Prediction of prostate cancer aggressiveness using magnetic resonance imaging radiomics: a dual-center study.

PURPOSE: The Gleason score (GS) and positive needles are crucial aggressive indicators of prostate cancer (PCa). This study aimed to investigate the usefulness of magnetic resonance imaging (MRI) radiomics models in predicting GS and positive needles of systematic biopsy in PCa. MATERIAL AND METHODS: A total of 218 patients with pathologically proven PCa were retrospectively recruited from 2 centers. Small-field-of-view high-resolution T2-weighted imaging and post-contrast delayed sequences were selected to extract radiomics features. Then, analysis of variance and recursive feature elimination were applied to remove redundant features. Radiomics models for predicting GS and positive needles were constructed based on MRI and various classifiers, including support vector machine, linear discriminant analysis, logistic regression (LR), and LR using the least absolute shrinkage and selection operator. The models were evaluated with the area under the curve (AUC) of the receiver-operating characteristic. RESULTS: The 11 features were chosen as the primary feature subset for the GS prediction, whereas the 5 features were chosen for positive needle prediction. LR was chosen as classifier to construct the radiomics models. For GS prediction, the AUC of the radiomics models was 0.811, 0.814, and 0.717 in the training, internal validation, and external validation sets, respectively. For positive needle prediction, the AUC was 0.806, 0.811, and 0.791 in the training, internal validation, and external validation sets, respectively. CONCLUSIONS: MRI radiomics models are suitable for predicting GS and positive needles of systematic biopsy in PCa. The models can be used to identify aggressive PCa using a noninvasive, repeatable, and accurate diagnostic method.

Corosolic acid delivered by exosomes from Eriobotrya japonica decreased pancreatic cancer cell proliferation and invasion by inducing SAT1-mediated ferroptosis.

BACKGROUND: In this study, we investigated whether Exo regulate the proliferation and invasion of PC. METHODS: In this study, we isolated the Eriobotrya japonica Exo using Ultra-high speed centrifugal method. Mass spectrum were used for Exo active components analysis. PC (Capan-1 and Bxpc-3) cells proliferation, migration, and apoptosis were detected using CCK8, ethynyldeoxyuridine, transwell, wound healing, and flow cytometry analyses. We also constructed a lung metastatic mouse model and subcutaneous tumor model to illustrate the regulation effect of Exo or active components. Proteomics were used to reveal the regulatory mechanism responsible for the observed effects. RESULTS: We isolated Eriobotrya japonica Exo and found that Exo treatment significantly suppressed cell migration and proliferation in both in vivo and in vitro using Capan-1. Mass spectrum for Exo active components analysis found that Exo contains high amounts of corosolic acid (CRA). The further study found that CRA treatment inhibit the proliferation, migration, and increased cell death of both Capan-1 and Bxpc-3 cells in a concentration-dependent manner. In vivo experiments confirmed that CRA inhibited pulmonary metastasis by decreasing the number of metastatic foci. Cell proteomics analysis showed that CRA treatment induced spermidine/spermine N1-acetyltransferase 1 (SAT1)-dependent ferroptosis. Treatment with the ferroptosis suppressor ferrostatin-1 significantly reversed CRA-induced cell apoptosis. CONCLUSION: The data suggested that corosolic acid delivered by exosomes from Eriobotrya japonica decreased pancreatic cancer cell proliferation and invasion by inducing SAT1-mediated ferroptosis.

Long-term benefits of hematopoietic stem cell-based macrophage/microglia delivery of GDNF to the CNS in a mouse model of Parkinson's disease.

