Hierarchical 2D/1D MOFs/electrospun ZIF-67 modified carbon nanofibers heterostructure electrode for high-performance asymmetric supercapacitor.

In this paper, a 2 dimensional (2D) metal-organic frameworks (MOFs) nanosheets grown on 1D ZIF-67 modified carbon nanofibers (CNFs) was designed and fabricated with a hierarchical heterostructure. The hierarchical 2D/1D MOFs/CCNF offers rich electrochemical active sites and favorable ion/electron diffusion pathways. The synergistic effect of Co, CNFs and MOFs from heterostructures contributes to superb electrochemical activities. Benefiting from the hierarchical heterostructures optimized by the mass ratio of ZIF-67/PAN and CCNF/NiMOF as well as the type of substrates, CCNF-20@MOF showed a specific capacity of 361.50 C g-1 at 0.5 A g-1, whose charge storage mechanism is dominated by diffusion control. Meanwhile, a bamboo-derived carbon material (BBC) was designed in the solid-state asymmetric supercapacitor (CCNF-20@MOF//BBC). The device exhibited an energy density of 38.89 Wh kg-1 at the power density of 800.02 W kg-1 and excellent cycling stability, that exceed many MOFs based devices. Moreover, it could be successfully used for LED light-emitting, demonstrating a good application prospect. This work provides a feasible strategy for the improved performance of MOFs and CNFs based materials in the field of energy storage.

First-in-human, phase 1 dose-escalation and dose-expansion study of a RET inhibitor SY-5007 in patients with advanced RET-altered solid tumors.

Oncogenic RET alteration is an important, tissue-agnostic therapeutic target across diverse cancers. We conducted a first-in-human phase 1 study on SY-5007, a potent and selective RET inhibitor, in patients with RET-altered solid tumors. Primary endpoints were safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D). Secondary endpoints included pharmacokinetics and preliminary anti-tumor activity. A total of 122 patients were enrolled (17 in dose-escalation phase and 105 in dose-expansion phase), including 91 with non-small cell lung cancer, 23 with medullary thyroid cancer, 7 with papillary thyroid cancer and 1 with gastric cancer. Treatment-related adverse events (TRAEs) were reported in 96.7% of patients, with the most common grade ≥ 3 TRAEs being hypertension (22.1%), diarrhea (16.4%), hypertriglyceridemia (6.6%), and neutropenia (6.6%). The exposure to SY-5007 was dose proportional. Among the 116 efficacy-evaluable patients, the overall objective response rate (ORR) was 57.8%, with 70.0% in treatment-naïve patients and 51.3% in previously treated patients. The median progression-free survival (PFS) was 21.1 months. Efficacy was observed regardless of tumor types and previous therapies. Biomarker analysis of 61 patients with circulating tumor DNA (ctDNA)-detectable RET alterations showed an ORR of 57.4% and median PFS of 13.8 months. Rapid ctDNA clearance of RET alteration correlated with faster responses and improved outcomes. In relapsed patients, off-target induced resistance was observed in 57.1% (12/21), with no on-target RET alterations identified. In conclusion, SY-5007 was well-tolerated and showed promising efficacy in patients with RET-altered solid tumors. Serial ctDNA monitoring may unveil treatment response and potential resistance mechanisms (NCT05278364).

The surface-based degree centrality of patients with lifelong premature ejaculation: A resting-state fMRI study.

The aim of this study was to investigate alterations in the resting-state brain functional network characteristics of lifelong premature ejaculation (PE) patients using surface-based degree centrality (DC), and to analyze the correlation between these alterations and clinical symptoms in PE patients. The study included individuals with lifelong PE (patient group, n = 36) and a control group matched by age and education level (control group, n = 22). Resting-state functional magnetic resonance imaging (fMRI) scans were performed on all participants. Surface-based degree centrality analysis was conducted and the differences between the two groups were compared using t-tests. Further, the DC values of brain regions showing significant differences were correlated with clinical symptoms. Compared to the control group, the patient group exhibited significantly reduced degree centrality (DC) values in the left precuneus and significantly increased DC values in the right supplementary motor area (SMA). Furthermore, intravaginal ejaculatory latency time (IELT) and Chinese Index of Premature Ejaculation (CIPE) values were positively correlated with left precuneus DC values and negatively correlated with right SMA DC values. Patients with primary lifelong ejaculation demonstrate abnormalities in key brain network nodes and their connections with relevant brain regions, which are strongly associate with clinical symptoms. These findings enhance our understanding of the neuronal pathological changes in PE patients.

