptide molecular probe called 68Ga-DOTA-PG1. It was derived from the BMS-71 cyclic peptide and was specifically designed to evaluate the expression of PD-L1 in tumors. The radiolabeling yield of 68Ga-DOTA-PG1 surpassed 97% while maintaining a radiochemical purity of over 99%. In vitro experiments demonstrated the effective targeting of PD-L1 in tumor cells by 68Ga-DOTA-PG1, with significantly higher cellular uptake observed in A375-hPD-L1 cells (PD-L1 + ) compared to A375 cells (PD-L1-). Biodistribution and PET imaging studies consistently showed specific accumulation of 68Ga-DOTA-PG1 in A375-hPD-L1 tumors, with a maximum uptake of 11.06 ± 1.70% ID/g at 2 h, significantly higher than the tumor uptake in A375 cells (1.70 ± 0.17% ID/g). These results strongly indicated that 68Ga-DOTA-PG1 held great promise as a PET radiotracer for imaging PD-L1-positive tumors.

Biomechanical Evaluation of Fourth Generation Minimally Invasive Distal First Metatarsal Osteotomy-Akin Osteotomy Technique on First Ray Articular Contact Properties.

BACKGROUND: Hallux valgus is a common deformity encountered but remains a complex clinical entity. Fourth-generation minimally invasive surgery (MIS) techniques consisting of a percutaneous distal metatarsal transverse osteotomy combined with an Akin osteotomy have been used to address mild to severe hallux valgus deformities. The benefits of an MIS approach include improved cosmesis, faster recovery, lower opiate requirement, immediate weightbearing, and favorable outcomes relative to a traditional, open procedure. An understudied area with respect to hallux valgus correction is the effect that osteotomies can have on the articular contact properties of the first ray following correction. METHODS: Sixteen paired cadaveric specimens were dissected to include the first ray and tested in a customized apparatus. Specimens were randomized to receive a distal transverse osteotomy translated either 50% or 100% of the width of the first metatarsal shaft. The osteotomy was performed with either a 0° or 20° distal angulation of the burr relative to the shaft in the axial plane. Specimens were tested in the intact state and following the distal first metatarsal osteotomy for peak pressure, contact area, contact force and center of pressure at the first metatarsophalangeal (MTP) and first tarsometatarsal (TMT) joints. An Akin osteotomy was then performed on each specimen, and peak pressure, contact area, contact force, and center of pressure were recalculated. RESULTS: There was a notable decrease in peak pressure, contact area, and contact force across the TMT joint with greater shifts of the capital fragment. However, at 100% translation of the capital fragment, distal angulation of the osteotomy by 20° appears to improve loading across the TMT joint. Addition of the Akin osteotomy at 100% translation also aids in increasing the contact force across the TMT joint. The MTP joint is less sensitive to changes in shifts and angulation of the capital fragment. The Akin osteotomy also leads to increased contact force across the MTP joint when the capital fragment is translated 100%. CONCLUSION: While the clinical significance is unknown, larger shifts of the capital fragment lead to greater load alterations at the level of the TMT joint than the MTP joint. Distal angulation of the capital fragment and the addition of an Akin osteotomy can aid in reducing the size of those changes. The Akin can lead to increased contact forces at the MTP joint with 100% translation of the capital fragment. LEVEL OF EVIDENCE: Not applicable, Biomechanical study.

Hypomethylation of Tumor necrosis factor-like cytokine 1A(TL1A) and its decoy receptor 3 expressive level increase has diagnostic value in HBV-associated cirrhosis.

For patients with cirrhosis, early diagnosis is the key to delaying the development of liver fibrosis and improving prognosis. This study aimed to investigate the clinical significance of TL1A, which is a susceptibility gene for hepatic fibrosis, and DR3 in the development of cirrhosis and fibrosis. We analyzed the expression of TL1A, DR3, and other inflammatory cytokines associated with liver fibrosis in serum and PBMCs in 200 patients.TL1A methylation level was lower in patients with HBV-associated LC than in the other groups. In addition, the mRNA level and serum of TL1A and DR3 expression levels were found to increase in the LC. Hypomethylation of the TL1A promoter is present in HBV-associated LC, and TL1A and DR3 are highly expressed in HBV-associated cirrhosis. These results indicate that TL1A and DR3 may play an important role in the pathogenesis of LC and TL1A methylation levels may serve as a noninvasive biomarker for early diagnosis and progression of LC.

