NIPSNAP3A regulates cellular homeostasis by modulating mitochondrial dynamics.

Mitochondria are essential for cell metabolism and survival as they produce the majority of cellular ATP through oxidative phosphorylation as well as regulate critical processes such as cell proliferation and apoptosis. NIPSNAP family of proteins are predominantly mitochondrial matrix proteins. However, the molecular and cellular functions of the NIPSNAPs, particularly NIPSNAP3A, have remained elusive. Here, we demonstrated that NIPSNAP3A knockdown in HeLa cells inhibited their proliferation and migration and attenuated apoptosis induced by Actinomycin D (Act-D). These findings suggested a complex relationship between cellular processes and mitochondrial functions, mediated by NIPSNAP3A. Further investigations revealed that NIPSNAP3A knockdown not only inhibited mitochondrial fission through reduction of DRP1-S616, but also suppressed cytochrome c release in apoptosis. Collectively, our findings highlight the critical role of NIPSNAP3A in coordinating cellular processes, likely through its influence on mitochondrial dynamics.

Comparative analysis of T-cell immunity between Streptococcus agalactiae susceptible and resistant tilapia (Oreochromis niloticus).

Nile tilapia (Oreochromis niloticus) is one of the important economic fish species cultured worldwide. However, Streptococcus agalactiae has emerged as a significant bacterial threat, severely impacting the economy of tilapia industry. The immune response underlying the resistance of tilapia to S. agalactiae are not well understood, hindering the reasonable evaluation of breeding and the formulation of effective strategies. In this study, we investigated the differences in T-cell immunity between S. agalactiae-resistant and -susceptible tilapia. Compared with susceptible tilapia, resistant tilapia exhibited a higher percentage of T cells and BrdU+ T cells during infection, indicating a superior proliferative capacity. Whether infected or not, T cells from resistant fish demonstrated a greater ability to resist apoptosis. Additionally, T cell effector genes, including interleukin (IL)-2, interferon (IFN)-γ, perforin A, and granzyme B were expressed at higher levels in resistant tilapia after infection. Along with these T-cell immune responses, resistant fish showed more effective clearance of infection. Our study elucidates the T-cell immune responses in resistant tilapia, which may contribute to the high resistance of tilapia to S. agalactiae, and provide valuable theoretical references for the selection and evaluation of disease-resistant fish strains in the future.

Soluble PD-L1 as a novel biomarker predicts poor outcomes and disease progression in de novo myelodysplastic syndromes.

The role of the compromised immune microenvironment, including immune checkpoints, in myelodysplastic syndromes (MDS) has been identified as critical This study aimed to investigate the expression patterns of immune checkpoints, particularly soluble PD-1/PD-L1 (sPD-1/sPD-L1) as well as PD-1 on effector T cell subsets, and assess their prognostic value and potential regulatory roles in MDS. 161 MDS patients were enrolled, including 129 patients were primarily diagnosed with de novo MDS, together with 59 MDS patients who underwent hypomethylating agents (HMAs) therapy. Plasma sPD-L1 level was elevated in newly diagnosed MDS patients, which was also found to be associated with MDS disease progression that further increase in higher IPSS-R score group. Patients with increased sPD-L1 expression at diagnosis exhibited notably poorer overall survival, and multivariate Cox analysis indicated that elevated sPD-L1 was an independent risk factor. Furthermore, the levels of multiple cytokines and membrane-bound PD-1 on T cells were found to correlate with sPD-1/sPD-L1 levels in plasma. Importantly, we also found sPD-L1 levels significantly increased in MDS patients who showed progression of disease following HMAs therapy. In conclusion, we found elevated plasma sPD-L1 levels in MDS patients are associated with disease progression and poorer overall survival. This study showed that sPD-L1 is a potential biomarker for prognosis and a target for immunotherapy in MDS.