Prenatal diagnosis, ultrasound findings, and pregnancy outcome of 17q12 deletion and duplication syndromes: a retrospective case series.

OBJECTIVE: Analyze the ultrasound findings, single-nucleotide polymorphism array (SNP-array) results, and pregnancy outcomes of fetuses with 17q12 deletions and duplications in the second and third trimesters. Explore the prenatal ultrasound characteristics and pregnancy outcomes of these fetuses. METHODS: Retrospective data were collected for 16 fetuses diagnosed with 17q12 deletion and seven fetuses with 17q12 duplication through SNP-array during prenatal diagnosis at a single Chinese tertiary medical center from January 2017 to December 2023. Maternal demographics, ultrasound findings of the fetuses, SNP-array results, pregnancy outcomes, and follow-up information were reviewed and analyzed. Peripheral blood from the parents was extracted to determine whether the CNVs in the fetuses were inherited or de novo. RESULTS: The copy-number variation (CNV) sizes ranged from 1.39 to 1.94 Mb in cases of 17q12 deletion and from 1.42 to 1.91 Mb in cases of 17q12 duplication. These CNVs included 15 OMIM genes, such as HNF1B, LHX1, and ACACA. In fetuses with a 17q12 deletion, the primary manifestation was renal abnormalities (93.8%, 15/16). Of these, 13 cases (81.3%, 13/16) exhibited bilateral or unilateral hyperechogenic kidneys, and 12 cases (75%, 12/16) had multicystic hyperechogenic kidneys. Two cases (12.5%, 2/16) showed multiple organ structural abnormalities. In fetuses with a 17q12 duplication, four cases (57.1%, 4/7) revealed cardiovascular system abnormalities, including tetralogy of fallot, pulmonary artery stenosis, ventricular septal defect, and tricuspid regurgitation. Two cases (28.6%, 2/7) presented with upper gastrointestinal obstruction. Additionally, one case was particularly unique, characterized by multiple structural malformations, such as ventricular septal defect, microcephaly, cleft lip, and palate. Nine cases opted for pregnancy termination, and 14 chose to continue the pregnancy. Two cases underwent surgical treatment after birth for upper gastrointestinal obstruction, and the prognosis was good. Among the 10 cases of 17q12 deletion, six cases showed consistent prenatal ultrasound findings and postnatal clinical features. Four cases were found to have discrepancies with prenatal ultrasound findings; while the renal ultrasound phenotype appeared normal during the last follow-up, two of these cases were subsequently diagnosed with neuropsychiatric phenotypes. CONCLUSION: Our study expanded the clinical phenotype spectrum of fetuses with 17q12 deletion and duplication, and conducted a preliminary evaluation of prenatal ultrasound findings and postnatal clinical phenotypes in follow-up cases. We further demonstrated a high correlation between fetuses with 17q12 deletion and hyperechogenic, multicystic kidneys. The primary manifestations in fetuses with 17q12 duplication are likely cardiovascular system malformations, which also exhibit a broad spectrum of phenotypic features.

Targeted Defect Repair and Multi-functional Interface Construction for the Direct Regeneration of Spent LiFePO4 Cathodes.

