Single-cell transcriptomic analysis of the immune microenvironment in pediatric acute leukemia.

Relapse and treatment resistance pose significant challenges in the management of pediatric B cell acute lymphoblastic leukemia (B-ALL) and acute myeloid leukemia (AML). The efficacy of immunotherapy in leukemia remains limited due to factors such as the immunosuppressive tumor microenvironment (TME) and lack of suitable immunotherapeutic targets. Thus, an in-depth characterization of the TME in pediatric leukemia is warranted to improve the efficacy of immunotherapy. Here, we used single-cell RNA sequencing (scRNA-seq) to characterize the TME of pediatric B-ALL and AML, focusing specifically on bone-marrow-derived T cells. Moreover, we investigated the transcriptome changes during the initiation, remission, and relapse stages of pediatric AML. Our findings revealed that specific functional expression programs correlated with fluctuations in various T cell subsets, which may be associated with AML progression and relapse. Furthermore, our analysis of cellular communication networks led to the identification of VISTA, CD244, and TIM3 as potential immunotherapeutic targets in pediatric AML. Finally, we detected elevated proportions of γδ T cells and associated functional genes in samples from pediatric patients diagnosed with B-ALL and AML, which could inform the development of novel therapeutic approaches, potentially focusing on γδ T cells.

Evolving consequences of right coronary artery to right atrium: coronary cameral fistula-a case report.

Background: Coronary cameral fistula is a rare diagnosis, which may be picked up incidentally on cardiac imaging. While majority of cases is asymptomatic, they can be complicated by myocardial ischaemia, arrhythmias, heart failure, infective endocarditis, and rarely rupture or thrombosis of the fistula leading to sudden death. Case summary: A 73-year-old female presents with fever, lethargy, and examination finding of a continuous cardiac murmur. CT coronary angiogram confirmed the presence of a coronary cameral fistula, with an aneurysmal RCA seen arising from the right coronary sinus, following an extensive tortuous course wrapping around the heart, and terminating at the right atrium. While there was initial streptococcus bacteraemia identified on blood culture sampling, no obvious masses were detected on the valves, chambers, or along the course of the fistula. Over time, she develops anginal chest pain and heart failure symptoms, with progressive dilatation of the right ventricle and functional tricuspid regurgitation secondary to shunting of the fistula into the right chambers. Surgical intervention was then pursued and successfully addressed these complications. Discussion: This case report highlights the importance of advanced imaging modalities for accurate diagnosis of coronary cameral fistulae, addressing late manifestations of the disease and the necessity for a collaborative, multidisciplinary approach in managing complex cardiac anomalies.

Plasma triglyceride is associated with the recurrence of atrial fibrillation after radiofrequency catheter ablation: A retrospective study.

BACKGROUND: The purpose of this study was to explore the association between triglycerides (TGs) and the risk of atrial fibrillation (AF) recurrence. METHODS AND RESULTS: Included were adult patients with AF who underwent radiofrequency catheter ablation in the Affiliated Changzhou Second People's Hospital of Nanjing Medical University. The enrolled patients were divided into the AF recurrence group and the sinus rhythm (SR) maintenance group. The univariate Cox regression analysis and Kaplan-Meier survival curve were performed estimate the association between TG and the risk of AF recurrence. Of the 402 patients, 79 (19.7%) experienced recurrence of AF after ablation. The TG level was significantly higher in the AF recurrence group than in the SR-maintaining group. Patients were grouped by quartile of TG levels, with Quartile 1 and Quartile 2 defined as the low concentration group, Quartile 3 as the moderate concentration group, and Quartile 4 as the high concentration group. Multivariate Cox regression analysis showed that the moderate concentration group (p = .02, hazard ratio [HR]: 2.331, 95% confidence interval [CI]: 1.141-4.762) and high concentration group (p = .007, HR: 2.873, 95% CI: 1.332-6.199) were associated with an increased risk of AF recurrence compared with the low concentration group. The median follow-up was 1.17 years, it is indicated that a higher risk of recurrent AF was observed in the moderate concentration and high concentration group (log-rank: χ2 = 7.540, p = .023). CONCLUSION: Our data suggest that an elevated TG level measured before catheter ablation is associated with an increased risk of AF recurrence.