Predicting skip metastasis in lateral lymph nodes of papillary thyroid carcinoma based on clinical and ultrasound features.

Background: Skip metastasis in papillary thyroid cancer (PTC), defined as lateral lymph node metastasis (LLNM) without the involvement of central lymph node metastasis (CLNM), is generally unpredictable. Our study aimed to develop a model to predict skip metastasis by using clinicopathological and ultrasound factors of PTC. Methods: We retrospectively reviewed the medical records of patients who underwent total thyroidectomy and central lymph node dissection (CLND) plus lateral lymph node dissection (LLND) between January 2019 and December 2021 at the First Affiliated Hospital of Soochow University. Furthermore, univariate and multivariate analyses assessed the clinical and ultrasound risk factors. Receiver operating characteristic (ROC) curves were used to find the optimal cut-off values for age and dominant nodule diameter. Multivariate logistic regression analysis results were used to construct a nomogram and were validated internally. Results: In all patients, the skip metastasis rate was 15.4% (41/267). Skip metastasis was more frequently found in patients with a tumour size ≤10 mm (OR 0.439; P = 0.033), upper tumour location (OR 3.050; P=0.006) and fewer CLNDs (OR 0.870; P = 0.005). After analysing the clinical and ultrasound characteristics of the tumour, five factors were ultimately associated with lateral lymph node skip metastasis and were used to construct the model. These factors were an age >40 years, tumour diameter <9.1 mm, upper tumour location, non-smooth margin and extrathyroidal extension. The internally evaluated calibration curves indicated an excellent correlation between the projected and actual skip metastasis probability. The nomogram performed well in discrimination, with a concordance index of 0.797 (95% CI, 0.726 to 0.867). Conclusions: This study screened for predictors of skip metastasis in PTC and established a nomogram that effectively predicted the risk of potential skip metastasis in patients preoperatively. The method can predict and distinguish skip metastases in PTC in a simple and inexpensive manner, and it may have future therapeutic utility.

An iron(III) complex-based supramolecular organic framework (SOF) as a theranostic platform via magnetic resonance imaging-guided chemotherapy.

It is crucially important to explore the additional metal-endowed functions of supramolecular organic frameworks (SOFs) for expanding their applications. In this work we have reported the performance of a SOF (designated as Fe(III)-SOF) as a theranostic platform via magnetic resonance imaging (MRI)-guided chemotherapy. The Fe(III)-SOF may be used as an MRI contrast agent for cancer diagnosis because the building unit (iron complex) contains high spin iron(III) ions. Additionally, the Fe(III)-SOF may also be used as a drug carrier because it possesses stable internal voids. We loaded doxorubicin (DOX) into the Fe(III)-SOF to obtain a DOX@Fe(III)-SOF. The Fe(III)-SOF showed good loading content (16.3%) and high loading efficiency (65.2%) for DOX. Additionally, the DOX@Fe(III)-SOF had a relatively modest relaxivity value (r2 = 19.745 mM-1 s-1) and exhibited the strongest negative contrast (darkest) at 12 h of post-injection. Furthermore, the DOX@Fe(III)-SOF effectively inhibited tumor growth and showed high anticancer efficiency. In addition, the Fe(III)-SOF was biocompatible and biosafe. Therefore, the Fe(III)-SOF was an excellent theranostic platform and may have potential applications in tumor diagnosis and treatment in the future. We believe that this work will initiate extensive research endeavors not only on the development of SOFs, but also on the construction of theranostic platforms based on SOFs.

Prognostic value of 18F-FDG PET/CT radiomic model based on primary tumor in patients with non-small cell lung cancer: A large single-center cohort study.

