18F-FDG PET/CT metrics-based stratification of large B-cell lymphoma receiving CAR-T cell therapy: immunosuppressive tumor microenvironment as a negative prognostic indicator in patients with high tumor burden.

Chimeric antigen receptor T (CAR-T) cell therapy has greatly improved the prognosis of relapsed and refractory patients with large B-cell lymphoma (LBCL). Early identification and intervention of patients who may respond poorly to CAR-T cell therapy will help to improve the efficacy. Ninety patients from a Chinese cohort who received CAR-T cell therapy and underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scans at the screening stage (median time to infusion 53.5 days, range 27-176 days), 1 month and 3 months after CAR-T cell infusion were analyzed, with RNA-sequencing conducted on 47 patients at the screening stage. Patients with maximum diameter of the largest lesion (Dmax) < 6 cm (N = 60) at screening stage showed significantly higher 3-month complete response rate (85.0% vs. 33.3%, P < 0.001), progression-free survival (HR 0.17; 95% CI 0.08-0.35, P < 0.001) and overall survival (HR 0.18; 95% CI 0.08-0.40, P < 0.001) than those with Dmax ≥ 6 cm (N = 30). Besides, at the screening stage, Dmax combined with extranodal involvement was more efficient in distinguishing patient outcomes. The best cut-off values for total metabolic tumor volume (tMTV) and total lesion glycolysis (tTLG) at the screening stage were 50cm3 and 500 g, respectively. A prediction model combining maximum standardized uptake value (SUVmax) at 1 month after CAR-T cell therapy (M1) and tTLG clearance rate was established to predict early progression for partial response/stable disease patients evaluated at M1 after CAR-T cell therapy and validated in Lyon cohort. Relevant association of the distance separating the two farthest lesions, standardized by body surface area to the severity of neurotoxicity (AUC = 0.74; P = 0.034; 95% CI, 0.578-0.899) after CAR-T cell therapy was found in patients received axicabtagene ciloleucel. In patients with Dmax ≥ 6 cm, RNA-sequencing analysis conducted at the screening stage showed enrichment of immunosuppressive-related biological processes, as well as increased M2 macrophages, cancer-associated fibroblasts, myeloid-derived suppressor cells, and intermediate exhausted T cells. Collectively, immunosuppressive tumor microenvironment may serve as a negative prognostic indicator in patients with high tumor burden who respond poorly to CAR-T cell therapy.

Dynamic cerebellar and sensorimotor network compensation in tremor-dominated Parkinson's disease.

AIM: Parkinson's disease (PD) tremor is associated with dysfunction in the basal ganglia (BG), cerebellum (CB), and sensorimotor networks (SMN). We investigated tremor-related static functional network connectivity (SFNC) and dynamic functional network connectivity (DFNC) in PD patients. METHODS: We analyzed the resting-state functional MRI data of 21 tremor-dominant Parkinson's disease (TDPD) patients and 29 healthy controls. We compared DFNC and SFNC between the three networks and assessed their associations with tremor severity. RESULTS: TDPD patients exhibited increased SFNC between the SMN and BG networks. In addition, they spent more mean dwell time (MDT) in state 2, characterized by sparse connections, and less MDT in state 4, indicating stronger connections. Furthermore, enhanced DFNC between the CB and SMN was observed in state 2. Notably, the MDT of state 2 was positively associated with tremor scores. CONCLUSION: The enhanced dynamic connectivity between the CB and SMN in TDPD patients suggests a potential compensatory mechanism. However, the tendency to remain in a state of sparse connectivity may contribute to the severity of tremor symptoms.

The novel HSP90 monoclonal antibody 9B8 ameliorates articular cartilage degeneration by inhibiting glycolysis via the HIF-1 signaling pathway.