Due to the low economic benefits and environmental pollution of traditional recycling methods, the disposal of spent LiFePO4 (SLFP) presents a significant challenge. The capacity fade of SLFP cathode is primarily caused by lithium loss and formation of a Fe (III) phase. Herein, a synergistic repair effect is proposed to achieve defect repair and multi-functional interface construction for the direct regeneration of SLFP. Tannic acid (TA) forms a compact coating precursor for a carbon layer on SLFP with abundant functional groups and creates a mildly acidic environment to enhance the reducibility of thiourea (TU). Therefore, TU reduces Fe (III) to Fe (II) and repairs Li-Fe anti-site defects of SLFP, while at the same time acting as a source of N/S-doping elements for the carbon layer at a lower temperature (140 °C). The multi-functional carbon layer improves the properties of the regenerated LiFePO4 (RLFP) due to the enhanced conductivity, structure maintenance and protection, and the improved kinetics of Li+ transport. Furthermore, the Fe─O and P─O bonds are strengthened, further enhancing the structural stability of the RLFP. Consequently, the RLFP demonstrates outstanding performance with a discharge capacity of 141.3 mAh g-1 and capacity retention of 72% after 1000 cycles at 1 C.

Thin Zinc Electrodes Stabilized with Organobromine-Partnered H2O-Zn-MeOH Cluster Ions for Practical Zinc-Metal Pouch Cells.

The utilization of thin zinc (Zn) anodes with a high depth of discharge is an effective strategy to increase the energy density of aqueous Zn metal batteries (ZMBs), but challenged by the poor reversibility of Zn electrode due to the serious Zn-consuming side reactions at the Zn||electrolyte interface. Here, we introduce 2-bromomethyl-1,3-dioxolane (BDOL) and methanol (MeOH) as electrolyte additive into aqueous ZnSO4 electrolyte. In the as-formulated electrolyte, BDOL with a strong electron-withdrawing group (-CH2Br) tends to pair with the H2O-Zn-MeOH complex, leading to the formation of organobromine-partnered H2O-Zn-MeOH cluster ions. During the Zn electrodeposition process, the formed ZnO-dominated by-products induce the polymerization of BDOL monomers, which are previously adsorbed on the electrode. As a result, a uniform dual-layer SEI with ZnO-dominated outer layer and polyether-dominated inner layer is built on the surface of Zn electrode. With such an in-situ formed dual-layer SEI, the Zn||Mg0.9Mn3O7·2.7H2O pouch cell using a 10-um Zn anode (corresponding to a low negative to positive areal capacity ratio of 3.56) successfully operated for 300 cycles with a high capacity retention of 86%, promising a high practical energy density of > 120 Wh/kg (based on the total mass of Zn and Mg0.9Mn3O7·2.7H2O).

The uncertain correlation of ANCAs in patients with lupus nephritis and crescents, an experience from Chinese centers.

BACKGROUND: The precise role of anti-neutrophil cytoplasmic antibodies (ANCAs) in the pathologic course of crescentic lupus nephritis (LN) remains unclear. Our study aimed to assess whether ANCA-positive serology in patients with LN and crescents is associated with different clinicopathologic features and outcomes. METHODS: We reviewed the records of 658 patients diagnosed with LN between 2010 and 2022. Among them, 64 (9.7%) patients who had complete follow-up and clinical data were reclassified as crescentic glomerulonephritis. Of these, 11 patients with incomplete ANCA data and 7 patients with less than 10 glomeruli under light microscopy were excluded; ultimately, 46 patients were enrolled: 12 with ANCA positivity and 34 with ANCA negativity. Clinicopathological characteristics and outcomes were analysed and compared. RESULTS: Our data did not reveal any differences in clinical or laboratory parameters or histopathological features except for a significantly higher level of proteinuria or proportion of nephrotic syndrome (p < 0.05) at presentation before biopsy in the ANCA-negative group than in the ANCA-positive group,and a lower level of serum albumin (p < 0.05) in the ANCA-negative group than in the ANCA-positive group. No significant differences in complete remission or partial response were detected between the two groups based on the 2021 KDIGO criterion. CONCLUSION: Short-term follow-up (average follow-up time of less than 3 years) did not reveal any difference in outcomes between ANCA-positive and ANCA-negative crescentic LN. However, the role of ANCAs in the pathological course of crescentic lupus nephropathy and the effect of ANCAs on long-term outcomes remain to be determined.

Immunotherapy for glioblastoma: current state, challenges, and future perspectives.