Microenvironment Responsive Hydrogel Exerting Inhibition of Cascade Immune Activation and Elimination of Synovial Fibroblasts for Rheumatoid Arthritis Therapy.

Rheumatoid arthritis (RA) is a progressive autoimmune disease and drug therapy has been restricted due to poor therapeutic efficacy and adverse effects. In RA synovium, dendritic cells present self-antigens to activate cascade immune pathway. Furthermore, downstream macrophages secrete high levels of pro-inflammatory cytokines; Hyperplasia of activated synovial fibroblasts (FLS) is responsible for hypoxic synovium microenvironment, secretion of cytokines/chemokines and erosion of bone/cartilage tissues. Positive feedback loop of inflammation between macrophages and FLS independent of antigen-presentation is constructed. Herein, an injectable pH-sensitive peptide hydrogel encapsulating siRNA/Methotrexate-polyethyleneimine (siMP, including sip65MP, sip38MP, siCD86MP) and Bismuthene nanosheet/Methotrexate-polyethyleneimine (BiMP) is successfully developed. Among them, siCD86MP reduces protein level of co-stimulatory molecule CD86 while sip65MP and sip38MP separately inhibit NF-κB and MAPK-p38 pathways of macrophages and FLS to suppress secretion of cytokines and MMPs. Meanwhile, reduction in anti-apoptotic property of FLS induced by inhibition of NF-κB pathway has a synergistic effect with photodynamic therapy (PDT) and photothermal therapy (PTT) mediated by BiMP for FLS elimination, effectively ameliorating hypoxic synovium microenvironment. After being injected into synovium, hydrogel responds to acidic microenvironment and serves as a reservoir for sustained drug release and inherent retention capacity of which enables cationic nanoparticles to bypass tissue barrier for precise synovium targeting. This brand-new drug delivery system combines modulating cascade immune pathway from beginning to end by RNAi and eliminating FLS for improving synovium microenvironment by phototherapy together, providing a robust strategy for clinical RA treatment.

Synthesis of gem-Difluorohomoallyl Amines via a Transition-Metal-Free Defluorinative Alkylation of Benzyl Amines with Trifluoromethyl Alkenes.

A mild and transition-metal-free defluorinative alkylation of benzyl amines with trifluoromethyl alkenes is reported. The features of this protocol are easy-to-obtain starting materials, a wide range of substrates, and functional group tolerance as well as high atom economy, thus offering a strategy to access a variety of gem-difluorohomoallyl amines, which are extensively distributed in pharmaceuticals and bioactive agents, with excellent chemoselectivity. The primary products can be further transformed to a diversity of 2-fluorinated pyrroline compounds.

Contrast-enhanced Imaging in Peripheral Pulmonary Lesions: The Role in US-guided Biopsies.

Purpose To compare the tissue adequacy and diagnostic accuracy of US-guided biopsies of peripheral pulmonary lesions (PPLs) with and without contrast agents. Materials and Methods A retrospective study was conducted at four medical centers in patients with PPLs who underwent US-guided percutaneous transthoracic needle biopsy (PTNB) between January 2017 and October 2022. The patients were divided into contrast-enhanced US (CEUS) and US groups based on whether prebiopsy CEUS evaluation was performed. Tissue adequacy and the diagnostic accuracy of PTNB, stratified by lesion size, were analyzed and compared between groups. A propensity score matching (PSM) analysis was conducted using the nearest-neighbor matching method. Results A total of 1027 lesions were analyzed, with 634 patients (mean age, 59.4 years ± 13.0 [SD]; 413 male) in the US group and 393 patients (mean age, 61.2 years ± 12.5; 270 male) in the CEUS group. The CEUS group produced more acceptable samples than the US group (98.2% vs 95.7%; P = .03) and achieved higher diagnostic accuracy (96.9% vs 94.2%; P = .04), with no evidence of a difference in sensitivity (96.7% vs 94.0%; P = .06). PSM and stratified analyses (n = 358 per group) indicated higher tissue adequacy (99.0% vs 95.7%; P = .04) and diagnostic accuracy (98.5% vs 92.9%; P = .006) in the CEUS group compared with the US group for 2-7-cm PPLs but not for lesions larger than 7 cm. Conclusion PTNB with prebiopsy CEUS evaluation demonstrated significantly better tissue adequacy and diagnostic accuracy compared with US guidance alone for PPLs ranging from 2 to 7 cm, with similar biopsy performance achieved between groups for lesions larger than 7 cm. Keywords: Contrast Material, Thoracic Diseases, Ultrasonography, Image-Guided Biopsy © RSNA, 2024.