Objectives: In the present study, we aimed to determine the prognostic value of the 18F-FDG PET/CT-based radiomics model when predicting progression-free survival (PFS) and overall survival (OS) in patients with non-small cell lung cancer (NSCLC). Methods: A total of 368 NSCLC patients who underwent 18F-FDG PET/CT before treatment were randomly assigned to the training (n = 257) and validation (n = 111) cohorts. Radiomics signatures from PET and CT images were obtained using LIFEx software, and then clinical and complex models were constructed and validated by selecting optimal parameters based on PFS and OS to construct radiomics signatures. Results: In the training cohort, the C-index of the clinical model for predicting PFS and OS in NSCLC patients was 0.748 and 0.834, respectively, and the AUC values ​​were 0.758 and 0.846, respectively. The C-index of the complex model for predicting PFS and OS was 0.775 and 0.881, respectively, and the AUC values ​​were 0.780 and 0.891, respectively. The C-index of the clinical model for predicting PFS and OS in the validation group was 0.729 and 0.832, respectively, and the AUC values ​​were 0.776 and 0.850, respectively. The C-index of the complex model for predicting PFS and OS was 0.755 and 0.867, respectively, and the AUC values ​​were 0.791 and 0.874, respectively. Moreover, decision curve analysis showed that the complex model had a higher net benefit than the clinical model. Conclusions: 18F-FDG PET/CT radiomics before treatment could predict PFS and OS in NSCLC patients, and the predictive power was higher when combined with clinical factors.

Molecular imaging of immune checkpoints in oncology: Current and future applications.

Immune checkpoint (IC) blockade therapy has become the first-line treatment for various cancers. However, the low response rate and acquired drug resistance severely restrict the clinical application of immune checkpoint inhibitors (ICIs). Nuclide molecular imaging of ICs can provide non-invasive and whole-body visualization of in vivo IC dynamic biodistribution. Therefore, molecular imaging of ICs can predict and monitor responses to ICIs as a complementary tool to existing immunohistochemical techniques. Herein, we outlined the current status and recent advances in molecular imaging of the "first-generation" and "next-generation" ICs in preclinical and clinical studies.

The correlation between PD-L1 expression and metabolic parameters of 18FDG PET/CT and the prognostic value of PD-L1 in non-small cell lung cancer.

OBJECTIVES: In the present study, we aimed to investigate the relationship between metabolic parameters of 18F-fluorodeoxyglucose positron emission computed tomography (18F-FDG PET/CT) and the expression of programmed death ligand-1 (PD-L1), as well as the prognostic value of PD-L1, in patients with surgically resected non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: A total of 169 NSCLC patients who received preoperative 18F-FDG PET were retrospectively enrolled in the present study. The correlation between PD-L1 and patient characteristics was evaluated. Based on the expression of PD-L1 and metabolic parameters, patients were classified into low-, medium-, or high-risk groups. RESULTS: The maximum standardized uptake value (SUVmax) and total lesion glycolysis (TLG) were significantly higher in NSCLC patients with high PD-L1 expression compared with the low expression group (P < 0.001 for all). Multivariate analysis revealed that pleural invasion (P < 0.001) and SUVmax (P < 0.001) were independent predictors of PD-L1 expression. Survival analysis showed that tumor stage (P = 0.004) and pleural invasion (P = 0.007) were independent prognostic indicators of progression-free survival (PFS). Tumor stage (P = 0.001), TLG (P = 0.039), and PD-L1 expression (P = 0.001) were independent prognostic indicators of overall survival (OS). Patients of the high-risk group with high PD-L1 expression and high TLG had a poor prognosis compared with the low-risk group (P < 0.05) and medium-risk group (P < 0.05). CONCLUSIONS: In NSCLC patients, the SUVmax of 18F-FDG PET/CT was a predictor of PD-L1 expression. The expression of PD-L1 and TLG were independent prognostic factors of OS. The risk stratification standard based on the PD-L1 expression and TLG provided valuable insights into the development of personalized treatment and follow-up. REGISTRATION NUMBER: ChiCTR2100051554.