Resistance to the SDHI Fungicide Pydiflumetofen in Fusarium solani: Risk Assessment and Resistance-Related Point Mutation in FsSdhC Gene.

Peanut root rot (PRR) is a prevalent and destructive plant disease attributed to Fusarium solani. Pydiflumetofen (Pyd) is a succinate dehydrogenase inhibitor (SDHI) with antifungal activity against F. solani, yet its resistance mechanism has been inadequately explored. In this study, the EC50 values for Pyd against 93 F. solani strains ranged from 0.0095 to 0.3815 µg/mL, with all strains displaying a minimal inhibitory concentration (MIC) of ≤1 µg/mL. Four Pyd-resistant (PR) mutants were obtained, exhibiting stable resistance levels and comparable fitness to their parental strains in terms of mycelia growth, hyphal tip morphology, asexual reproduction, and virulence assessment. Five-point mutations, including FsSdhC1A82V, FsSdhC2L76M, FsSdhC2L135V, FsSdhC2F137L, and FsSdhC2F147L, were identified in the PR mutants. However, molecular docking analysis indicated that only FsSdhC1A82V and FsSdhC2L135V could influence the sensitivity of F. solani to Pyd. These findings help evaluate F. solani's resistance to Pyd and guide future PRR management with this fungicide.

The Evaluation of Gastric Cancer Lymphovascular Invasion Using CT Volume Perfusion.

BACKGROUND: The best treatment option for patients with resectable gastric cancer is radical gastric cancer surgery. However, the postoperative overall survival rate is low. Lymphovascular invasion (LVI) is a risk factor for cancer recurrence and a stand-alone predictor of a poor post-operative prognosis for gastric cancer (GC) patients. Current evaluation of tumor LVI performed on histological specimens, which can only be assessed after surgery, is also limited by intra-tumoural heterogeneity via biopsy. This study explored the value of CT volume perfusion in assessing tumors' lymphovascular invasion of gastric cancer. METHODS: 59 gastric cancer patients confirmed by pathology who underwent both computed tomography (CT) volume perfusion examinations and gastrectomy surgery were prospectively included. Tumour lymphovascular invasion (LVI, positive or negative) was evaluated. The relationship between clinicopathological variables associated with LVI and CT perfusion parameters was analyzed by univariate analysis, followed by multivariate logistic regression analysis and receiver operating characteristic (ROC) analysis. RESULTS: The LVI-positive and LVI-negative groups differed significantly in terms of time to start (TTS), mean transit time (MTT), Tmax, and flow extraction product (FEP). Both FEP (odds ratio (OR), 1.048; 95% confidence interval (CI): 1.005-1.092) and MTT (OR, 0.549; 95% CI: 0.351-0.858) have the potential to be employed as independent predictors of LVI (both p < 0.05). There were different correlations between LVI, lower MTT and greater FEP. The specificity of MTT (87.88%) was higher than that of FEP (72.73%), while the sensitivity of MTT (53.85%) was lower than that of FEP (57.69%). Compared to MTT and FEP alone, the combination demonstrated a comparatively higher area under the curve (AUC) (0.797) and sensitivity (84.62%). CONCLUSIONS: CT volume perfusion helps evaluate LVI in gastric cancer before surgery. MTT and FEP are independent predictors for LVI, and the combination variation has better diagnostic performance. Clinical Trial Register: Jiangmen Central Hospital, https://www.chictr.org.cn/showproj.html?proj=24375, ChiCTR1800014455.

First Report of the Root-Knot Nematode Meloidogyne incognita Parasitizing Chenopodium album in China.