Glioblastoma (GBM) is an aggressive and lethal type of brain tumor in human adults. The standard of care offers minimal clinical benefit, and most GBM patients experience tumor recurrence after treatment. In recent years, significant advancements have been made in the development of novel immunotherapies or other therapeutic strategies that can overcome immunotherapy resistance in many advanced cancers. However, the benefit of immune-based treatments in GBM is limited because of the unique brain immune profiles, GBM cell heterogeneity, and immunosuppressive tumor microenvironment. In this review, we present a detailed overview of current immunotherapeutic strategies and discuss the challenges and potential molecular mechanisms underlying immunotherapy resistance in GBM. Furthermore, we provide an in-depth discussion regarding the strategies that can overcome immunotherapy resistance in GBM, which will likely require combination therapies.

Dual targeting macrophages and microglia is a therapeutic vulnerability in models of PTEN-deficient glioblastoma.

Tumor-associated macrophages and microglia (TAMs) are critical for tumor progression and therapy resistance in glioblastoma (GBM), a type of incurable brain cancer. We previously identified lysyl oxidase (LOX) and olfactomedin like-3 (OLFML3) as essential macrophage and microglia chemokines, respectively, in GBM. Here, single-cell transcriptomics and multiplex sequential immunofluorescence followed by functional studies demonstrate that macrophages negatively correlate with microglia in the GBM tumor microenvironment. LOX inhibition in PTEN-deficient GBM cells upregulates OLFML3 expression via the NF-κB-PATZ1 signaling pathway, inducing a compensatory increase of microglia infiltration. Dual targeting macrophages and microglia via inhibition of LOX and the CLOCK-OLFML3 axis generates potent anti-tumor effects and offers a complete tumor regression in more than 60% of animals when combined with anti-PD1 therapy in PTEN-deficient GBM mouse models. Thus, our findings provide a translational triple therapeutic strategy for this lethal disease.

Advancing gastrointestinal stromal tumor management: The role of imagomics features in precision risk assessment.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) vary widely in prognosis, and traditional pathological assessments often lack precision in risk stratification. Advanced imaging techniques, especially magnetic resonance imaging (MRI), offer potential improvements. This study investigates how MRI imagomics can enhance risk assessment and support personalized treatment for GIST patients. AIM: To assess the effectiveness of MRI imagomics in improving GIST risk stratification, addressing the limitations of traditional pathological assessments. METHODS: Analyzed clinical and MRI data from 132 GIST patients, categorizing them by tumor specifics and dividing into risk groups. Employed dimension reduction for optimal imagomics feature selection from diffusion-weighted imaging (DWI), T1-weighted imaging (T1WI), and contrast enhanced T1WI with fat saturation (CE-T1WI) fat suppress (fs) sequences. RESULTS: Age, lesion diameter, and mitotic figures significantly correlated with GIST risk, with DWI sequence features like sphericity and regional entropy showing high predictive accuracy. The combined T1WI and CE-T1WI fs model had the best predictive efficacy. In the test group, the DWI sequence model demonstrated an area under the curve (AUC) value of 0.960 with a sensitivity of 80.0% and a specificity of 100.0%. On the other hand, the combined performance of the T1WI and CE-T1WI fs models in the test group was the most robust, exhibiting an AUC value of 0.834, a sensitivity of 70.4%, and a specificity of 85.2%. CONCLUSION: MRI imagomics, particularly DWI and combined T1WI/CE-T1WI fs models, significantly enhance GIST risk stratification, supporting precise preoperative patient assessment and personalized treatment plans. The clinical implications are profound, enabling more accurate surgical strategy formulation and optimized treatment selection, thereby improving patient outcomes. Future research should focus on multicenter studies to validate these findings, integrate advanced imaging technologies like PET/MRI, and incorporate genetic factors to achieve a more comprehensive risk assessment.

Unraveling the nexus of nesprin in dilated cardiomyopathy: From molecular insights to therapeutic prospects.