Osteoarthritis (OA) is a prevalent chronic degenerative disease that affects the bones and joints, particularly in middle-aged and elderly individuals. It is characterized by progressive joint pain, swelling, stiffness, and deformity. Notably, treatment with a heat shock protein 90 (HSP90) inhibitor has significantly curtailed cartilage destruction in a rat model of OA. Although the monoclonal antibody 9B8 against HSP90 is recognized for its anti-tumor properties, its potential therapeutic impact on OA remains uncertain. This study investigated the effects of 9B8 on OA and its associated signaling pathways in interleukin-1ß (IL-1ß)-stimulated human chondrocytes and a rat anterior cruciate ligament transection (ACLT) model. A specific concentration of 9B8 preserved cell viability against IL-1ß-induced reduction. In vitro, 9B8 significantly reduced the expression of extracellular matrix-degrading enzyme such as disintegrin and metallopeptidase-4 (ADAMTS4) of thrombospondin motifs, matrix metalloproteinase-13 (MMP-13), as well as cellular inflammatory factors such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which were upregulated by IL-1ß. In vivo, 9B8 effectively protected the articular cartilage and subchondral bone of the rat tibial plateau from ACLT-induced damage. Additionally, gene microarray analysis revealed that IL-1ß substantially increased the expression of SLC2A1, PFKP, and ENO2 within the HIF-1 signaling pathway, whereas 9B8 suppressed the expression of these genes. Thus, 9B8 effectively mitigates ACLT-induced osteoarthritis in rats by modulating the HIF-1 signaling pathway, thereby inhibiting overexpression involved in glycolysis. These results collectively indicate that 9B8 is a promising novel drug for the prevention and treatment of OA.

The kynurenine pathway regulated by intestinal innate lymphoid cells mediates postoperative cognitive dysfunction.

Postoperative cognitive dysfunction (POCD) is a prevalent neurological complication that can impair learning and memory for days, months, or even years after anesthesia/surgery. POCD is strongly associated with an altered composition of the gut microbiota (dysbiosis), but the accompanying metabolic changes and their role in gut-brain communication and POCD pathogenesis remain unclear. Here, the present study reports that anesthesia/surgery in aged mice induces elevated intestinal indoleamine 2,3-dioxygenase (IDO) expression and activity, which shifts intestinal tryptophan (TRP) metabolism toward more IDO-catalyzed kynurenine (KYN) and less gut bacteria-catabolized indoleacetic acid (IAA). Both anesthesia/surgery and intraperitoneal KYN administration induce increased KYN levels that correlate with impaired spatial learning and memory, whereas dietary IAA supplementation attenuates the anesthesia/surgery-induced cognitive impairment. Mechanistically, anesthesia/surgery increases interferon-γ (IFN-γ)-producing group 1 innate lymphoid cells (ILC1) in the small intestine lamina propria and elevates intestinal IDO expression and activity, as indicated by the higher ratio of KYN to TRP. The IDO inhibitor 1-MT and antibodies targeting IFN-γ or ILCs mitigate anesthesia/surgery-induced cognitive dysfunction, suggesting that intestinal ILC1 expansion and the ensuing IFN-γ-induced IDO upregulation may be the primary pathway mediating the shift to the KYN pathway in POCD. The ILC1-KYN pathway in the intestine could be a promising therapeutic target for POCD.

Serum tumor markers: potential indicators for occult lymph node metastasis in clinical T1 - 2N0M0 small cell lung cancer patients.

In their letter-to-the-editor entitled "Letter to the Editor: Incidence rate of occult lymph node metastasis in clinical T1 - 2N0M0 small cell lung cancer patients and radiomic prediction based on contrast-enhanced CT imaging: a multicenter study", Prof. Chen et al. provided insightful comments and suggestions on our original study. We appreciate the authors' feedback and have conducted a preliminary exploration of the predictive value of serum tumor markers (TMs) for occult lymph node metastasis (OLM) in clinical T1 - 2N0M0 (cT1 - 2N0M0) small cell lung cancer (SCLC) patients. The results indicate that neuron-specific enolase (NSE), carbohydrate antigen 125 (CA125), and squamous cell carcinoma antigen (SCC) have potential predictive value for detecting OLM in cT1 - 2N0M0 SCLC patients. Additionally, further exploration and confirmation through prospective, large-scale studies with robust external validation are needed.