Common lambsquarters (Chenopodium album Linn.) is one of the most problematic weeds associated with crops worldwide due to its fast-growing, high fecundity, and wide tolerance to various conditions. Meanwhile, C. album is also an herbaceous vegetable plant, and the leaves and young shoots of this plant are considered nutritious in the human diet (Aman et al. 2016). In September 2023, C. album plants exhibiting yellowing, stunted growth, and extensive galled root symptoms were collected from a yam field in Fengqiu (34°54'24"N; 114°34'57"E), Henan Province, China. At the selected sampling site, we randomly selected 100 C. album plants, and the disease incidence was 73% on a 0.67-ha field. A RKN species belonging to the genus Meloidogyne was found, comprising an average of 550 second-stage juveniles (J2s) from 100 g of the 10 to 30 cm soil layer. The J2s were isolated from fresh soil with a Baermann funnel. C. album roots were thoroughly washed with tap water and dissected. Nematodes at different stages were collected and morphologically identified. Females and egg masses were obtained by dissecting galls. Females were white with a protruding neck, globular to pear-shaped. The perineal patterns of females predominantly exhibited a pronounced dorsal arch, characterized by either a square or trapezoid shape, lacking obvious lateral lines. Males isolated from root galls were vermiform, annulated, and showed a trapezoidal labial region, including a high head cap that was concaved at the center of the top end in lateral view. J2s were distinguished by the conspicuous, round stylet knobs, and they had wrinkled tails with a hyaline region and an obtuse tip. Morphological measurements are described in the supplementary material. All features were consistent with the morphological characteristics of Meloidogyne incognita (Eisenback and Hirschmann 1981). Identification was accomplished with subsequent species-specific PCR and sequencing analysis. The genomic DNA of 10 individual females was extracted, and the molecular identification was carried out with M. incognita-specific primers Mi-F/Mi-R, and Inc-K14-F/Inc-K14-R (Meng et al. 2004; Randig et al. 2002). PCR amplification generated 955 and 399 bp fragments for the analyzed samples, respectively, and the amplicons were confirmed by sequence analyses. The sequences were deposited in GenBank under accession number PP836070 and PP836071. BLASTn searches showed 100% identity with available GenBank M. incognita sequences (accession no. MK410954, OQ427638). To verify reproduction on C. album, 10 healthy plants (30 days old) grown in pots with sterilized soil were inoculated with 1,000 M. incognita J2s under greenhouse conditions (light/dark: 16 h/8 h, temperature: 25-28°C). Five uninoculated plants were used as negative control. Two months after inoculation, stunted growth and root-galling symptoms were observed similar to those in field, whereas control plants remained symptomless. Many root galls and egg masses were observed in all inoculated plants. The root galling index (scale of 0 to 10; Poudyal et al. 2005) was ~7 and nematode reproduction factor (final population density/initial population density) was 5.3. The morphological features of the nematodes reisolated from root tissue closely match the description of M. incognita, fulfilling Koch's postulates. The pathogenicity test was carried out twice with similar results. M. incognita is an emerging disease of economic importance in many crop plants worldwide, and may cause serious economic losses (Phani et al. 2021). This widely distributed C. album plant is likely a reservoir for the pathogen and serves as an alternate host for nematodes. The findings are significant for the integrated management practices of RKNs, particularly for crops that are infested with C. album. To our knowledge, this is the first report of the nematode parasitizing C. album in China. The development of effective short- and long-term control procedures is urgently needed for managing M. incognita.

Deep learning architecture with shunted transformer and 3D deformable convolution for voxel-level dose prediction of head and neck tumors.