Dilated cardiomyopathy is a complex and debilitating heart disorder characterized by the enlargement and weakening of the cardiac chambers, leading to impaired contractility and heart failure. Nesprins, a family of nuclear envelope spectrin repeat proteins that include isoforms Nesprin-1/-2, are integral components of the LInker of Nucleoskeleton and Cytoskeleton complex. They facilitate the connection between the nuclear envelope and the cytoskeleton, crucial for maintaining nuclear architecture, migration and positioning, and mechanical transduction and signaling. Nesprin-1/-2 are abundantly expressed in cardiac and skeletal muscles.They have emerged as key players in the pathogenesis of dilated cardiomyopathy. Mutations in synaptic nuclear envelope-1/-2 genes encoding Nesprin-1/-2 are associated with dilated cardiomyopathy, underscoring their significance in cardiac health. This review highlights the all known cases of Nesprin-1/-2 related dilated cardiomyopathy, focusing on their interactions with the nuclear envelope, their role in mechanical transduction, and their influence on gene expression. Moreover, it delves into the underlying mechanisms through which Nesprin dysfunction disrupts nuclear-cytoskeletal coupling, leading to abnormal nuclear morphology, impaired mechanotransduction, and altered gene regulation. The exploration of Nesprin's impact on dilated cardiomyopathy offers a promising avenue for therapeutic interventions aimed at ameliorating the disease. This review provides a comprehensive overview of recent advancements in understanding the pivotal role of Nesprins in dilated cardiomyopathy research.

An osmesl mutant delayed rice leaf senescence through inhibiting cell death by OsBI-1.

Leaf senescence following heading in rice is subject to rigorous regulation, with many of the underlying control mechanisms remaining largely unknown. In this study, we identified a novel gene, OsMESL, which exerts a positive regulatory effect on leaf senescence in rice. The T-DNA insertion mutant known as osmesl and RNA interference plants displayed a phenotype characterized by stay-green after heading. Genetic analysis indicated that the mutant phenotype could be rescued through complementation, while the overexpression of OsMESL accelerated leaf senescence after heading, underscoring OsMESL's positive regulatory role in rice leaf senescence. Subsequent investigations revealed that OsMESL modulates the process of cell death by influencing the stability of its interacting protein, the cell death suppressor OsBI-1, thereby governing leaf senescence. Furthermore, the leaves of the osmesl mutant exhibited a delayed reduction in photosynthesis, along with increased grain length and 1000-grain weight. In conclusion, we identified OsMESL as a novel positive regulator of leaf senescence in rice, which likely participates in leaf senescence through the mediation of cell death by OsBI-1, resulting in the phenotype of stay-green in the osmesl mutant after heading.

The asymmetric opening of HIV-1 Env by a potent CD4 mimetic enables anti-coreceptor binding site antibodies to mediate ADCC.

HIV-1 envelope glycoproteins (Env) from primary HIV-1 isolates typically adopt a pretriggered "closed" conformation that resists to CD4-induced (CD4i) non-neutralizing antibodies (nnAbs) mediating antibody-dependent cellular cytotoxicity (ADCC). CD4-mimetic compounds (CD4mcs) "open-up" Env allowing binding of CD4i nnAbs, thereby sensitizing HIV-1-infected cells to ADCC. Two families of CD4i nnAbs, the anti-cluster A and anti-coreceptor binding site (CoRBS) Abs, are required to mediate ADCC in combination with the indane CD4mc BNM-III-170. Recently, new indoline CD4mcs with improved potency and breadth have been described. Here, we show that the lead indoline CD4mc, CJF-III-288, sensitizes HIV-1-infected cells to ADCC mediated by anti-CoRBS Abs alone, contributing to improved ADCC activity. Structural and conformational analyses reveal that CJF-III-288, in combination with anti-CoRBS Abs, potently stabilizes an asymmetric "open" State-3 Env conformation, This Env conformation orients the anti-CoRBS Ab to improve ADCC activity and therapeutic potential.

Lipid-laden macrophages recycle myelin to feed glioblastoma.