Interplay of humic acid and Cr(VI) on green microalgae: Metabolic responses and chromium enrichment.

Dissolved organic matter (DOM) present in aquatic environments can significantly influence microalgal metabolism and the enrichment of heavy metals. However, the specific mechanism through which typical DOM affects the enrichment of the heavy metal chromium (Cr) in green algae remains unclear. This study investigates the impacts of varying concentrations of humic acid (HA), selected as a representative DOM in water, on the growth, metabolism, and Cr enrichment in Chlorella vulgaris, a typical green alga. The results indicated that low concentrations of HA were capable of enhancing Cr enrichment in C. vulgaris, with the highest Cr enrichment rate recorded at 41.50 % at TOC = 10 mg/L. The enrichment of Cr in algal cells primarily occurred through cell proliferation and complexation reduction of extracellular polymeric substances (EPS). In the presence of HA, C. vulgaris predominantly removed Cr through extracellular adsorption, accounting for 79.76-85.88 % of the total Cr removal. Furthermore, carboxyl complexation and hydroxyl reduction within EPS facilitated both the enrichment of Cr (18.72-21.49 %) and the reduction of Cr(VI) (63.93-74.10 %). These findings provide valuable insights into strategies for mitigating heavy metal pollution and managing associated risks in aquatic environments.

Cell Membrane-Camouflaged Biomimetic Magnetic Fluorescent Nanoparticles with Enhanced Stability for High-Performance Lead Drug Discovery.

Biomimetic nanoengineering empowers nanoparticles with enhanced biointerfacial capabilities by directly utilizing cell membranes (CMs) of natural origin. This top-down technique provides a powerful tool for the screening of potentially active compounds in complex matrices. Herein, cartilaginous end plate (CEP) cell membrane biomimetic Nile red (NR)-loaded zeolitic imidazolate frameworks-8 (ZIF-8) modified magnetic graphene oxide (CEP/MGO-ZIF-8-NR) nanocomposites with enhanced stability were accurately prepared by chemical bonding and used as a drug discovery platform for the specific identification and effective extraction of drug leads with anti-intervertebral disc degeneration (IDD) in Yaobitong capsules (YBTCs). The constructed CEP/MGO-ZIF-8-NR exhibited excellent magnetic properties, fluorescence properties, and stability. In addition, drug binding experiments showed that the CEP/MGO-ZIF-8-NR nanocomposites possessed higher adsorption capacity, faster adsorption rate, and superior selectivity compared with uncoated MGO-ZIF-8-NR. Ultimately, four potential bioactive molecules, including ginsenoside Ro, ginsenoside Rg1, astringin, and chikusetsusaponin V methyl ester, were successfully screened and identified in vitro from YBTC. The results of the CCK-8 assay and BrdU ELISA kit showed that the screened compounds promoted CEP cell proliferation in a concentration-dependent manner. Cellular distribution experiments revealed that CEP/MGO-ZIF-8-NR could rapidly escape from lysosomes and into the cytoplasm. And the pharmacological activity of these compounds was further confirmed by real-time cytomorphological imaging of CEP cells by confocal laser scanning microscopy (CLSM). Overall, this surface engineering strategy endows bioaffinity sample pretreatment materials with tremendous versatility, improves drug screening efficiency, and broadens the horizons and methodologies for drug lead discovery.

CT-based radiomic consensus clustering association with tumor biological behavior in clinical stage IA adenocarcinoma: a retrospective study.