Effects of cooking with solid fuel on hearing loss in Chinese adults-Based on two cohort studies.

The association between cooking fuel and hearing loss still needs more research to clarify, and two longitudinal cohort studies were explored to find if solid fuel use for cooking affected hearing in Chinese adults. The data from Chinese Health and Retirement Longitudinal Survey (CHARLS) and Chinese Longitudinal Healthy Longevity Survey (CLHLS) were analyzed. Participants (older than 18) without hearing loss at baseline and follow-up visits were included, which were divided into clean fuel and solid fuel groups. Hearing loss rate was from follow-up visits (both in year 2011) until the recent one (year 2018 in CHARLS and 2019 in CLHLS). Cox regressions were applied to examine the associations with adjustment for potential confounders. Fixed-effect meta-analysis was used to pool the results. A total of 9049 participants (average age 8.34 ± 9.12 [mean ± SD] years; 4247 [46.93%] males) were included in CHARLS cohort study and 2265 participants (average age, 78.75 ± 9.23 [mean ± SD] years; 1148 [49.32%] males) in CLHLS cohort study. There were 1518 (16.78%) participants in CHARLS cohort and 451 (19.91%) participants in CLHLS cohort who developed hearing loss. The group of using solid fuel for cooking had a higher risk of hearing loss (CHARLS: HR, 1.16; 95% CI 1.03-1.30; CLHLS: HR, 1.43; 95% CI 1.11-1.84) compared with the one of using clean fuel. Pooled hazard ratio showed the incidence of hearing loss in the solid fuel users was 1.17 (1.03, 1.29) times higher than that of clean fuel users. Hearing loss was associated with solid fuel use and older people were at higher risk. It is advised to replace solid fuel by clean fuel that may promote health equity.

Hexagonal Bipyramidal Mn3Ge5 Cluster and Its One-Dimensional Ferrimagnetic Sandwich Nanowire: Mn3Ge3 Rings as Structural Motifs.

Bipyramidal structures featuring planar rings serve as potential building blocks for one-dimensional (1D) nanostructures. Pure Ge atoms typically prefer to form three-dimensional rather than planar structures. Although a few-metal-doped bipyramids with pure Ge planar rings are predicted for constructing Ge-based 1D nanostructures, there is limited knowledge about those with both Ge and doped atoms on the same planar rings. Here, we report a hexagonal bipyramidal Mn3Ge5 cluster containing a Mn3Ge3 six-membered ring with the potential to construct a 1D germanium-based nanostructure. We investigated the structures and properties of Mn3Ge5-/0 using anion photoelectron spectroscopy and theoretical calculations. Mn3Ge5- has a C3v symmetric distorted hexagonal bipyramidal structure, while Mn3Ge5 has a C2v symmetric hexagonal bipyramidal structure. Chemical bonding analyses show that Mn3Ge5- could be considered as a [Mn3]V[Ge5]6- complex. First-principles calculations indicate that Mn3Ge5 may be used to construct a 1D ferrimagnetic [Mn3Ge5]∞ nanostructure.

LC-MS/MS and EMIT measure the whole blood concentration of cyclosporine A: The two methods yield concordant results within the dynamic range of the latter, but the former shows broader application scenarios.