Tumor-associated microglia and macrophages (TAMs) make up the largest immune cell population in the glioblastoma (GBM) tumor microenvironment (TME). Given the heterogeneity and plasticity of TAMs in the GBM TME, understanding the context-dependent cancer cell-TAM symbiotic interaction is crucial for understanding GBM biology and developing effective therapies. In a recent issue of Cell, Kloosterman and colleagues identified a subpopulation of GPNMBhigh lipid-laden microglia and macrophages (LLMs) in GBM. Mesenchymal-like (MES-like) GBM cells help to generate the LLM phenotype. Reciprocally, LLMs are epigenetically rewired to recycle myelin and transfer the lipid from myelin to cancer cells, fueling MES-like GBM progression in an LXR/ABCA1-dependent manner. Together, leveraging LLMs opens new therapeutic possibilities for rewiring the metabolism-mediated tumor-TAM interaction during GBM progression.

Electrophoresis-Correlative Ion Mobility Deepens Single-cell Proteomics in Capillary Electrophoresis Mass Spectrometry.

Detection of trace-sensitive signals is a current challenge is single-cell mass spectrometry (MS) proteomics. Separation prior to detection improves the fidelity and depth of proteome identification and quantification. We recently recognized capillary electrophoresis (CE) electrospray ionization (ESI) for ordering peptides into mass-to-charge (m/z)-dependent series, introducing electrophoresis-correlative (Eco) data-independent acquisition. Here, we demonstrate that these correlations based on electrophoretic mobility (µ ef ) in the liquid phase are transferred into the gas phase, essentially temporally ordering the peptide ions into charge-dependent ion mobility (IM, 1/K 0 ) trends (ρ > 0.97). Rather than sampling the entire IM region broadly, we pursued these predictable correlations to schedule narrower frames. Compared to classical ddaPASEF, Eco-framing significantly enhanced the resolution of IM on a trapped ion mobility mass spectrometer (timsTOF PRO). This approach returned ∼50% more proteins from HeLa proteome digests approximating to one-to-two cells, identifying ∼962 proteins from ∼200 pg in <20 min of effective electrophoresis, without match-between-runs. As a proof of principle, we deployed Eco-ddaPASEF on 1,157 proteins by analyzing <4% of the total proteome in single, yolk-laden embryonic stem cells (∼80-µm) that were isolated from the animal cap of the South African clawed frog ( Xenopus laevis ). Quantitative profiling of 9 different blastomeres revealed detectable differences among these cells, which are normally fated to form the ectoderm but retain pluripotentiality. Eco-framing effectively deepens the proteome sensitivity in IMS using ddaPASEF, raising the possibility of a proteome-driven classification of embryonic cell differentiation.

Prognostic role of dynamic changes in inflammatory indicators in patients with non-small cell lung cancer treated with immune checkpoint inhibitors-a retrospective cohort study.