Glial cell line-derived neurotrophic factor (GDNF) protects dopaminergic neurons in various models of Parkinson's disease (PD). Cell-based GDNF gene delivery mitigates neurodegeneration and improves both motor and non-motor functions in PD mice. As PD is a chronic condition, this study aims to investigate the long-lasting benefits of hematopoietic stem cell (HSC)-based macrophage/microglia-mediated CNS GDNF (MMC-GDNF) delivery in an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model. The results indicate that GDNF treatment effectively ameliorated MPTP-induced motor deficits for up to 12 months, which coincided with the protection of nigral dopaminergic neurons and their striatal terminals. Also, the HSC-derived macrophages/microglia were recruited selectively to the neurodegenerative areas of the substantia nigra. The therapeutic benefits appear to involve two mechanisms: (1) macrophage/microglia release of GDNF-containing exosomes, which are transferred to target neurons, and (2) direct release of GDNF by macrophage/microglia, which diffuses to target neurons. Furthermore, the study found that plasma GDNF levels were significantly increased from baseline and remained stable over time, potentially serving as a convenient biomarker for future clinical trials. Notably, no weight loss, altered food intake, cerebellar pathology, or other adverse effects were observed. Overall, this study provides compelling evidence for the long-term therapeutic efficacy and safety of HSC-based MMC-GDNF delivery in the treatment of PD.

Preclinical development of novel PD-L1 tracers and first-in-human study of [68Ga]Ga-NOTA-RW102 in patients with lung cancers.

BACKGROUND: The programmed cell death protein-1 (PD-1)/programmed death receptor ligand 1 (PD-L1) axis critically facilitates cancer cells' immune evasion. Antibody therapeutics targeting the PD-1/PD-L1 axis have shown remarkable efficacy in various tumors. Immuno-positron emission tomography (ImmunoPET) imaging of PD-L1 expression may help reshape solid tumors' immunotherapy landscape. METHODS: By immunizing an alpaca with recombinant human PD-L1, three clones of the variable domain of the heavy chain of heavy-chain only antibody (VHH) were screened, and RW102 with high binding affinity was selected for further studies. ABDRW102, a VHH derivative, was further engineered by fusing RW102 with the albumin binder ABD035. Based on the two targeting vectors, four PD-L1-specific tracers ([68Ga]Ga-NOTA-RW102, [68Ga]Ga-NOTA-ABDRW102, [64Cu]Cu-NOTA-ABDRW102, and [89Zr]Zr-DFO-ABDRW102) with different circulation times were developed. The diagnostic efficacies were thoroughly evaluated in preclinical solid tumor models, followed by a first-in-human translational investigation of [68Ga]Ga-NOTA-RW102 in patients with non-small cell lung cancer (NSCLC). RESULTS: While RW102 has a high binding affinity to PD-L1 with an excellent KD value of 15.29 pM, ABDRW102 simultaneously binds to human PD-L1 and human serum albumin with an excellent KD value of 3.71 pM and 3.38 pM, respectively. Radiotracers derived from RW102 and ABDRW102 have different in vivo circulation times. In preclinical studies, [68Ga]Ga-NOTA-RW102 immunoPET imaging allowed same-day annotation of differential PD-L1 expression with specificity, while [64Cu]Cu-NOTA-ABDRW102 and [89Zr]Zr-DFO-ABDRW102 enabled longitudinal visualization of PD-L1. More importantly, a pilot clinical trial shows the safety and diagnostic value of [68Ga]Ga-NOTA-RW102 immunoPET imaging in patients with NSCLCs and its potential to predict immune-related adverse effects following PD-L1-targeted immunotherapies. CONCLUSIONS: We developed and validated a series of PD-L1-targeted tracers. Initial preclinical and clinical evidence indicates that immunoPET imaging with [68Ga]Ga-NOTA-RW102 holds promise in visualizing differential PD-L1 expression, selecting patients for PD-L1-targeted immunotherapies, and monitoring immune-related adverse effects in patients receiving PD-L1-targeted treatments. TRIAL REGISTRATION NUMBER: NCT06165874.

Understanding suicidal ideation disparity between sexual minority and heterosexual Chinese young men: a multiple mediation model of social support sources, self-esteem, and depressive symptoms.