Background: Research has demonstrated that radiomics models are capable of forecasting the characteristics of lung cancer. Nevertheless, due to radiomics' poor interpretability, its applicability in clinical settings remains restricted. This investigation sought to verify the correlation between radiomics features (RFs) and the biological behavior of clinical stage IA adenocarcinomas. Methods: A retrospective analysis was conducted on patients diagnosed with clinical stage IA lung adenocarcinoma who underwent resection between May 2005 and December 2018. Detailed radiomics examination of the primary tumor was carried out utilizing preoperative computed tomography (CT) images. Subsequently, patients were grouped based on their RFs using consensus clustering, enabling comparison of tumor biological characteristics among the clusters. Survival disparities among the clusters were evaluated through Kaplan-Meier and Cox analyses. Results: A consensus cluster analysis was performed on 669 patients [median age, 58 years; interquartile range (IQR), 50-64 years, 257 males, 412 females], and three distinct clusters were identified. Cluster 2 was associated with radiological solid adenocarcinoma [119 of 324 (36.7%), P<0.001], larger tumors with median tumor size of 2.1 cm with IQR of 1.7 to 2.5 cm (P<0.001), central tumor [91 of 324 (28.1%), P=0.002], pleural invasion [87 of 324 (26.9%), P<0.001], occult lymph node metastasis (ONM) [106 of 324 (32.7%), P<0.001], and a higher frequency of metastasis or recurrence [62 of 324 (19.1%), P<0.001]. The frequency of histological grade 3 was the highest in Cluster 3 [8 of 34 (23.5%), P<0.001]. Cluster 1 was associated with pure ground glass nodules (pGGNs) [184 of 310 (59.4%), P<0.001], smaller tumors with median tumor size of 1.1 cm with IQR of 0.8 to 1.4 cm (P<0.001), no pleural invasion [276 of 310 (89.0%), P<0.001], histological grade 1 [114 of 248 (46.0%), P<0.001], ONM negative [292 of 310 (94.2%), P<0.001], and a lower rate of metastasis or recurrence [298 of 310 (96.1%), P<0.001]. Conclusions: Differences in tumor biological behavior were detected among consensus clusters based on the RFs of clinical stage IA adenocarcinoma.

Advances in research on potential therapeutic approaches for Niemann-Pick C1 disease.

Niemann-Pick disease type C1 (NP-C1) is a rare and devastating recessive inherited lysosomal lipid and cholesterol storage disorder caused by mutations in the NPC1 or NPC2 gene. These two proteins bind to cholesterol and cooperate in endosomal cholesterol transport. Characteristic clinical manifestations of NP-C1 include hepatosplenomegaly, progressive neurodegeneration, and ataxia. While the rarity of NP-C1 presents a significant obstacle to progress, researchers have developed numerous potential therapeutic approaches over the past two decades to address this condition. Various methods have been proposed and continuously improved to slow the progression of NP-C1, although they are currently at an animal or clinical experimental stage. This overview of NP-C1 therapy will delve into different theoretical treatment strategies, such as small molecule therapies, cell-based approaches, and gene therapy, highlighting the complex therapeutic challenges associated with this disorder.

Transcranial photobiomodulation on the left inferior frontal gyrus enhances Mandarin Chinese L1 and L2 complex sentence processing performances.

This study investigated the causal enhancing effect of transcranial photobiomodulation (tPBM) over the left inferior frontal gyrus (LIFG) on syntactically complex Mandarin Chinese first language (L1) and second language (L2) sentence processing performances. Two (L1 and L2) groups of participants (thirty per group) were recruited to receive the double-blind, sham-controlled tPBM intervention via LIFG, followed by the sentence processing, the verbal working memory (WM), and the visual WM tasks. Results revealed a consistent pattern for both groups: (a) tPBM enhanced sentence processing performance but not verbal WM for linear processing of unstructured sequences and visual WM performances; (b) Participants with lower sentence processing performances under sham tPBM benefited more from active tPBM. Taken together, the current study substantiated that tPBM enhanced L1 and L2 sentence processing, and would serve as a promising and cost-effective noninvasive brain stimulation (NIBS) tool for future applications on upregulating the human language faculty.

FOXO3 Activates MFN2 Expression to Maintain the Autophagy Response in Cancer Cells Under Amino Acid Deprivation.