Background: Immune checkpoint inhibitors (ICIs) have become one of the standard treatments for non-small cell lung cancer (NSCLC) patients without driver mutations. However, a considerable proportion of patients suffer from severe immune side effects and fail to respond to ICIs. As effective biomarkers, programmed cell death ligand 1 (PD-L1) expression, microsatellite instability (MSI), the tumor mutation burden (TMB) and tumor-infiltrating lymphocytes (TILs) require invasive procedures that place heavy physical and psychological burdens on patients. This study aims to identify simple and effective markers to optimize patient selection through therapeutic decisions and outcome prediction. Methods: This retrospective study comprised 95 patients with metastatic NSCLC who were treated with ICIs either as the standard of care or in a clinical trial. The following data were extracted from the medical records. The baseline and dynamic neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were calculated in the present study. Responses were assessed by computed tomography (CT) imaging and classified according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 every 6-12 weeks during treatment. Results: In total, 95 patients were included in the present study. The median age of patients was 61 years, 83.2% (79/95) patients were male, 62.1% (59/95) were former or current smokers, 66.3% (63/95) had adenocarcinoma, 93.7% (89/95) had stage IV disease, and 87.4% were without molecular alterations. A higher overall response rate (ORR) and prolonged median progression-free survival (PFS) was observed in patients with a lower cycle 3 (C3) NLR [7.7 vs. 5.5 months, hazard ratio (HR): 1.70, 95% confidence interval (CI): 0.90-3.22; P=0.12] and derived NLR (dNLR) (8.2 vs. 5.6 months, HR: 1.67, 95% CI: 0.94-2.97; P=0.08). After two cycles of ICI treatment, patients who had an increased NLR, dNLR, and PLR had a lower ORR and an inferior median PFS than those with a decreased NLR (5.5 vs. 8.5 months, HR: 1.87, 95% CI: 1.09-3.21; P=0.02), dNLR (5.6 vs. 8.4 months, HR: 1.49, 95% CI: 0.87-2.57; P=0.15), and PLR (11.8 vs. 5.5 months, HR: 2.28, 95% CI: 1.32-3.94; P=0.003). Moreover, patients with both an increased NLR and PLR had a worse ORR and median PFS than those with either an increased NLR or PLR, or both an increased NLR and PLR (11.8 vs. 5.5 vs. 5.6 months, P=0.003). In addition, the dynamic changes in the PLR could serve as an independent predictive factor of PFS in NSCLC patients treated with ICIs. Conclusions: Elevated dynamic changes in the NLR and PLR were associated with lower response rates and shorter PFS in the patients with NSCLC treated with ICIs. Our results also highlight the role of dynamic changes in the PLR in identifying patients with NSCLC who could benefit from ICIs.

Proteomic Profiles of Maternal Plasma Extracellular Vesicles for Prediction of Preeclampsia.

PROBLEM: Preeclampsia is a heterogeneous syndrome of diverse etiologies and molecular pathways leading to distinct clinical subtypes. Herein, we aimed to characterize the extracellular vesicle (EV)-associated and soluble fractions of the maternal plasma proteome in patients with preeclampsia and to assess their value for disease prediction. METHOD OF STUDY: This case-control study included 24 women with term preeclampsia, 23 women with preterm preeclampsia, and 94 healthy pregnant controls. Blood samples were collected from cases on average 7 weeks before the diagnosis of preeclampsia and were matched to control samples. Soluble and EV fractions were separated from maternal plasma; EVs were confirmed by cryo-EM, NanoSight, and flow cytometry; and 82 proteins were analyzed with bead-based, multiplexed immunoassays. Quantile regression analysis and random forest models were implemented to evaluate protein concentration differences and their predictive accuracy. Preeclampsia subgroups defined by molecular profiles were identified by hierarchical cluster analysis. Significance was set at p < 0.05 or false discovery rate-adjusted q < 0.1. RESULTS: In preterm preeclampsia, PlGF, PTX3, and VEGFR-1 displayed differential abundance in both soluble and EV fractions, whereas angiogenin, CD40L, endoglin, galectin-1, IL-27, CCL19, and TIMP1 were changed only in the soluble fraction (q < 0.1). The direction of changes in the EV fraction was consistent with that in the soluble fraction for nine proteins. In term preeclampsia, CCL3 had increased abundance in both fractions (q < 0.1). The combined EV and soluble fraction proteomic profiles predicted preterm and term preeclampsia with an AUC of 78% (95% CI, 66%-90%) and 68% (95% CI, 56%-80%), respectively. Three clusters of preeclampsia featuring distinct clinical characteristics and placental pathology were identified based on combined protein data. CONCLUSIONS: Our findings reveal distinct alterations of the maternal EV-associated and soluble plasma proteome in preterm and term preeclampsia and identify molecular subgroups of patients with distinct clinical and placental histopathologic features.

In Situ, Fusion-Free, Multiplexed Detection of Small Extracellular Vesicle miRNAs for Cancer Diagnostics.