Prognostic Value of Radiomic Features of 18F-FDG PET/CT in Patients With B-Cell Lymphoma Treated With CD19/CD22 Dual-Targeted Chimeric Antigen Receptor T Cells.

OBJECTIVE: In the present study, we aimed to evaluate the prognostic value of PET/CT-derived radiomic features for patients with B-cell lymphoma (BCL), who were treated with CD19/CD22 dual-targeted chimeric antigen receptor (CAR) T cells. Moreover, we explored the relationship between baseline radiomic features and the occurrence probability of cytokine release syndrome (CRS). METHODS: A total of 24 BCL patients who received 18F-FDG PET/CT before CAR T-cell infusion were enrolled in the present study. Radiomic features from PET and CT images were extracted using LIFEx software, and the least absolute shrinkage and selection operator (LASSO) regression was used to select the most useful predictive features of progression-free survival (PFS) and overall survival (OS). Receiver operating characteristic curves, Cox proportional hazards model, and Kaplan-Meier curves were conducted to assess the potential prognostic value. RESULTS: Contrast extracted from neighbourhood grey-level different matrix (NGLDM) was an independent predictor of PFS (HR = 15.16, p = 0.023). MYC and BCL2 double-expressor (DE) was of prognostic significance for PFS (HR = 7.02, p = 0.047) and OS (HR = 10.37, p = 0.041). The combination of NGLDM_ContrastPET and DE yielded three risk groups with zero (n = 7), one (n = 11), or two (n = 6) factors (p < 0.0001 and p = 0.0004, for PFS and OS), respectively. The PFS was 85.7%, 63.6%, and 0%, respectively, and the OS was 100%, 90.9%, and 16.7%, respectively. Moreover, there was no significant association between PET/CT variables and CRS. CONCLUSIONS: In conclusion, radiomic features extracted from baseline 18F-FDG PET/CT images in combination with genomic factors could predict the survival outcomes of BCL patients receiving CAR T-cell therapy.

Radiomic Features of 18F-FDG PET in Hodgkin Lymphoma Are Predictive of Outcomes.

Purpose: In the present study, we aimed to investigate whether the radiomic features of baseline 18F-FDG PET can predict the prognosis of Hodgkin lymphoma (HL). Methods: A total 65 HL patients (training cohort: n = 49; validation cohort: n = 16) were retrospectively enrolled in the present study. A total of 47 radiomic features were extracted from pretreatment PET images. The least absolute shrinkage and selection operator (LASSO) regression was used to select the most useful prognostic features in the training cohort. The distance between the two lesions that were the furthest apart (D max) was recorded. The receiver operating characteristic (ROC) curve, Kaplan-Meier method, and Cox proportional hazards model were used to assess the prognostic factors. Results: Long-zone high gray-level emphasis extracted from a gray-level zone-length matrix (LZHGEGLZLM) (HR = 9.007; p=0.044) and Dmax (HR = 3.641; p=0.048) were independently correlated with 2-year progression-free survival (PFS). A prognostic stratification model was established based on both risk predictors, which could distinguish three risk categories for PFS (p=0.0002). The 2-year PFS was 100.0%, 64.7%, and 33.3%, respectively. Conclusions: LZHGEGLZLM and Dmax were independent prognostic factors for survival outcomes. Besides, we proposed a prognostic stratification model that could further improve the risk stratification of HL patients.

Review: Radionuclide Molecular Imaging Targeting HER2 in Breast Cancer with a Focus on Molecular Probes into Clinical Trials and Small Peptides.

As the most frequently occurring cancer worldwide, breast cancer (BC) is the leading cause of cancer-related death in women. The overexpression of HER2 (human epidermal growth factor receptor 2) is found in about 15% of BC patients, and it is often associated with a poor prognosis due to the effect on cell proliferation, migration, invasion, and survival. As a result of the heterogeneity of BC, molecular imaging with HER2 probes can non-invasively, in real time, and quantitatively reflect the expression status of HER2 in tumors. This will provide a new approach for patients to choose treatment options and monitor treatment response. Furthermore, radionuclide molecular imaging has the potential of repetitive measurements, and it can help solve the problem of heterogeneous expression and conversion of HER2 status during disease progression or treatment. Different imaging probes of targeting proteins, such as monoclonal antibodies, antibody fragments, nanobodies, and affibodies, are currently in preclinical and clinical development. Moreover, in recent years, HER2-specific peptides have been widely developed for molecular imaging techniques for HER2-positive cancers. This article summarized different types of molecular probes targeting HER2 used in current clinical applications and the developmental trend of some HER2-specific peptides.