The lack of amino acids triggers the autophagic response. Some studies have shown such starvation conditions also induce mitochondrial fusion, revealing a close correlation between the two processes. Although Mitofusin-2 (MFN2) has been demonstrated to play a role in fusion regulation, its role in the autophagic response and the variables that activate MFN2 under stress remain unknown. In this investigation, we screened and confirmed that forkhead box protein O3 (FOXO3) participates in MFN2's expression during short periods of starvation. Luciferase reporter test proved that FOXO3 facilitates MFN2's transcription by binding to its promoter region, and FOXO3 downregulation directly depresses MFN2's expression. Consequently, inhibiting the FOXO3-MFN2 axis results in the loss of mitochondrial fusion, disrupting the normal morphology of mitochondria, impairing the degradation of substrates, and reducing autophagosome accumulation, ultimately leading to the blockage of the autophagy. In conclusion, our work demonstrates that the FOXO3-MFN2 pathway is essential for adaptive changes in mitochondrial morphology and cellular autophagy response under nutritional constraints.

Advancements in understanding substantia nigra hyperechogenicity via transcranial sonography in Parkinson's disease and its clinical implications.

Amidst rising Parkinson's disease (PD) incidence in an aging global population, the need for non-invasive and reliable diagnostic methods is increasingly critical. This review evaluates the strategic role of transcranial sonography (TCS) in the early detection and monitoring of PD. TCS's ability to detect substantia nigra hyperechogenicity offers profound insights into its correlation with essential neuropathological alterations-namely, iron accumulation, neuromelanin depletion, and glial proliferation-fundamental to PD's pathophysiology. Our analysis highlights TCS's advantages, including its non-invasiveness, cost-effectiveness, and ease of use, positioning it as an invaluable tool for early diagnosis and continual disease progression monitoring. Moreover, TCS assists in identifying potential risk and protective factors, facilitating tailored therapeutic strategies to enhance clinical outcomes. This review advocates expanding TCS utilization and further research to maximize its diagnostic and prognostic potential in PD management, contributing to a more nuanced understanding of the disease.

Novel Susceptibility Genes and Biomarkers for Obstructive Sleep Apnea: Insights from Genetic and Inflammatory Proteins.

STUDY OBJECTIVES: Numerous observational studies link obstructive sleep apnea (OSA) to inflammatory proteins, yet the directionality of these associations remains ambiguous. Therefore, we aimed to clarify the potential associations of gene-predicted inflammatory proteins with OSA. METHODS: Based on genome-wide association study data, we applied Mendelian randomization (MR) to explore potential connections between circulating inflammatory proteins and OSA, primarily using the inverse variance weighting method for robustness. Cochran's Q test, MR‒Egger intercept test, MR-PRESSO, and leave-one-out method were used to perform sensitivity tests for pleiotropy and heterogeneity. Replication analyses and meta-analyses were performed using other independent data. Steiger tests and multivariate MR assessed the independent effects of exposure factors, and the functional mapping and annotation (FUMA) platform was used to identify key genes to enhance the understanding of genetics. RESULTS: Our investigation revealed 21 circulating inflammatory proteins significantly associated with OSA-related phenotypes. Notably, IL-10RA, IL-18R1, TNFSF14, CCL23, ADA, and SLAMF1 had significant effects on multiple phenotypes. After FDR correction, IL-18R1, SLAMF1, IL-10RA, and IL-17C were identified as important candidates for OSA, and multivariate MR analysis strengthened the independent heritability of 20 inflammatory factors. The FUMA platform revealed seven overlapping genes: ROBO1, PRIM1, NACA, SHBG, HSD17B6, RBMS2, and WWOX. All reverse MR analyses and sensitivity analyses confirmed the robustness of these associations. CONCLUSIONS: Our results underscore crucial associations between inflammatory proteins and OSA pathogenesis, revealing new correlates and susceptibility genes. These findings advance biomarker identification for OSA risk and highlight the importance of genetic and inflammatory profiles in OSA management.

Breast phyllodes tumour with epithelioid feature predisposes to malignant transformation.