Tumor-derived small extracellular vesicle (sEV) microRNAs (miRNAs) are emerging biomarkers for cancer diagnostics. Conventional sEV miRNA detection methods necessitate the lysis of sEVs, rendering them laborious and time-consuming and potentially leading to damage or loss of miRNAs. Membrane fusion-based in situ detection of sEV miRNAs involves the preparation of probe-loaded vesicles (e.g., liposomes or cellular vesicles), which are typically sophisticated and require specialist equipment. Membrane perforation methods employ chemical treatments that can induce severe miRNA degradation or leaks. Inspired by previous studies that loaded nucleic acids into EVs or cells using hydrophobic tethers for therapeutic applications, herein, we repurposed this strategy by conjugating a hydrophobic tether onto molecular beacons to aid their transportation into sEVs, allowing for in situ detection of miRNAs in a fusion-free and multiplexing manner. This method enables simultaneous detection of multiple miRNA species within serum-derived sEVs for the diagnosis of prostate cancer, breast cancer, and gastric cancer with an accuracy of 83.3%, 81.8%, and 100%, respectively, in a cohort of 66 individuals, indicating that it holds a high application potential in clinical diagnostics.

Esketamine use for primary intelligent analgesia in adults with severe burns: A double-blind randomized trial with effects on analgesic efficacy, gastrointestinal function and mental state.

BACKGROUND: Opioid consumption for analgesia in burn patients is enormous. Non-opioid analgesics for burn pain management may result in opioid sparing, reducing opioid-related adverse reactions and drug tolerance or addiction. METHODS: A dual-center, randomized controlled trial assessed Esketamine for the perioperative period in patients with severe [20-50 % total body surface area (TBSA)] and extensive (≥ 50 % TBSA) burns, comparing analgesia with standard anesthesia. Sixty patients were randomly allocated (1:1 ratio) to two arms. In the Treatment Arm, patients received intra-operative Esketamine and postoperative intravenous primary intelligent analgesia pump with Esketamine. Patients in the Control Arm received the same intervention as Treatment Arm without Esketamine. The primary endpoint was subjective analgesic efficacy (SAE) evaluated on Day 28 or the day before hospital discharge. Secondary outcomes included the postoperative Numeric Pain Rating (NPR) Scale at rest (NPRr) and during movement (NPRm) and opioid consumption. Gastrointestinal dysfunction Scores (GIDS) and serum markers of intestinal injury [intestinal fatty acid-binding protein 2 (iFabp2) and apolipoproteinA2 (ApoA2)] were measured in the 1st and 4th post-injury weeks. Depression and sleep quality were assessed by relevant questionnaires. RESULTS: Fifty-five patients were included in the analysis. Esketamine-treated Arm recorded a better analgesic efficacy than the Control Arm (proportion of patients with Grade 1 or 2 SAE scores, 67.9 % vs. 40.7 %, p = 0.022). Esketamine-treated patients had lower NPRm values (p = 0.033) and lower daily opioid consumption (p = 0.033) when compared with Controls. Esketamine-treated patients showed comparable gastrointestinal recovery to those in the Control Arm. The overall sleep quality might be improved in the Treatment Arm. CONCLUSIONS: Esketamine use is safe for perioperative primary intelligent analgesia of severe burns, resulting in improved resting pain control and lower opioid requirements. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trial Registry (www.chictr.org.cn/) (ChiCTR2000034069).

Triphasic Hydroxysilylation of Alkenes by Mechanically Piezoelectric Catalysis.

The 1,2-hydroxysilylation of alkenes is crucial for synthesizing organosilicon compounds which are key intermediates in material science, pharmaceuticals, and organic synthesis. The development of strategies employing hydrogen atom transfer pathways is currently hindered by the existence of various competing reactions. Herein, we reported a novel mechanochemical strategy for the triphasic 1,2-hydroxysilylation of alkenes through a single-electron-transfer pathway. Our approach not only circumvents competitive reactions to enable the first-ever 1,2-hydroxysilylation of unactivated alkenes but also pioneers the research in mechanic force-induced triphasic reactions under ambient conditions. This gentle method offers excellent compatibility with various functional groups, operates under simple and solvent-free conditions, ensures rapid reaction time. Preliminary mechanistic investigations suggest that silylboronate can be transformed to a silicon radical by highly polarized Li2TiO3 particles and oxygen under ball-milling condition.