Combining Multiple Methods for Recycling of Kish Graphite from Steelmaking Slags and Oil Sorption Performance of Kish-Based Expanded Graphite.

The utilization of industrial waste as renewable resources is an essential issue of sustainable development. Kish graphite is a precipitate of excess carbon generated during the cooling of molten iron and one of the byproducts associated with steel slags. The scale-up recycling of kish graphite from steelmaking slags is a promising way to develop natural graphite alternatives. However, only one means cannot work efficiently because of the unusual occurrence of associated impurities; combining multiple separation methods is the solution. In this paper, we proposed an integrated beneficiation process, pneumatic separation-flotation-sonication-magnetic separation, to recycle kish graphite flakes with a high graphitization degree and investigated the sorption performance of various oils on kish-based expanded graphite. The new process avoided shortages such as the sediments of iron particles in the flotation cell and the loss of clean graphite in the magnetic separation. Consequently, the carbon content of kish graphite reached ∼95% after separation and >99% after acid leaching. The macroscopic structural defects of kish particles created more active sites, made the intercalation of KG-GICs faster, and yielded better-staged compounds. The kish graphite-based expanded graphite presented an octopus-like shape and exhibited an expansion volume of ∼150 mL/g. Furthermore, the developed macropore structure of the obtained kish graphite-based expanded graphite led to a superior sorption performance for oils. This work supplies one feasible and promising way to recycle kish graphite from steelmaking slags and use it.

The complex structure of GRL0617 and SARS-CoV-2 PLpro reveals a hot spot for antiviral drug discovery.

SARS-CoV-2 is the pathogen responsible for the COVID-19 pandemic. The SARS-CoV-2 papain-like cysteine protease (PLpro) has been implicated in playing important roles in virus maturation, dysregulation of host inflammation, and antiviral immune responses. The multiple functions of PLpro render it a promising drug target. Therefore, we screened a library of approved drugs and also examined available inhibitors against PLpro. Inhibitor GRL0617 showed a promising in vitro IC50 of 2.1 µM and an effective antiviral inhibition in cell-based assays. The co-crystal structure of SARS-CoV-2 PLproC111S in complex with GRL0617 indicates that GRL0617 is a non-covalent inhibitor and it resides in the ubiquitin-specific proteases (USP) domain of PLpro. NMR data indicate that GRL0617 blocks the binding of ISG15 C-terminus to PLpro. Using truncated ISG15 mutants, we show that the C-terminus of ISG15 plays a dominant role in binding PLpro. Structural analysis reveals that the ISG15 C-terminus binding pocket in PLpro contributes a disproportionately large portion of binding energy, thus this pocket is a hot spot for antiviral drug discovery targeting PLpro.

Evaluation of PD-L1 Expression Level in Patients With Non-Small Cell Lung Cancer by 18F-FDG PET/CT Radiomics and Clinicopathological Characteristics.