AIMS: Phyllodes tumours (PTs) are relatively common fibroepithelial tumours comprising epithelial and stromal component. Usually, PTs show a spindle cell morphology with a fibroblast phenotype, while some tumour cells exhibit epithelioid morphological features and sarcomatoid transformation. However, the molecular characteristics of this morphology subset remain unclear. This study aimed to summarise the clinicopathological, morphological and molecular characteristics of seven cases of PT with epithelioid features. METHODS: Morphological and clinicopathological characteristics were observed and retrieved. Immunohistochemistry, immunofluorescence and electron microscope were performed on seven cases of epithelioid PT to explore immunophenotypic and ultrastructural characteristics. Transcriptomic and proteomic analyses were conducted to compare differentially expressed genes and proteins between epithelioid PT and classical PT. RESULTS: Patients with epithelioid PT exhibit a high recurrence rate (42.8%). Morphologically, in addition to having epithelioid cytological features, neoplastic stromal cells exhibit moderate to marked atypia and often exhibit sarcomatoid transformation, similar to the characteristics of borderline PT. Transcriptomic and proteomic analyses demonstrated that epithelioid PTs are distinct from classical PTs in gene expression and protein abundance levels. Immunohistochemical analysis showed that among all differentially expressed proteins, epithelioid PT showed abnormal p16/retinoblastoma expression patterns, similar to those of malignant PT. CONCLUSIONS: Epithelioid PT has unique morphological characteristics, biological behaviour and protein expression profile, which meets the diagnostic criteria of borderline PT and is prone to sarcomatoid transformation. It may be a special morphological subgroup of borderline PT and has partial characteristics of malignant PT, which should be taken seriously in pathological diagnosis and clinical management.

Avermectin induced vascular damage in zebrafish larvae: association with mitochondria-mediated apoptosis and VEGF/Notch signaling pathway.

Avermectin is a highly effective insecticide that has been widely used in agriculture since the 1990s. In recent years, the safety of avermectin for non-target organisms has received much attention. The vasculature is important organs in the body and participate in the composition of other organs. However, studies on the vascular safety of avermectin are lacking. The vasculature of zebrafish larvae is characterized by ease of observation and it is a commonly used model for vascular studies. Therefore, zebrafish larvae were used to explore the potential risk of avermectin on the vasculature. The results showed that avermectin induced vascular damage throughout the body of zebrafish larvae, including the head, eyes, intestine, somite, tail and other vasculature. The main forms of damage are reduction in vascular diameter, vascular area and vascular abundance. Meanwhile, avermectin induced a decrease in the number of endothelial cells and apoptosis within the vasculature. In addition, vascular damage may be related to impairment of mitochondrial function and mitochondria-mediated apoptosis. Finally, exploration of the molecular mechanisms revealed abnormal alterations in the expression of genes related to the VEGF/Notch signaling pathway. Therefore, the VEGF/Notch signaling pathway may be an important mechanism for avermectin-induced vascular damage in zebrafish larvae. This study demonstrates the vascular toxicity of avermectin in zebrafish larvae and reveals the possible molecular mechanism, which would hopefully draw more attention to the safety of avermectin in non-target organisms.

Predicting MET exon 14 skipping mutation in pulmonary sarcomatoid carcinoma by whole-tumour texture analysis combined with clinical and conventional contrast-enhanced computed tomography features.

Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare, highly malignant type of non-small cell lung cancer (NSCLC) with a poor prognosis. Targeted drugs for MET exon 14 (METex14) skipping mutation can have considerable clinical benefits. This study aimed to predict METex14 skipping mutation in PSC patients by whole-tumour texture analysis combined with clinical and conventional contrast-enhanced computed tomography (CECT) features. Methods: This retrospective study included 56 patients with PSC diagnosed by pathology. All patients underwent CECT before surgery or other treatment, and both targeted DNA- and RNA-based next-generation sequencing (NGS) were used to detect METex14 skipping mutation status. The patients were divided into two groups: METex14 skipping mutation and nonmutation groups. Overall, 1,316 texture features of the whole tumour were extracted. We also collected 12 clinical and 20 conventional CECT features. After dimensionality reduction and selection, predictive models were established by multivariate logistic regression analysis. Models were evaluated using the area under the curve (AUC), and the clinical utility of the model was assessed by decision curve analysis. Results: METex14 skipping mutation was detected in 17.9% of PSCs. Mutations were found more frequently in those (I) who had smaller long- or short-axis diameters (P=0.02, P=0.01); (II) who had lower T stages (I, II) (P=0.02); and (III) with pseudocapsular or annular enhancement (P=0.03). The combined model based on the conventional and texture models yielded the best performance in predicting METex14 skipping mutation with the highest AUC (0.89). The conventional and texture models also had good performance (AUC =0.83 conventional; =0.88 texture). Conclusions: Whole-tumour texture analysis combined with clinical and conventional CECT features may serve as a noninvasive tool to predict the METex14 skipping mutation status in PSC.