Objectives: Although sexual minorities have reported higher levels of suicidal ideation than heterosexuals across cultures, the role of various psychosocial factors underlying this disparity among young men has been understudied, particularly in China. This study examined the multiple mediating effects of psychosocial factors between sexual orientation and suicidal ideation in Chinese sexual minority and heterosexual young men. Methods: 302 Chinese cisgender men who identified as gay or bisexual, and 250 cisgender heterosexual men (n=552, aged 18-39 years) completed an online questionnaire measuring perceived social support, self-esteem, depressive symptoms, and suicidal ideation. Results: Young sexual minority men reported significantly higher suicidal ideation and lower social support than their heterosexual peers. Structural equation modelling revealed two multiple indirect pathways. One pathway indicated that sexual orientation was indirectly related to suicidal ideation via family support and depressive symptoms. Another pathway indicated that sexual orientation was indirectly related to suicidal ideation via support from friends, self-esteem, and depressive symptoms. Conclusions: This study is among the first to examine the potentially cascading relationships between sexual orientation and psychosocial factors with suicidal ideation in a Chinese sample of young men. The findings highlight several promising psychosocial targets (i.e., improving family/friend support and increasing self-esteem) for suicide interventions among sexual minority males in China.

ImmunoPET imaging of Trop2 in patients with solid tumours.

Accurately predicting and selecting patients who can benefit from targeted or immunotherapy is crucial for precision therapy. Trophoblast cell surface antigen 2 (Trop2) has been extensively investigated as a pan-cancer biomarker expressed in various tumours and plays a crucial role in tumorigenesis through multiple signalling pathways. Our laboratory successfully developed two 68Ga-labelled nanobody tracers that can rapidly and specifically target Trop2. Of the two tracers, [68Ga]Ga-NOTA-T4, demonstrated excellent pharmacokinetics in preclinical mouse models and a beagle dog. Moreover, [68Ga]Ga-NOTA-T4 immuno-positron emission tomography (immunoPET) allowed noninvasive visualisation of Trop2 heterogeneous and differential expression in preclinical solid tumour models and ten patients with solid tumours. [68Ga]Ga-NOTA-T4 immunoPET could facilitate clinical decision-making through patient stratification and response monitoring during Trop2-targeted therapies.

An Innovative Concept of Membrane-Free Redox Flow Batteries with Near-Zero Contact Distance Between Electrodes.

Given that the ion-exchange membrane takes up more than 30% of redox flow battery (RFB) cost, considerable cost reduction is anticipated with the membrane-free design. However, eliminating the membrane/separator would expose the membrane-free RFBs to a higher risk of short-circuits, and the dendrite growth may aggravate this issue. The current strategy based on expanding distances between electrodes is proposed to address short-circuit issues. Nevertheless, this approach would decrease the energy efficiency (EE) and could not restrain dendrite growth fundamentally. Herein, an inexpensive and electron-insulating boron nitride nanosheets (BNNSs)-Nylon hybrid interlayer (BN/Nylon) is developed for general membrane-free RFBs to achieve "near-zero distance" contact between electrodes. And the Lewis acid sites (B atoms) in BNNS can interact with the Lewis base anions in electrolytes, enabling a reduced Pb2+concentration gradient. Additionally, the ultrahigh thermal conductivity and mechanical strength of BNNSs promote the uniform plating/stripping process of Pb and PbO2. Compared with conventional soluble lead RFBs, introducing BN/Nylon interlayers boosts EE by ≈38.2% at 25 mA cm-2, and extends the cycle life to 100 cycles. This innovative strategy premieres the application of the BN/Nylon interlayer concept, offering a novel perspective for the development of general membrane-free RFBs.

CENPA and BRCA1 are potential biomarkers associated with immune infiltration in heart failure and pan-cancer.

Heart failure (HF) and cancer are the two leading causes of death worldwide and affect one another in a bidirectional way. We aimed to identify hub therapeutic genes as potential biomarkers for the identification and treatment of HF and cancer. Gene expression data of heart samples from patients with ischemic HF (IHF) and healthy controls were retrieved from the GSE42955 and GSE57338 databases. Difference analysis and weighted gene co-expression network analysis (WGCNA) were used to identify key modules associated with IHF. The overlapping genes were subjected to gene and protein enrichment analyses to construct a protein-protein interaction (PPI) network, which was screened for hub genes among the overlapping genes. A total of eight hub genes were subjected to correlation, immune cell infiltration, and ROC analyses. Then we analyzed the roles of two significant genes in 33 tumor types to explore their potential as common targets in HF and cancer. A total of 85 genes were identified by WGCNA and differentially expressed gene (DEG) analyses. BRCA1, MED17, CENPA, RXRA, RXRB, SMARCA2, CDCA2, and PMS2 were identified as the hub genes with IHF. Finally, CENPA and BRCA1 were identified as potential common targets for IHF and cancer. These findings provide new perspectives for expanding our understanding of the etiology and underlying mechanisms of HF and cancer.