Intensity-modulated radiation therapy (IMRT) has been widely used in treating head and neck tumors. However, due to the complex anatomical structures in the head and neck region, it is challenging for the plan optimizer to rapidly generate clinically acceptable IMRT treatment plans. A novel deep learning multi-scale Transformer (MST) model was developed in the current study aiming to accelerate the IMRT planning for head and neck tumors while generating more precise prediction of the voxel-level dose distribution. The proposed end-to-end MST model employs the shunted Transformer to capture multi-scale features and learn a global dependency, and utilizes 3D deformable convolution bottleneck blocks to extract shape-aware feature and compensate the loss of spatial information in the patch merging layers. Moreover, data augmentation and self-knowledge distillation are used to further improve the prediction performance of the model. The MST model was trained and evaluated on the OpenKBP Challenge dataset. Its prediction accuracy was compared with three previous dose prediction models: C3D, TrDosePred, and TSNet. The predicted dose distributions of our proposed MST model in the tumor region are closest to the original clinical dose distribution. The MST model achieves the dose score of 2.23 Gy and the DVH score of 1.34 Gy on the test dataset, outperforming the other three models by 8%-17%. For clinical-related DVH dosimetric metrics, the prediction accuracy in terms of mean absolute error (MAE) is 2.04% for D 99 , 1.54% for D 95 , 1.87% for D 1 , 1.87% for D mean , 1.89% for D 0.1 c c , respectively, superior to the other three models. The quantitative results demonstrated that the proposed MST model achieved more accurate voxel-level dose prediction than the previous models for head and neck tumors. The MST model has a great potential to be applied to other disease sites to further improve the quality and efficiency of radiotherapy planning.

3D live imaging and phenotyping of CAR-T cell mediated-cytotoxicity using high-throughput Bessel oblique plane microscopy.

Clarification of the cytotoxic function of T cells is crucial for understanding human immune responses and immunotherapy procedures. Here, we report a high-throughput Bessel oblique plane microscopy (HBOPM) platform capable of 3D live imaging and phenotyping of chimeric antigen receptor (CAR)-modified T-cell cytotoxicity against cancer cells. The HBOPM platform has the following characteristics: an isotropic subcellular resolution of 320 nm, large-scale scouting over 400 interacting cell pairs, long-term observation across 5 hours, and quantitative analysis of the Terabyte-scale 3D, multichannel, time-lapse image datasets. Using this advanced microscopy platform, several key subcellular events in CAR-T cells are captured and comprehensively analyzed; these events include the instantaneous formation of immune synapses and the sustained changes in the microtubing morphology. Furthermore, we identify the actin retrograde flow speed, the actin depletion coefficient, the microtubule polarization and the contact area of the CAR-T/target cell conjugates as essential parameters strongly correlated with CAR-T-cell cytotoxic function. Our approach will be useful for establishing criteria for quantifying T-cell function in individual patients for all T-cell-based immunotherapies.

Water-filtered infrared A radiation hyperthermia combined with immunotherapy for advanced gastrointestinal tumours.

This study pioneered the use of WIRA whole-body infrared hyperthermia combined with ICI therapy to treat GIT and verified the feasibility and safety of HIT. The final results showed a DCR of 55.6%, with a median PFS of 53.5 days, median OS of 134 days, and an irAE incidence of 22.2%. Therefore, we believe that HIT can exert multiple synergistic sensitisation effects, thereby providing clinical benefits to patients with advanced GITs, increasing overall safety, and improving patients' QOL.

INTRODUCTION: This study aimed to validate the effectiveness, safety and feasibility of water­filtered infrared A radiation (WIRA) whole­body hyperthermia combined with immune checkpoint inhibitor (ICI) therapy (HIT) and evaluate the real­world clinical application prospects. METHODS: This open­label single­arm phase 2 clinical trial (NCT06022692) aimed to enrol advanced gastrointestinal tumour (GIT) patients with the MSS/pMMR phenotype. The patients were treated with whole­body hyperthermia on Days 1 and 8 of each HIT cycle along with administration of tislelizumab on Day 2. RESULTS: Between 1 June 2020 and 31 May 2022, 18 patients were enrolled in the study, including those with gastric cancer (n = 6), colon cancer (n = 7), rectal cancer (n = 3) and appendiceal cancer (n = 2). As of 19 May 2023, 17 of the 18 patients had died, including 14 deaths caused by tumour progression and three deaths caused by diseases other than cancer, while one patient was still undergoing follow­up. In terms of efficacy, the median DCR was 55.6%, while the median PFS and OS were 53.5 days and 134 days, respectively. Four patients (22.2%) experienced immune­related adverse events, and none of the patients reported grade 3 or higher irAEs. Hyperthermia was followed by an increase in the number of tumour immune­activated cells. CONCLUSIONS: HIT can provide survival benefits in patients with GITs by activating antitumour immune function and shows good safety and feasibility.