PURPOSE: In the present study, we aimed to evaluate the expression of programmed death-ligand 1 (PD-L1) in patients with non-small cell lung cancer (NSCLC) by radiomic features of 18F-FDG PET/CT and clinicopathological characteristics. METHODS: A total 255 NSCLC patients (training cohort: n = 170; validation cohort: n = 85) were retrospectively enrolled in the present study. A total of 80 radiomic features were extracted from pretreatment 18F-FDG PET/CT images. Clinicopathologic features were compared between the two cohorts. The least absolute shrinkage and selection operator (LASSO) regression was used to select the most useful prognostic features in the training cohort. Radiomics signature and clinicopathologic risk factors were incorporated to develop a prediction model by using multivariable logistic regression analysis. The receiver operating characteristic (ROC) curve was used to assess the prognostic factors. RESULTS: A total of 80 radiomic features were extracted in the training dataset. In the univariate analysis, the expression of PD-L1 in lung tumors was significantly correlated with the radiomic signature, histologic type, Ki-67, SUVmax, MTV, and TLG (p< 0.05, respectively). However, the expression of PD-L1 was not correlated with age, TNM stage, and history of smoking (p> 0.05). Moreover, the prediction model for PD-L1 expression level over 1% and 50% that combined the radiomic signature and clinicopathologic features resulted in an area under the curve (AUC) of 0.762 and 0.814, respectively. CONCLUSIONS: A prediction model based on PET/CT images and clinicopathological characteristics provided a novel strategy for clinicians to screen the NSCLC patients who could benefit from the anti-PD-L1 immunotherapy.

Applications of PET in Diagnosis and Prognosis of Leukemia.

As a malignant hematopoietic stem cell disease, leukemia remains life-threatening due to its increasing incidence rate and mortality rate. Therefore, its early diagnosis and treatment play a very important role. In the present work, we systematically reviewed the current applications and future directions of positron emission tomography (PET) in patients with leukemia, especially 18F-FDG PET/CT. As a useful imaging approach, PET significantly contributes to the diagnosis and treatment of different types of leukemia, especially in the evaluation of extramedullary infiltration, monitoring of leukemia relapse, detection of Richter's transformation (RT), and assessment of the inflammatory activity associated with acute graft versus host disease. Future investigations should be focused on the potential of PET/CT in the prediction of clinical outcomes in patients with leukemia and the utility of novel radiotracers.

The value of 18F-FDG PET/CT in the prediction of clinical outcomes of patients with acute leukemia treated with allogeneic hematopoietic stem cell transplantation.

The present study aimed to determine whether 18F-FDG PET/CT performed before and/or after allogeneic hematopoietic stem cell transplantation (allo-HSCT) can predict clinical outcomes in acute leukemia (AL). A total of 79 examinations comprising 72 patients with AL who underwent 18F-FDG PET/CT before and/or after allo-HSCT were retrospectively enrolled between January 2011 and January 2019. Outcomes were assessed using overall survival (OS) and disease-free survival (DFS). A total of 63 examinations were PET-positive, while 16 examinations were PET-negative. Increased BM and splenic 18F-FDG uptake were observed in 24 (19/79) and 14% (11/79) of examinations, respectively. 18F-FDG-avid lymph nodes were observed in 38% (30/79) of examinations. ENEMES involvement was detected in 44% (35/79) of examinations. The presence of ENEMES involvement [OS hazard ratio (HR), 6.399; 95% confidence interval (CI), 1.843-22.224; P=0.003; post-HSCT OS: HR, 7.203; 95% CI, 1.510-34.369; P=0.013; DFS HR, 3.671; 95% CI, 1.145-11.768; P=0.029], post-transplantation minimal residual disease (DFS HR, 4.381; 95% CI, 1.594-12.040; P=0.004; pre-HSCT OS HR, 11.455; 95% CI, 1.336-98.179; P=0.026) and disease status (OS HR, 0.330; 95% CI, 0.128-0.848; P=0.021; post-HSCT OS HR, 0.195; 95% CI, 0.050-0.762; P=0.019; DFS: HR, 0.278; 95% CI, 0.091-0.851; P=0.025) could serve as an adverse prognostic factor in patients with AL treated with allo-HSCT. 18F-FDG PET/CT before and/or after allo-HSCT was a predictor for OS and DFS in patients with AL. ENEMES involvement detected using 18F-FDG PET/CT may help identify patients with AL who are likely to have unfavorable clinical outcomes.

Sunitinib inhibits RNase L by destabilizing its active dimer conformation.