A Rotating Cathode with Periodical Changes in Electrolyte Layer Thickness for High-Rate Li‒O2 Batteries.

Li-O2 batteries (LOBs) possess the highest theoretical gravimetric energy density among all types of secondary batteries, but they are still far from practical applications. The poor rate performance resulting from the slow mass transfer is one of the primary obstacles in LOBs. To solve this issue, a rotating cathode with periodic changes in the electrolyte layer thickness is designed, decoupling the maximum transfer rate of Li+ and O2. During rotation, the thinner electrolyte layer on the cathode facilitates the O2 transfer, and the thicker electrolyte layer enhances the Li+ transfer. As a result, the rotating cathode enables the LOBs to undergo 58 cycles at 2.5 mA cm-2 and discharge stably even at a high current density of 7.5 mA cm-2. Besides, it also makes the batteries exhibit a large discharge capacity of 6.8 mAh cm-2, and the capacity decay is much slower with increasing current density. Notably, this rotating electrode holds great promise for utilization in other electrochemical cells involving gas-liquid-solid triple-phase interfaces, suggesting a viable approach to enhance the mass transfer in such systems.

PFKFB3 regulates breast cancer tumorigenesis and Fulvestrant sensitivity by affecting ERα stability.

Estrogen receptor alpha (ERα) is expressed in approximately 70% of breast cancer cases and determines the sensitivity and effectiveness of endocrine therapy. 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase3 (PFKFB3) is a glycolytic enzyme that is highly expressed in a great many human tumors, and recent studies have shown that it plays a significant role in improving drug sensitivity. However, the role of PFKFB3 in regulating ERα expression and the underlying mechanism remains unclear. Here, we find by using immunohistochemistry (IHC) that PFKFB3 is elevated in ER-positive breast cancer and high expression of PFKFB3 resulted in a worse prognosis. In vitro and in vivo experiments verify that PFKFB3 promotes ER-positive breast cancer cell proliferation. The overexpression of PFKFB3 promotes the estrogen-independent ER-positive breast cancer growth. In an estrogen-free condition, RNA-sequencing data from MCF7 cells treated with siPFKFB3 showed enrichment of the estrogen signaling pathway, and a luciferase assay demonstrated that knockdown of PFKFB3 inhibited the ERα transcriptional activity. Mechanistically, down-regulation of PFKFB3 promotes STUB1 binding to ERα, which accelerates ERα degradation by K48-based ubiquitin linkage. Finally, growth of ER-positive breast cancer cells in vivo was more potently inhibited by fulvestrant combined with the PFKFB3 inhibitor PFK158 than for each drug alone. In conclusion, these data suggest that PFKFB3 is identified as an adverse prognosis factor for ER-positive breast cancer and plays a previously unrecognized role in the regulation of ERα stability and activity. Our results further explores an effective approach to improve fulvestrant sensitivity through the early combination with a PFKFB3 inhibitor.

Concurrent JCPyV-DNAemia Is Correlated With Poor Graft Outcome in Kidney Transplant Recipients with Polyomavirus-associated Nephropathy.