The mitochondrial TSPO ligand Atriol mitigates metabolic-associated steatohepatitis by downregulating CXCL1.

BACKGROUND AND AIMS: The mitochondrial translocator protein (TSPO, 18 kDa) is pivotal in binding cholesterol and facilitating its transfer from the outer to the inner mitochondrial membrane. Atriol is a TSPO ligand disrupting cholesterol binding by targeting the cholesterol-recognition amino acid consensus domain. Prior research has shown that TSPO deficiency improved metabolic-associated steatohepatitis (MASH). We hypothesized that Atriol may have the potential to alleviate MASH. METHODS AND RESULTS: In vitro cell culture studies revealed that Atriol treatment effectively mitigated MASH by restoring mitochondrial function, inhibiting the NF-κB signaling pathway, and reducing hepatic stellate cell (HSC) activation. SD male rats were fed a GAN diet for 10 months to induce MASH. During the final two weeks of feeding, rats received intraperitoneal Atriol administration daily. Atriol treatment significantly ameliorated MASH by reducing lipid accumulation, diminishing hepatic lobular inflammation and fibrosis, decreasing cell death, and inhibiting excessive bile acid synthesis. Moreover, Atriol restored mitochondrial function in primary hepatocytes isolated from MASH rats. In search of the mechanism(s) governing these effects, we found that Atriol downregulated the proinflammatory chemokine CXCL1 through the NF-κB signaling pathway or via myeloperoxidase (MPO) in HSCs and Kupffer cells. Additionally, in vitro, studies further suggested that CXCL1 treatment induced dysfunctional mitochondria, inflammation, HSCs activation, and macrophage migration, whereas Atriol countered these effects. Finally, the mitigating effects of Atriol on MASH were reproduced by pharmacological inhibition of NF-κB or MPO and neutralization of CXCL1. CONCLUSION: Atriol ameliorates MASH both in vitro and in vivo, demonstrating its potential therapeutic benefits in managing MASH.

A circular network of adenosine-mediated mitochondrial dysfunction as coregulators of acute myocardial infarction.

This study aims to explore the molecular mechanisms and associated pathways of myocardial infarction (MI). We employed a variety of analytical methods, including Mendelian Randomization (MR) analysis, transcriptome microarray data analysis, gene function and pathway enrichment analysis, untargeted metabolomic mass spectrometry analysis, and gene-metabolite interaction network analysis. The MR analysis results revealed a significant impact of mitochondrial DNA copy number on MI and coronary artery bypass grafting. Transcriptome analysis unveiled numerous differentially expressed genes associated with myocardial ischemia, with enrichment observed in cardiac function and energy metabolism pathways. Metabolomic analysis indicated a significant downregulation of mitochondrial regulation pathways in ischemic myocardium. T500 metabolite quantification analysis identified 90 differential metabolites between MI and Sham groups, emphasizing changes in metabolites associated with energy metabolism. Gene-metabolite interaction network analysis revealed the significant roles of key regulatory molecules such as HIF1A, adenosine, TBK1, ATP, NRAS, and EIF2AK3, in the pathogenesis of myocardial ischemia. In summary, this study provides important insights into the molecular mechanisms of MI and highlights interactions at multiple molecular levels, contributing to the establishment of new theoretical foundations for the diagnosis and treatment of MI.

Taxodin A, a Cytotoxic C30 Terpenoid from Taxodium mucronatum with a Unique Skeleton.