Cyclosporine A (CsA) is a widely used immunosuppressive drug with a narrow therapeutic index and large individual differences. Its therapeutic and toxic effects are closely related to blood drug concentrations, requiring routine therapeutic drug monitoring (TDM). The current main methods for TDM of CsA are enzyme multiplied immunoassay technique (EMIT) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). However, few study on the method comparison of the EMIT and LC-MS/MS for the measurement of whole blood CsA concentration in children has been reported. In this study, we developed a simple and sensitive LC-MS/MS assay for the determination of CsA, and 657 cases of CsA concentrations were determined from 197 pediatric patients by a routine EMIT assay and by the validated in-house LC-MS/MS method on the same batch of samples, aimed to address the aforementioned concern. Consistency between the two assays was evaluated using linear regression and Bland-Altman analysis. The linear range of LC-MS/MS was 0.500-2000 ng/mL and that of the EMIT was 40-500 ng/mL, respectively. Overall, the correlation between the two methods was significant (r-value ranging from 0.8842 to 0.9441). Unsatisfactory consistency was observed in the concentrations < 40 ng/mL (r = 0.7325) and 200-500 ng/mL (r = 0.6851). Bland-Altman plot showed a mean bias of -18.0 % (±1.96 SD, -73.8 to 37.8 %) between EMIT and LC-MS/MS. For Passing-Bablok regression between EMIT and LC-MS/MS did not differ significantly (p > 0.05). In conclusion, the two methods were closely correlated, but the CsA concentration by LC-MS/MS assay was slightly higher than that by EMIT method. Switching from the EMIT assay to the LC-MS/MS method was acceptable, and the LC-MS/MS method will receive broader application in clinical settings due to its better analytical capabilities, but the results need to be further verified in different laboratories.

Zn-Mediated Fragmentation of N-Alkoxyphthalimides Enabling the Synthesis of gem-Difluoroalkenes.

Zn-mediated generation of alkoxyl radicals from N-alkoxyphthalimides emerged as an efficient approach for forming diverse and valuable alkyl radicals through ß-scission or a hydrogen atom transfer process. The alkyl radical species can be further trapped by α-trifluoromethyl alkenes to construct a series of gem-difluoroalkenes.

A novel treatment modality for rheumatoid arthritis: Inflammation-targeted multifunctional metal-organic frameworks with synergistic phototherapy and chemotherapy.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease with complex pathogenesis. Single chemotherapy struggles to eliminate the disease permanently and reduce the pain owing to drug resistance and inadequate delivery to target cells. This study developed hyaluronic acid (HA)-modified and methotrexate (MTX)-load metal-organic frameworks (denoted as FT-HA-MTX NPs), combining photothermal therapy (PTT), photodynamic therapy (PDT), and chemotherapy to inhibit the progression of RA. In vitro experiments proved that the obtained NPs exhibited good biocompatibility and commendable photothermal conversion efficiency of 36.3 %. Additionally, they promoted ∙OH and O2 production via the Fenton reaction, which dramatically alleviated hypoxia and enhanced ROS generation, and induced substantial mortality in activated RAW 264.7 cells, with cell viability of 31.72 %. Cellular uptake and in vivo imaging confirmed that the modification of HA enabled the NPs to specifically target activated macrophage, ensured prolonged retention of NPs in inflamed synovial tissues, and reduced systemic toxicity. In vivo, after FT-HA-MTX NPs treatment with laser irradiation, the levels of TNF-α and IL-1ß in the synovial tissue were reduced by approximately 50 % compared to those in the inflamed synovium, demonstrating a significant enhancement in the anti-inflammatory effect (p < 0.001). In conclusion, FT-HA-MTX NPs are promising inflammation-targeted multifunctional nanoparticles that combine PTT, PDT, and chemotherapy, thereby significantly inhibiting the progression of RA while reducing systemic toxicity.

Study on energy evolution and fractal characteristics of sandstone with different fracture dip angles under uniaxial compression.