BACKGROUND: Co-infection of JC polyomavirus (JCPyV) and BK polyomavirus (BKPyV) is uncommon in kidney transplant recipients, and the prognosis is unclear. This study aimed to investigate the effect of concurrent JCPyV-DNAemia on graft outcomes in BKPyV-infected kidney transplant recipients with polyomavirus-associated nephropathy (PyVAN). METHODS: A total of 140 kidney transplant recipients with BKPyV replication and PyVAN, 122 without concurrent JCPyV-DNAemia and 18 with JCPyV-DNAemia were included in the analysis. Least absolute shrinkage and selection operator regression analysis and multivariate Cox regression analysis were used to identify prognostic factors for graft survival. A nomogram for predicting graft survival was created and evaluated. RESULTS: The median tubulitis score in the JCPyV-DNAemia-positive group was higher than in JCPyV-DNAemia-negative group (P = 0.048). At last follow-up, the graft loss rate in the JCPyV-DNAemia-positive group was higher than in the JCPyV-DNAemia-negative group (50% versus 25.4%; P = 0.031). Kaplan-Meier analysis showed that the graft survival rate in the JCPyV-DNAemia-positive group was lower than in the JCPyV-DNAemia-negative group (P = 0.003). Least absolute shrinkage and selection operator regression and multivariate Cox regression analysis demonstrated that concurrent JCPyV-DNAemia was an independent risk factor for graft survival (hazard ratio = 4.808; 95% confidence interval: 2.096-11.03; P < 0.001). The nomogram displayed favorable discrimination (C-index = 0.839), concordance, and clinical applicability in predicting graft survival. CONCLUSIONS: Concurrent JCPyV-DNAemia is associated with a worse graft outcome in BKPyV-infected kidney transplant recipients with PyVAN.

ImmunoPET/CT imaging of clear cell renal cell carcinoma with [18F]RCCB6: a first-in-human study.

PURPOSE: The cluster of differentiation (CD70) is a potential biomarker of clear cell renal cell carcinoma (ccRCC). This study aims to develop CD70-targeted immuno-positron emission tomography/computed tomography (immunoPET/CT) imaging tracers and explore the diagnostic value in preclinical studies and the potential value in detecting metastases in ccRCC patients. METHODS: Four novel CD70-specific single-domain antibodies (sdAbs) were produced and labelled with 18F by the aluminium fluoride restrained complexing agent (AlF-RESCA) method to develop radiotracers. The visualisation properties of the tracers were evaluated in a subcutaneous ccRCC patient-derived xenograft (PDX) model. In a registered prospective clinical trial (NCT06148220), six patients with pathologically confirmed RCC were included and underwent immunoPET/CT examination exploiting one of the developed tracers (i.e., [18F]RCCB6). RESULTS: We engineered four sdAbs (His-tagged RCCB3 and RCCB6, His-tag-free RB3 and RB6) specifically targeting recombinant human CD70 without cross-reactivity to murine CD70. ImmunoPET/CT imaging with [18F]RCCB3 and [18F]RCCB6 demonstrated a high tumour-to-background ratio in a subcutaneous ccRCC PDX model, with the latter showing better diagnostic potential supported by higher tumour uptake and lower bone accumulation. In comparison, [18F]RB6, developed by sequence optimisation, has significantly lower kidney accumulation than that of [18F]RCCB6. In a pilot translational study, [18F]RCCB6 immunoPET/CT displayed ccRCC metastases in multiple patients and demonstrated improved imaging contrast and diagnostic value than 18F-FDG PET/CT in a patient with ccRCC. CONCLUSION: The work successfully developed a series of CD70-targeted immunoPET/CT imaging tracers. Of them, [18F]RCCB6 clearly and specifically identified inoculated ccRCCs in preclinical studies. Clinical translation of [18F]RCCB6 suggests potential for identifying recurrence and/or metastasis in ccRCC patients.

Oncogenic circ-SLC16A1 promotes progression of non-small cell lung cancer via regulation of the miR-1287-5p/profilin 2 axis.