A Prognostic Model Based on Nutritional Indexes for Patients With Pan-Cancer: A Real-World Cohort Study.

BACKGROUND: The aim was to identify the nutritional indexes, construct a prognostic model, and develop a nomogram for predicting individual survival probability in pan-cancers. METHODS: Nutritional indicators, clinicopathological characteristics, and previous major treatment details of the patients were collected. The enrolled patients were randomly divided into training and validation cohorts. Least absolute shrinkage and selection operator (Lasso) regression cross-validation was used to determine the variables to include in the cox regression model. The training cohort was used to build the prediction model, and the validation cohort was used to further verify the discrimination, calibration, and clinical effectiveness of the model. RESULTS: A total of 2020 patients were included. The median OS was 56.50 months (95% CI, 50.36-62.65 months). In the training cohort of 1425 patients, through Lasso regression cross-validation, 13 characteristics were included in the model. Cox proportional hazards model was developed and visualized as a nomogram. The C-indexes of the model for predicting 1-, 3-, 5-, and 10-year OS were 0.848, 0.826, 0.814, and 0.799 in the training cohort and 0.851, 0.819, 0.814, and 0.801 in the validation cohort. The model showed great calibration in the two cohorts. Patients with a score of less than 274.29 had a better prognosis (training cohort: HR, 6.932; 95% CI, 5.723-8.397; log-rank p < 0.001; validation cohort: HR, 8.429; 95% CI, 6.180-11.497; log-rank p < 0.001). CONCLUSION: The prognostic model based on the nutritional indexes of pan-cancer can divide patients into different survival risk groups and performed well in the validation cohort.

Research trends in functionalized Fe3O4 composites based on affinity recognition systems for targeted extraction of natural products.

In recent years, target-specific affinity recognition systems based on Fe3O4-based composites have proven to be an effective method for screening natural products. Herbal medicines contain a wide range of natural products and are considered to be a major source for the development of novel drugs. However, the process of isolating and obtaining these bioactive components for the production of novel drugs is complex. Meanwhile, the complexity and diversity of herbal constituents have posed a great challenge to the screening studies of herbal active ingredients. Currently, traditional extraction and screening studies of active ingredients in herbal medicine include extraction and chromatographic separation technology development, serum medicinal chemistry, metabolomics and computerized virtual screening. In order to achieve integrated targeting of Fe3O4 for extraction and separation of natural products from herbs, various Fe3O4-based composites need to be synthesized so that the composites can be further functionalized and modified. Composites such as Fe3O4@SiO2, Fe3O4-based magnetic graphene oxide and Fe3O4-based magnetic carbon nanotubes were used to achieve targeted extraction and isolation of natural products from herbal medicines. The main extraction techniques involved based on these Fe3O4-based composites are molecularly imprinted techniques, immobilized ligand fishing techniques, and cell membrane-coated bionanotechnology methods. This article will present recent advances in the synthesis and modification of Fe3O4 composites and their applications for the extraction of natural products in conjunction with molecular imprinting, immobilization-targeted fishing, and cell-membrane-coated biomimetic techniques, as well as the future goals and challenges of functionalized modification of Fe3O4 composites for the targeted extraction of natural products, like protein overexpression modification, doping of fluorescent substances and genetic engineering development. A deeper understanding of the multi-level, multidisciplinary, and applied studies in materials science and phytochemistry will be provided by this article.