In order to investigate the failure modes and instability mechanism of fractured rock. Uniaxial compression tests were conducted on sandstone specimens with different dip angles. Based on rock energy dissipation theory and fractal theory, the energy evolution characteristics and fragmentation fractal characteristics in the process of deformation and failure of specimens were analyzed. The results show that the peak strength and elastic modulus of fractured rock mass are lower than those of intact samples, and both show an exponential increase with the increase of fracture dip angle. The energy evolution laws of different fracture specimens are roughly similar and can be classified into four stages based on the stress-strain curve: pressure-tight, elastic, plastic, and post-destructive. The total strain energy, elastic strain energy, and dissipated strain energy of the specimen at the peak stress point increased exponentially with crack inclination, and the dissipated strain energy and compressive strength conformed to a power function growth relationship. The distribution of the fragments after the failure of the fracture sample has fractal characteristics, and the fractal dimension increases with the increase of the fracture dip angle. In addition, the higher the compressive strength of the specimen, the greater the energy dissipation, the more serious the degree of fragmentation, and the greater the fractal dimension. The data fitting further shows that there is a power function relationship between the dissipated strain energy and the fractal dimension. The research results can provide a theoretical basis for the stability of rock mass engineering and structural deformation control.

Soybean steroids improve crop abiotic stress tolerance and increase yield.

Sterols have long been associated with diverse fields, such as cancer treatment, drug development, and plant growth; however, their underlying mechanisms and functions remain enigmatic. Here, we unveil a critical role played by a GmNF-YC9-mediated CCAAT-box transcription complex in modulating the steroid metabolism pathway within soybeans. Specifically, this complex directly activates squalene monooxygenase (GmSQE1), which is a rate-limiting enzyme in steroid synthesis. Our findings demonstrate that overexpression of either GmNF-YC9 or GmSQE1 significantly enhances soybean stress tolerance, while the inhibition of SQE weakens this tolerance. Field experiments conducted over two seasons further reveal increased yields per plant in both GmNF-YC9 and GmSQE1 overexpressing plants under drought stress conditions. This enhanced stress tolerance is attributed to the reduction of abiotic stress-induced cell oxidative damage. Transcriptome and metabolome analyses shed light on the upregulation of multiple sterol compounds, including fucosterol and soyasaponin II, in GmNF-YC9 and GmSQE1 overexpressing soybean plants under stress conditions. Intriguingly, the application of soybean steroids, including fucosterol and soyasaponin II, significantly improves drought tolerance in soybean, wheat, foxtail millet, and maize. These findings underscore the pivotal role of soybean steroids in countering oxidative stress in plants and offer a new research strategy for enhancing crop stress tolerance and quality from gene regulation to chemical intervention.

Diagnostic efficacy of contrast-enhanced gastric ultrasonography in staging gastric cancer: a meta-analysis.

BACKGROUND: As comprehensive surgical management for gastric cancer becomes increasingly specialized and standardized, the precise differentiation between ≤T1 and ≥T2 gastric cancer before endoscopic intervention holds paramount clinical significance. OBJECTIVE: To evaluate the diagnostic efficacy of contrast-enhanced gastric ultrasonography in differentiating ≤T1 and ≥T2 gastric cancer. METHODS: PubMed, Web of Science, and Medline were searched to collect studies published from January 1, 2000 to March 16, 2023 on the efficacy of either double contrast-enhanced gastric ultrasonography (D-CEGUS) or oral contrast-enhanced gastric ultrasonography (O-CEGUS) in determining T-stage in gastric cancer. The articles were selected according to specified inclusion and exclusion criteria, and the quality of the included literature was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 scale. Meta-analysis was performed using Stata 12 software with data from the 2 × 2 crosslinked tables in the included literature. RESULTS: In total, 11 papers with 1124 patients were included in the O-CEGUS analysis, which revealed a combined sensitivity of 0.822 (95% confidence interval [CI] = 0.753-0.875), combined specificity of 0.964 (95% CI = 0.925-0.983), and area under the summary receiver operating characteristic (sROC) curve (AUC) of 0.92 (95% CI = 0.89-0.94). In addition, five studies involving 536 patients were included in the D-CEGUS analysis, which gave a combined sensitivity of 0.733 (95% CI = 0.550-0.860), combined specificity of 0.982 (95% CI = 0.936-0.995), and AUC of 0.93 (95% CI = 0.91-0.95). According to the I2 and P values ​​of the forest plot, there was obvious heterogeneity in the combined specificities of the included papers. Therefore, the two studies with the lowest specificities were excluded from the O-CEGUS and D-CEGUS analyses, which eliminated the heterogeneity among the remaining literature. Consequently, the combined sensitivity and specificity of the remaining studies were 0.794 (95% CI = 0.710-0.859) and 0.976 (95% CI = 0.962-0.985), respectively, for the O-CEDUS studies and 0.765 (95% CI = 0.543-0.899) and 0.986 (95% CI = 0.967-0.994), respectively, for the D-CEGUS studies. The AUCs were 0.98 and 0.99 for O-CEGUS and D-CEGUS studies, respectively. CONCLUSION: Both O-CEGUS and D-CEGUS can differentiate ≤T1 gastric cancer from ≥T2 gastric cancer, thus assisting the formulation of clinical treatment strategies for patients with very early gastric cancer. Given its simplicity and cost-effectiveness, O-CEGUS is often favored as a staging method for gastric cancer prior to endoscopic intervention.