BACKGROUND: Circular RNAs (circRNAs) are single-stranded RNAs with covalently closed structures that have been implicated in cancer progression. However, the regulatory mechanisms remain largely unclear. So, the aim of this study was to reveal the role and regulatory mechanisms of circ-SLC16A1. METHODS: In this study, next-generation sequencing was used to identify abnormally expressed circRNAs between cancerous and para-carcinoma tissues. Fluorescence in situ hybridization and quantitative reverse transcription polymerase chain reaction were performed to assess the expression patterns of circ-solute carrier family 16 member 1 (SLC16A1) in non-small cell lung cancer (NSCLC) cells and tissue specimens. The dual-luciferase reporter assay was utilized to identify downstream targets of circ-SLC16A1. Transwell migration, wound healing, 5-ethynyl-2'-deoxyuridine incorporation, cell counting, and colony formation assays were conducted to assess the proliferation and migration of NSCLC cells. A mouse tumor xenograft model was employed to determine the roles of circ-SLC16A1 in NSCLC progression and metastasis in vivo. RESULTS: The results found that circ-SLC16A1 was upregulated in NSCLC cells and tissues. Downregulation of circ-SLC16A1 inhibited tumor growth by reducing proliferation, lung metastasis, and lymphatic metastasis of NSCLC cells, and arrested the cell cycle in the G1 phase. Also, silencing of circ-SLC16A1 promoted apoptosis of NSCLC cells. The results of bioinformatics analysis and the dual-luciferase reporter assay confirmed that microRNA (miR)-1287-5p and profilin 2 (PFN2) are downstream targets of circ-SLC16A1. PFN2 overexpression or circ-SLC16A1 inhibition restored proliferation and migration of NSCLC cells after silencing of circ-SLC16A1. PFN2 overexpression restored migration and proliferation of NSCLC cells post miR-1287-5p overexpression. CONCLUSIONS: Collectively, these findings show that miR-1287-5p/PFN2 signaling was associated with downregulation of circ-SLC16A1 and reduced invasion and proliferation of NSCLC cells. So, circ-SLC16A1 is identified as a mediator of multiple pro-oncogenic signaling pathways in NSCLC and can be targeted to suppress tumor progression.

Synergistic Radiation Effects in PPD CMOS Image Sensors Induced by Neutron Displacement Damage and Gamma Ionization Damage.

The synergistic effects on the 0.18 µm PPD CISs induced by neutron displacement damage and gamma ionization damage are investigated. The typical characterizations of the CISs induced by the neutron displacement damage and gamma ionization damage are presented separately. The CISs are irradiated by reactor neutron beams up to 1 × 1011 n/cm2 (1 MeV neutron equivalent fluence) and 60Co γ-rays up to the total ionizing dose level of 200 krad(Si) with different sequential order. The experimental results show that the mean dark signal increase in the CISs induced by reactor neutron radiation has not been influenced by previous 60Co γ-ray radiation. However, the mean dark signal increase in the CISs induced by 60Co γ-ray radiation has been remarkably influenced by previous reactor neutron radiation. The synergistic effects on the PPD CISs are discussed by combining the experimental results and the TCAD simulation results of radiation damage.

Comparison of oncological and functional outcomes in Lower-limb osteosarcoma pediatric patient : A large single-center retrospective cohort study.

OBJECTIVE: Treating pediatric osteosarcoma in long bones is challenging due to skeletal immaturity, which restricts the generalizability of insights derived from adult patients. Are there disparities in outcomes? How should surgical protocols be tailored for children of varying ages? What are the specific postoperative complications? A large single-center retrospective cohort study of 345 patients under 14 years old with lower-limb osteosarcoma treated in our department since 2000 was conducted to address these inquiries. METHODS: A retrospective analysis of 345 pediatric patients with lower-limb osteosarcoma admitted to our department between 2000 and 2019 was conducted. Clinical and functional outcomes were compared based on age groups, surgical methods, type of prosthesis, and primary tumor location. Patients were divided into the Low-age group (≤10 y old) and the High-age group (>10 y old). Overall Survival rate (OS), Progression-Free Survival rate (PFS), and prosthesis survival rate were assessed using Kaplan-Meier curves, Non-parametric survival analysis (log-rank test) and Univariate cox regression were used for comparison. The incidence of complications, local relapse rate (LRR), metastasis rate, final limb-salvage and amputation rate, and Musculoskeletal Tumor Society (MSTS) score of different independent groups were further evaluated using χ2 test or Fisher's exact test, and t-test was employed to evaluate the measurement data. RESULTS: The average age of the patients was 11.10±2.32 years (ranging from 4 to 14 y), with an average follow-up duration of 48.17 months. The 5, 10, and 15-year OS rates were 50.3%, 43.8%, and 37.9%, respectively. The Progression-Free survival rate was 44.8% at 5 years and 41.1% at 10 years. The final limb salvage rate was 61.45%, while the final amputation rate was 38.55%. The low-age group had a higher amputation rate compared to the high-age group (48.00% vs. 33.18%, P =0.009). The overall LRR was 9.28%, and the incidence of metastasis was 28.99%. The LRR of the limb-salvage group was higher than the amputation group ( P =0.004). The low-age group experienced more prosthesis-related complications than the high-age group ( P =0.001). The most common prosthesis-related complication in the low-age group was soft-tissue failure, while the periprosthetic infection was most frequent in the high-age group. The high-age group had a higher cumulative prosthesis survival compared to the low-age group ( P =0.0097). Modular prosthesis showed better MSTS scores and higher cumulative prosthetic survival than expandable prosthesis in pediatric patients ( P <0.05). CONCLUSION: Limb preservation in pediatric patients becomes increasingly efficacious with advancing age, while consideration of amputation is warranted for younger patients. The prevailing postoperative complications associated with prosthesis encompass soft tissue failure and periprosthetic infection. Younger patients diagnosed with lower limb osteosarcoma exhibit a heightened amputation rate and a greater incidence of prosthesis-related complications.