Taxodin A (1), a unique C30 terpenoid featuring an unprecedented skeleton composed of an abietane-type diterpene and a menthane-type monoterpene, was obtained from the leaves and branches of Taxodium mucronatum. The structure and absolute configuration of compound 1 was unequivocally established by the combination of extensive spectroscopic analyses and X-ray single-crystal diffraction analysis. Compound 1 exhibited potent cytotoxic activities against A549, SMMC-7721, MDA-MB-231, and SW480 cell lines with IC50 values of 15.35±0.73, 8.49±0.35, 17.53±0.79, 18.93±0.60 µM, respectively.

Skin marker combined with surface-guided auto-positioning for breast DIBH radiotherapy daily initial patient setup: An optimal schedule for both accuracy and efficiency.

BACKGROUND AND PURPOSE: By employing three surface-guided radiotherapy (SGRT)-assisted positioning methods, we conducted a prospective study of patients undergoing SGRT-based deep inspiration breath-hold (DIBH) radiotherapy using a Sentine/Catalys system. The aim of this study was to optimize the initial positioning workflow of SGRT-DIBH radiotherapy for breast cancer. MATERIALS AND METHODS: A total of 124 patients were divided into three groups to conduct a prospective comparative study of the setup accuracy and efficiency for the daily initial setup of SGRT-DIBH breast radiotherapy. Group A was subjected to skin marker plus SGRT verification, Group B underwent SGRT optical feedback plus auto-positioning, and Group C was subjected to skin marker plus SGRT auto-positioning. We evaluated setup accuracy and efficiency using cone-beam computed tomography (CBCT) verification data and the total setup time. RESULTS: In groups A, B, and C, the mean and standard deviation of the translational setup-error vectors were small, with the highest values of the three directions observed in group A (2.4 ± 1.6, 2.9 ± 1.8, and 2.8 ± 2.1 mm). The rotational vectors in group B (1.8 ± 0.7°, 2.1 ± 0.8°, and 1.8 ± 0.7°) were significantly larger than those in groups A and C, and the Group C setup required the shortest amount of time, at 1.5 ± 0.3 min, while that of Group B took the longest time, at 2.6 ± 0.9 min. CONCLUSION: SGRT one-key calibration was found to be more suitable when followed by skin marker/tattoo and in-room laser positioning, establishing it as an optimal daily initial set-up protocol for breast DIBH radiotherapy. This modality also proved to be suitable for free-breathing breast cancer radiotherapy, and its widespread clinical use is recommended.

High-multiplex single-cell imaging analysis reveals tumor immune contexture associated with clinical outcomes after CAR T cell therapy.

Chimeric antigen receptor (CAR) T cell therapy has made great progress in treating lymphoma, yet patient outcomes still vary greatly. The lymphoma microenvironment may be an important factor in the efficacy of CAR T therapy. In this study, we designed a highly multiplexed imaging mass cytometry (IMC) panel to simultaneously quantify 31 biomarkers from 13 patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL) who received CAR19/22 T cell therapy. A total of 20 sections were sampled before CAR T cell infusion or after infusion when relapse occurred. A total of 35 cell clusters were identified, annotated, and subsequently redefined into 10 metaclusters. The CD4+ T cell fraction was positively associated with remission duration. Significantly higher Ki67, CD57, and TIM3 levels and lower CD69 levels in T cells, especially the CD8+/CD4+ Tem and Te cell subsets, were seen in patients with poor outcomes. Cellular neighborhood containing more immune cells was associated with longer remission. Fibroblasts and vascular endothelial cells resided much closer to tumor cells in patients with poor response and short remission after CAR T therapy. Our work comprehensively and systematically dissects the relationship between cell composition, state, and spatial arrangement in the DLBCL microenvironment and the outcomes of CAR T cell therapy, which is beneficial to predict CAR T therapy efficacy.

Response of the Symbiotic Microbial Community of Dioscorea opposita Cultivar Tiegun to Root-Knot Nematode Infection.