Association between triglyceride glucose and acute kidney injury in patients with acute myocardial infarction: a propensity score­matched analysis.

BACKGROUND: Acute kidney injury (AKI) in patients with acute myocardial infarction (AMI) often indicates a poor prognosis. OBJECTIVE: This study aimed to investigate the association between the TyG index and the risk of AKI in patients with AMI. METHODS: Data were taken from the Medical Information Mart for Intensive Care (MIMIC) database. A 1:3 propensity score (PS) was set to match patients in the AKI and non-AKI groups. Multivariate logistic regression analysis, restricted cubic spline (RCS) regression and subgroup analysis were performed to assess the association between TyG index and AKI. RESULTS: Totally, 1831 AMI patients were included, of which 302 (15.6%) had AKI. The TyG level was higher in AKI patients than in non-AKI patients (9.30 ± 0.71 mg/mL vs. 9.03 ± 0.73 mg/mL, P < 0.001). Compared to the lowest quartile of TyG levels, quartiles 3 or 4 had a higher risk of AKI, respectively (Odds Ratiomodel 4 = 2.139, 95% Confidence Interval: 1.382-3.310, for quartile 4 vs. quartile 1, Ptrend < 0.001). The risk of AKI increased by 34.4% when the TyG level increased by 1 S.D. (OR: 1.344, 95% CI: 1.150-1.570, P < 0.001). The TyG level was non-linearly associated with the risk of AKI in the population within a specified range. After 1:3 propensity score matching, the results were similar and the TyG level remained a risk factor for AKI in patients with AMI. CONCLUSION: High levels of TyG increase the risk of AKI in AMI patients. The TyG level is a predictor of AKI risk in AMI patients, and can be used for clinical management.

Synovium microenvironment-responsive injectable hydrogel inducing modulation of macrophages and elimination of synovial fibroblasts for enhanced treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a progressive autoimmune disease accompanied by joint swelling, cartilage erosion and bone damage. Drug therapy for RA has been restricted due to poor therapeutic effect, recurrence and adverse effects. Macrophages and synovial fibroblasts both play important roles in the pathology of RA. Macrophages secrete large amount of pro-inflammatory cytokines, while synovial fibroblasts are tightly correlated with hypoxia synovium microenvironment, cytokine release, recruitment of pro-inflammatory cells, bone and cartilage erosion. Therefore, in this timely research, an injectable and pH-sensitive peptide hydrogel loading methotrexate (MTX) and bismuthene nanosheet/polyethyleneimine (BiNS/PEI) has been developed to reduce the activity of macrophages and eliminate over-proliferated synovial fibroblasts simultaneously. MTX can reduce the cytokine secretion of macrophages/anti-apoptosis property of synovial fibroblasts and BiNS/PEI can eliminate synovial fibroblasts via photodynamic therapy (PDT) and photothermal therapy (PTT) routes. The hydrogel was injected into the acidic inflammatory synovium for precise targeting and served as a drug reservoir for pH responsive and sustained drug release, while improving the bioavailability and reducing the toxicity of MTX. Excellent therapeutic efficacy has been achieved in both in vivo and in vitro studies, and this unique drug delivery system provides a new and robust strategy to eliminate synovial fibroblasts and modulate immune system for RA treatment in clinical.