The Role of Leukocytes in Myeloproliferative Neoplasms Thromboinflammation.

Classic myeloproliferative neoplasms lacking the Philadelphia chromosome are stem cell disorders characterized by the proliferation of myeloid cells in the bone marrow and increased counts of peripheral blood cells. The occurrence of thrombotic events is a common complication in myeloproliferative neoplasms. The heightened levels of cytokines play a substantial role in the morbidity and mortality of these patients, establishing a persistent proinflammatory condition that culminates in thrombosis. The etiology of thrombosis remains intricate and multifaceted, involving blood cells and endothelial dysfunction, the inflammatory state, and the coagulation cascade, leading to hypercoagulability. Leukocytes play a pivotal role in the thromboinflammatory process of myeloproliferative neoplasms by releasing various proinflammatory and prothrombotic factors as well as interacting with other cells, which contributes to the amplification of the clotting cascade and subsequent thrombosis. The correlation between increased leukocyte counts and thrombotic risk has been established. However, there is a need for an accurate biomarker to assess leukocyte activation. Lastly, tailored treatments to address the thrombotic risk in myeloproliferative neoplasms are needed. Therefore, this review aims to summarize the potential mechanisms of leukocyte involvement in myeloproliferative neoplasm thromboinflammation, propose potential biomarkers for leukocyte activation, and discuss promising treatment options for controlling myeloproliferative neoplasm thromboinflammation.

Feature Fusion for Multi-Coil Compressed MR Image Reconstruction.

Magnetic resonance imaging (MRI) occupies a pivotal position within contemporary diagnostic imaging modalities, offering non-invasive and radiation-free scanning. Despite its significance, MRI's principal limitation is the protracted data acquisition time, which hampers broader practical application. Promising deep learning (DL) methods for undersampled magnetic resonance (MR) image reconstruction outperform the traditional approaches in terms of speed and image quality. However, the intricate inter-coil correlations have been insufficiently addressed, leading to an underexploitation of the rich information inherent in multi-coil acquisitions. In this article, we proposed a method called "Multi-coil Feature Fusion Variation Network" (MFFVN), which introduces an encoder to extract the feature from multi-coil MR image directly and explicitly, followed by a feature fusion operation. Coil reshaping enables the 2D network to achieve satisfactory reconstruction results, while avoiding the introduction of a significant number of parameters and preserving inter-coil information. Compared with VN, MFFVN yields an improvement in the average PSNR and SSIM of the test set, registering enhancements of 0.2622 dB and 0.0021 dB respectively. This uplift can be attributed to the integration of feature extraction and fusion stages into the network's architecture, thereby effectively leveraging and combining the multi-coil information for enhanced image reconstruction quality. The proposed method outperforms the state-of-the-art methods on fastMRI dataset of multi-coil brains under a fourfold acceleration factor without incurring substantial computation overhead.

Severely polarized extracellular acidity around tumour cells.