Yam is an important medicinal and edible dual-purpose plant with high economic value. However, nematode damage severely affects its yield and quality. One of the major effects of nematode infestations is the secondary infection of pathogenic bacteria or fungi through entry wounds made by the nematodes. Understanding the response of the symbiotic microbial community of yam plants to nematodes is crucial for controlling such a disease. In this study, we investigated the rhizosphere and how endophytic microbiomes shift after nematode infection during the tuber expansion stage in the Dioscorea opposita Thunb. cultivar Tiegun. Our results revealed that soil depth affected the abundance of nematodes, and the relative number of Meloidogyne incognita was higher in the diseased soil at a depth of 16 to 40 cm than those at a depth of 0 to 15 and 41 to 70 cm. The abundance of and interactions among soil microbiota members were significantly correlated with root-knot nematode (RKN) parasitism at various soil depths. However, the comparison of the microbial α-diversity and composition between healthy and diseased rhizosphere soil showed no difference. Compared with healthy soils, the co-occurrence networks of M. incognita-infested soils included a higher ratio of positive correlations linked to plant health. In addition, we detected a higher abundance of certain taxonomic groups belonging to Chitinophagaceae and Xanthobacteraceae in the rhizosphere of RKN-infested plants. The nematodes, besides causing direct damage to plants, also possess the ability to act synergistically with other pathogens, especially Ramicandelaber and Fusarium, leading to the development of disease complexes. In contrast to soil samples, RKN parasitism specifically had a significant effect on the composition and assembly of the root endophytic microbiota. The RKN colonization impacted a wide variety of endophytic microbiomes, including Pseudomonas, Sphingomonas, Rhizobium, Neocosmospora, and Fusarium. This study revealed the relationship between RKN disease and changes in the rhizosphere and endophytic microbial community, which may provide novel insights that help improve biological management of yam RKNs.

Combined effects of copper and cadmium exposure on ovarian function and structure in Nile Tilapia (Oreochromis niloticus).

With the rapid development of industrialization and urbanization, the issue of copper (Cu) and cadmium (Cd) pollution in aquatic ecosystems has become increasingly severe, posing threats to the ovarian tissue and reproductive capacity of aquatic organisms. However, the combined effects of Cu and Cd on the ovarian development of fish and other aquatic species remain unclear. In this study, female Nile tilapia (Oreochromis niloticus) were individually or co-exposed to Cu and/or Cd in water. Ovarian and serum samples were collected at 15, 30, 60, 90, and 120 days, and the bioaccumulation, ovarian development, and hormone secretion were analyzed. Results showed that both single and combined exposure significantly reduced the gonadosomatic index and serum hormone levels, upregulated estrogen receptor (er) and progesterone receptor (pr) gene transcription levels, and markedly affected ovarian metabolite levels. Combined exposure led to more adverse effects than single exposure. The data demonstrate that the Cu and Cd exposure can impair ovarian function and structure, with more pronounced adverse effects under Cu and Cd co-exposure. The Cu and Cd affect the metabolic pathways of nucleotides and amino acids, leading to ovarian damage. This study highlights the importance of considering combined toxicant exposure in aquatic toxicology research and provides insights into the potential mechanisms underlying heavy metal-induced reproductive toxicity in fish.

Emerging Role of Interleukin-38 (IL-38) in the Development of Rheumatoid Arthritis.