The pseudokinase (PK) RNase L is a functional ribonuclease and plays important roles in human innate immunity. The ribonuclease activity of RNase L can be regulated by the kinase inhibitor sunitinib. The combined use of oncolytic virus and sunitinib has been shown to exert synergistic effects in anticancer therapy. In this study, we aimed to uncover the mechanism of action through which sunitinib inhibits RNase L. We solved the crystal structures of RNase L in complex with sunitinib and its analogs toceranib and SU11652. Our results showed that sunitinib bound to the ATP-binding pocket of RNase L. Unexpectedly, the αA helix linking the ankyrin repeat-domain and the PK domain affected the binding mode of sunitinib and resulted in an unusual flipped orientation relative to other structures in PDB. Molecular dynamics simulations and dynamic light scattering results support that the binding of sunitinib in the PK domain destabilized the dimer conformation of RNase L and allosterically inhibited its ribonuclease activity. Our study suggested that dimer destabilization could be an effective strategy for the discovery of RNase L inhibitors and that targeting the ATP-binding pocket in the PK domain of RNase L was an efficient approach for modulating its ribonuclease activity.

Prognostic Values of Baseline 18F-FDG PET/CT in Patients with Peripheral T-Cell Lymphoma.

PURPOSE: In the present study, we aimed to investigate whether the metabolic parameters on baseline 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) could be used to predict prognosis in peripheral T-cell lymphomas (PTCL). METHODS: A total of 51 nodal PTCL patients who underwent baseline 18F-FDG PET/CT were retrospectively evaluated in the present study. Total metabolic tumor volume (TMTV), total lesion glycolysis (TLG), and maximum standardized uptake value (SUVmax) were also assessed. Besides, the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) was also included. Log-rank test and Cox regression analysis were used to evaluate progression-free survival (PFS) and overall survival (OS). RESULTS: The median follow-up was 18 months. Patients with low TLG, TMTV, and SUVmax levels had a significantly better clinical outcome than those with high TLG, TMTV, and SUVmax levels. The 2-year PFS rates of the high- and low-TMTV groups were 34.62% and 80%, respectively (p < 0.001), whereas the corresponding 2-year OS rates were 46.15% and 84.00%, respectively (p < 0.001), whereas the corresponding 2-year OS rates were 46.15% and 84.00%, respectively (p < 0.001), whereas the corresponding 2-year OS rates were 46.15% and 84.00%, respectively (p < 0.001), whereas the corresponding 2-year OS rates were 46.15% and 84.00%, respectively (p < 0.001), whereas the corresponding 2-year OS rates were 46.15% and 84.00%, respectively (p < 0.001), whereas the corresponding 2-year OS rates were 46.15% and 84.00%, respectively (p < 0.001), whereas the corresponding 2-year OS rates were 46.15% and 84.00%, respectively (p < 0.001), whereas the corresponding 2-year OS rates were 46.15% and 84.00%, respectively (p < 0.001), whereas the corresponding 2-year OS rates were 46.15% and 84.00%, respectively (p < 0.001), whereas the corresponding 2-year OS rates were 46.15% and 84.00%, respectively (p < 0.001), whereas the corresponding 2-year OS rates were 46.15% and 84.00%, respectively (p < 0.001), whereas the corresponding 2-year OS rates were 46.15% and 84.00%, respectively (n = 10), intermediate-risk group with TMTV > 62.405 or NCCN-IPI score of 4-8 (2-year PFS and OS were 52.4% and 66.7%, respectively, n = 10), intermediate-risk group with TMTV > 62.405 or NCCN-IPI score of 4-8 (2-year PFS and OS were 52.4% and 66.7%, respectively, n = 10), intermediate-risk group with TMTV > 62.405 or NCCN-IPI score of 4-8 (2-year PFS and OS were 52.4% and 66.7%, respectively. CONCLUSIONS: Baseline TMTV and TLG were independent predictors of PFS and OS in PTCL patients, and SUVmax and NCCN-IPI scores were also independent predictors of OS. Moreover, the combination of TMTV and NCCN-IPI scores improved patient risk-stratification at the initial stage and might contribute to the adjustment of the therapeutic regime. This trial is registered with ChiCTR1900025526.