Extracellular pH impacts many molecular, cellular and physiological processes, and hence is tightly regulated. Yet, in tumours, dysregulated cancer cell metabolism and poor vascular perfusion cause the tumour microenvironment to become acidic. Here by leveraging fluorescent pH nanoprobes with a transistor-like activation profile at a pH of 5.3, we show that, in cancer cells, hydronium ions are excreted into a small extracellular region. Such severely polarized acidity (pH <5.3) is primarily caused by the directional co-export of protons and lactate, as we show for a diverse panel of cancer cell types via the genetic knockout or inhibition of monocarboxylate transporters, and also via nanoprobe activation in multiple tumour models in mice. We also observed that such spot acidification in ex vivo stained snap-frozen human squamous cell carcinoma tissue correlated with the expression of monocarboxylate transporters and with the exclusion of cytotoxic T cells. Severely spatially polarized tumour acidity could be leveraged for cancer diagnosis and therapy.

The Value of Dual Time Point 18F-FDG PET/CT Imaging in Differentiating Lymph Node Metastasis From Reactive Hyperplasia in Bladder Urothelial Carcinoma.

RATIONALE AND OBJECTIVES: This study explored the clinical value of dual time-point 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) imaging for differentiating lymph node metastasis from lymph nodes with reactive hyperplasia. METHODS: 250 lymph nodes from 153 bladder cancer patients who underwent 18F-FDG PET/computed tomography (CT) delayed diuretic imaging were analyzed. The maximum and mean standardized uptake values (SUVmax and SUVmean, respectively), metabolic tumor volume (MTV), and related delay indices before and after PET delayed imaging were obtained. Relationships with outcomes were analyzed using nonparametric and multivariate analyses. Receiver operating characteristic curves and nomograms were drawn to predict lymph node metastasis. RESULTS: Delayed PET/CT imaging showed better detection of hyperplasia and metastatic lymph nodes. Delayed imaging with a cutoff SUVmax of 2.0 or 2.5 increased the detection rate of metastatic lymph nodes by 4.1%, and 6.9%, respectively. Delayed imaging often showed speckle-like radioactive foci in lymph nodes with reactive hyperplasia and increased FDG uptake throughout the nodes in metastatic lymph nodes. The lymph node short-axis diameter, SUVmean, and delayed index of MTV (DIMTV) were independent predictors for differentiating metastatic lymph nodes from reactive hyperplasia, and their combination showed better differentiation performance than the individual predictors. In high-risk patients, the probability of lymph node metastasis was as high as 97.6%. CONCLUSION: Dual time-point imaging can detect more metastatic lymph nodes. Some lymph nodes with hyperplasia show speckle-like radioactive foci on delayed imaging. The lymph node short-axis diameter, SUVmean, and DIMTV are three important parameters for predicting lymph node metastasis.

A phase II study of efficacy and safety of the MEK inhibitor tunlametinib in patients with advanced NRAS-mutant melanoma.

BACKGROUND: NRAS-mutant melanoma is an aggressive subtype with poor prognosis; however, there is no approved targeted therapy to date worldwide. METHODS: We conducted a multicenter, single-arm, phase II, pivotal registrational study that evaluated the efficacy and safety of the MEK inhibitor tunlametinib in patients with unresectable, stage III/IV, NRAS-mutant melanoma (NCT05217303). The primary endpoint was objective response rate (ORR) assessed by independent radiological review committee (IRRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The secondary endpoints included progression-free survival (PFS), disease control rate (DCR), duration of response(DOR), overall survival (OS) and safety. FINDINGS: Between November 2, 2020 and February 11, 2022, a total of 100 patients were enrolled. All (n = 100) patients received at least one dose of tunlametinib (safety analysis set [SAS]) and 95 had central laboratory-confirmed NRAS mutations (full analysis set [FAS]). In the FAS, NRAS mutations were observed at Q61 (78.9%), G12 (15.8%) and G13 (5.3%). The IRRC-assessed ORR was 35.8%, with a median DOR of 6.1 months. The median PFS was 4.2 months, DCR was 72.6% and median OS was 13.7 months. Subgroup analysis showed that in patients who had previously received immunotherapy, the ORR was 40.6%. No treatment-related deaths occurred. INTERPRETATION: Tunlametinib showed promising antitumor activity with a manageable safety profile in patients with advanced NRAS-mutant melanoma, including those who had prior exposure to immunotherapy. The findings warrant further validation in a randomized clinical trial.