[Analysis of genetic variants and molecular pathogenesis in a Chinese pedigree affected with Multiple epiphyseal dysplasia].

OBJECTIVE: To analyze the genetic variant and molecular pathogenesis in a Chinese pedigree affected with Multiple epiphyseal dysplasia (MED). METHODS: A MED pedigree which had presented at the Beijing Jishuitan Hospital Affiliated to Capital Medical University on September 13, 2020 was selected as the study subject. Clinical data of the pedigree were collected. Peripheral blood samples were drawn from pedigree members for the extraction of genomic DNA. Whole exome sequencing (WES) was carried out for the pedigree. Candidate variant was verified by Sanger sequencing. Wild type and mutant SLC26A2 expression plasmids were constructed and transfected into human primary chondrocytes. The effect of the variants on the protein localization and cell proliferation was determined by immunofluorescence and CCK8 assays. RESULTS: WES and Sanger sequencing revealed that the proband has harbored compound heterozygous variants of the SLC26A2 gene, including a paternally derived c.484G>T (p.Val162Leu) missense variant and a maternally derived c.485_486delTG (p.Val162Glyfs*12) frameshifting variant. The SLC26A2WT and its mutant SLC26A2Val162Leu and SLC26A2Val162Glyfs*12 expression plasmids were distributed in the nuclei and cytoplasm of human primary chondrocytes. Compared with SLC26A2WT, the expressions of SLC26A2Val162Leu and SLC26A2Val162Glyfs*12 were decreased, along with reduced proliferation of human primary chondrocytes. CONCLUSION: The c.484G>T and c.485_486delTG compound heterozygous variants of the SLC26A2 gene may affect the proliferation of human primary chondrocytes and underlay the pathogenesis of MED in this pedigree.

Biallelic variants in SLC26A2 cause multiple epiphyseal dysplasia-4 by disturbing chondrocyte homeostasis.

BACKGROUND: Multiple epiphyseal dysplasia-4 (MED-4, MIM 226900) is a rare autosomal recessive disease characterized by disproportionate height and early onset osteoarthritis of the lower limbs. MED-4 is caused by homozygous or compound heterozygous pathogenic variants in the SLC26A2 gene. However, the underlying pathogenic mechanisms in chondrocytes remains unknown. This study aimed to identify the pathogenic variants within a MED-4 family and explore the molecular etiology of this condition in human primary chondrocyte cells. METHODS: Clinical data were recorded and peripheral blood samples were collected for analysis. Whole exome sequencing (WES) and bioinformatic analyses were performed to determine causative variants. Wild-type SLC26A2 and corresponding mutant expression plasmids were constructed and transfected into human primary chondrocytes. The expression and subcellular distribution of SLC26A2 protein in chondrocytes were detected by immunoblotting and immunofluorescence. Effects of these variants on chondrocytes viability and apoptosis were measured by Cell Counting Kit-8 (CCK-8) assay. Expression of genes related to cartilage homeostasis was subsequently analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: We identified two compound heterozygous variants c.1020_1022delTGT(p.Val341del) and c.1262 T > C(p.Ile421Thr) in the SLC26A2 gene in the patients. Mutant SLC26A2Val341del and SLC26A2Ile421Thr proteins were distributed in relatively few cells and were observed only within the nucleus. The viability of chondrocytes with the SLC26A2 variant group was similar to the wild-type (WT) group. However, the protein expressions of SLC26A2Val341del and SLC26A2Ile421Thr were decreased compared with SLC26A2WT. Expression levels of matrix metallopeptidase 13 (MMP13), α-1 chain of type X collagen (COL10A1), and Runt-related transcription factor 2 (RUNX2) were significantly decreased in the variant group. However, aggrecan (ACAN) expression was higher in the variant group than the WT group. CONCLUSIONS: Overall, our data demonstrate that the variants p.Val341del and p.Ile421Thr in SLC26A2 cause MED-4 and that these two variants promote chondrocyte proliferation while inhibiting chondrocyte differentiation.