INTRODUCTION: Rheumatoid arthritis (RA) is an incurable autoimmune disease. The role of interleukin-38 (IL-38), an anti-inflammatory cytokine, in RA is not fully understood, and its clinical relevance in RA remains unclear. This study aims to investigate the correlation of IL-38 with disease activity and the clinical manifestation of RA. METHODS: In this cross-sectional study, patients with treatment-naïve RA (n = 63) and healthy controls (HC) (n = 60) were consecutively enrolled over a 15-month period. Patients with RA were categorized into three subgroups-low disease activity (LDA), moderate disease activity (MDA) and high disease activity (HDA)-using the Disease Activity Score in 28 joints based on C-reactive protein (DAS28-CRP). Circulating levels of IL-38, tumour necrosis factor (TNF), IL-6, IL-17, IL-1ß, and 25(OH)D were assessed using enzyme-linked immunosorbent assay (ELISA). Clinical data, including duration, tender joints count (TJC), swollen joints count (SJC), patient global assessment (PGA), evaluator global assessment (EGA), bone mineral density (BMD), clinical disease activity index (CDAI), simplified disease activity index (SDAI), DAS28-CRP, joint musculoskeletal ultrasound (MSUS), and serological indicators were recorded. We determined the correlation between IL-38 and disease activity, as well as clinical manifestation in RA. RESULTS: At the macroscopic level, musculoskeletal ultrasonography of joints in different stages of disease activity in RA suggests that, as the disease progresses, arthritis in the hand becomes more severe, accompanied by synovial thickening and pronounced blood flow signals in the joint area. The expression of IL-38, TNF, IL-6, IL-17 and IL-1ß significantly increased in patients with RA compared to HC. Noteworthy differences were observed in the blood flow signal score, synovial signal score, IL-38, TNF, IL-6, IL-17 and IL-1ß among the three subgroups (LDA, MDA and HDA). As disease activity increased in patients with RA, the blood flow signal score, synovial signal score and expression of TNF, IL-6, IL-17 and IL-1ß exhibited a gradual increase, while the expression of IL-38 showed the opposite pattern. Inverse correlations were identified between IL-38 and pro-inflammatory cytokines (IL-6, IL-17), as well as key clinical parameters, including disease duration, SJC, TJC and DAS28-CRP score. CONCLUSION: IL-38, intricately linked to the pathogenesis of RA, emerges as a promising therapeutic target for the management of this debilitating disease.

Case report: The utilization of crizotinib and brentuximab vedotin as a bridge to autologous stem cell transplantation and followed by CD30-directed CAR-T cell therapy in relapsed/refractory ALK+ ALCL.

Background: Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ ALCL) is a rare, mature T-cell non-Hodgkin lymphoma. The prognosis of patients with relapsed or refractory ALCL following first-line chemotherapy is extremely poor. NCCN guidelines recommend intensified chemotherapy with or without ASCT consolidation for r/r ALCL, however, this is not an effective treatment for all ALK+ALCL. Case report: Herein, we report a patient with relapsed/refractory ALK+ ALCL who received crizotinib and brentuximab vedotin as bridging therapy, followed by autologous stem cell transplantation and sequential anti-CD30 CAR T cell therapy. Conclusion: The patient achieved complete remission and long-term disease-free survival of months and continues to be followed up. The combination therapy model in this case may provide guidance for the management of relapsed/refractory ALK+ ALCL, and further prospective trials are needed to confirm its effectiveness.

Advances in nanotechnology-based targeted-contrast agents for computed tomography and magnetic resonance.

X-ray computed tomography (CT) and magnetic resonance (MR) imaging are essential tools in modern medical diagnosis and treatment. However, traditional contrast agents are inadequate in the diagnosis of various health conditions. Consequently, the development of targeted nano-contrast agents has become a crucial area of focus in the development of medical image-enhancing contrast agents. To fully understand the current development of nano-contrast agents, this review provides an overview of the preparation methods and research advancements in CT nano-contrast agents, MR nano-contrast agents, and CT/MR multimodal nano-contrast agents described in previous publications. Due to the physicochemical properties of nanomaterials, such as self-assembly and surface modifiability, these specific nano-contrast agents can greatly improve the targeting of lesions through various preparation methods and clearly highlight the distinction between lesions and normal tissues in both CT and MR. As a result, they have the potential to be used in the early stages of disease to improve diagnostic capacity and level in medical imaging.