Genetic analysis of cervical cancer with lymph node metastasis.

OBJECTIVE: To find out the differences in gene characteristics between cervical cancer patients with and without lymph node metastasis, and to provide reference for therapy. METHODS: From January 2018 to June 2022, recurrent cervical cancer patients 39 cases with lymph node metastasis and 73 cases without lymph node metastasis underwent testing of 1,021 cancer-related genes by next-generation sequencing. Maftools software was used to analyze somatic single nucleotide/insertion-deletion variation mutation, co-occurring mutation, cosmic mutation characteristics, oncogenic signaling pathways. RESULTS: EP300 and FBXW7 were significantly enriched in lymph node-positive patients. Lymph node-positive patients with EP300 or FBXW7 mutations had lower overall survival (OS) after recurrence. Both lymph node-positive and -negative patients had plenty of co-occurring mutations but few mutually exclusive mutations. Lymph node-positive co-occurring mutation number ≥6 had lower OS, while lymph node-negative co-occurring mutation number ≥3 had lower OS after recurrence. The etiology of SBS3 was defects in DNA double strand break repair by homologous recombination, which exclusively exist in lymph node-positive patients. There was no difference in median tumor mutation burden (TMB) between positive and negative lymph nodes, but TMB was significantly associated with PIK3CA mutation. CONCLUSION: The somatic SNV/Indels of EP300 and FBXW7, SBS3 homologous recombination-mediated DNA repair defect were enriched in lymph node-positive patients. For lymph node-positive patients, EP300 or FBXW7 mutations predicted poor prognosis. No matter lymph node-positive or negative, more co-occurring mutation number predicted poor prognosis. PIK3CA mutation may account for the higher TMB and help identify patients who benefit from immunotherapy.

Mn(II)-Based Metal Halide with Near-Unity Quantum Yield for White LEDs and High-Resolution X-ray Imaging.

Metal halides have drawn great interest as luminescent materials and scintillators due to their outstanding optical properties. Exploring new types of phosphors with easy production processes, excellent photophysical properties, high light yields, and environmentally friendly compositions is crucial and quite challenging. Herein, a novel Mn(II)-based metal halide (4-BTP)2MnBr4 was produced using a facile solvent evaporation method, which exhibited a strong green emission peaking at 524 nm from the d-d transition of tetrahedral-coordinated Mn2+ ion and a near-unity quantum yield. The prepared white light-emitting diode device has a wide color gamut of 100.7% NTSC with CIE chromaticity coordinates of (0.32, 0.32). In addition, (4-BTP)2MnBr4 demonstrates excellent characteristics in X-ray scintillation, including a high light yield of 98 000 photons/MeV, a sensitive detection limit of 37.4 nGy/s, excellent resistance to radiation damage, and successful demonstration of X-ray imaging with high resolution at 21.3 lp/mm, revealing the potential for application in diagnostic X-ray medical imaging and industry radiation detection.

Senaparib as first-line maintenance therapy in advanced ovarian cancer: a randomized phase 3 trial.

Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors as maintenance therapy after first-line chemotherapy have improved progression-free survival in women with advanced ovarian cancer; however, not all PARP inhibitors can provide benefit for a biomarker-unselected population. Senaparib is a PARP inhibitor that demonstrated antitumor activity in patients with solid tumors, including ovarian cancer, in phase 1 studies. The multicenter, double-blind, phase 3 trial FLAMES randomized (2:1) 404 females with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III-IV) and response to first-line platinum-based chemotherapy to senaparib 100 mg (n = 271) or placebo (n = 133) orally once daily for up to 2 years. The primary endpoint was progression-free survival assessed by blinded independent central review. At the prespecified interim analysis, the median progression-free survival was not reached with senaparib and was 13.6 months with placebo (hazard ratio 0.43, 95% confidence interval 0.32-0.58; P < 0.0001). The benefit with senaparib over placebo was consistent in the subgroups defined by BRCA1 and BRCA2 mutation or homologous recombination status. Grade ≥3 treatment-emergent adverse events occurred in 179 (66%) and 27 (20%) patients, respectively. Senaparib significantly improved progression-free survival versus placebo in patients with advanced ovarian cancer after response to first-line platinum-based chemotherapy, irrespective of BRCA1 and BRCA2 mutation status and with consistent benefits observed between homologous recombination subgroups, and was well tolerated. These results support senaparib as a maintenance treatment for patients with advanced ovarian cancer after a response to first-line chemotherapy. ClinicalTrials.gov identifier: NCT04169997 .

Mechanistic Insights into Yifei Sanjie Pill's Regulation of EMT to Enhance Gefitinib Treatment effect in NSCLC by in silico analysis and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: The Yi-Fei San-Jie pill (YFSJ) is a well-known Chinese medicine that has been used to treat non-small cell lung cancer in China for decades. AIM OF THE STUDY: Previous studies have shown that YFSJ combined with gefitinib can effectively inhibit the proliferation of gefitinib-resistant non-small cell lung cancer (NSCLC) cell lines by promoting apoptosis and autophagy, but the molecular biological mechanisms involved and whether YFSJ combined with gefitinib can have synergistic effects still need to be further explored. Thus, the present study aimed to establish an in silico and experimental framework to decipher the underlying mechanism by which YFSJ augments the efficacy of gefitinib in treating NSCLC. MATERIALS AND METHODS: Integrated approaches, including microarray analysis, network pharmacology, RNA sequencing, bioinformatics algorithm analysis and in vivo and in vitro experiments, were applied to elucidate the underlying mechanism. RESULTS: Analysis of microarray datasets indicated that gefitinib may play a role in the regulation of the epithelial-mesenchymal transition (EMT) of PC9 cells. EMT-related Gene Ontology (GO) terms and the MAPK pathway were found to be enriched in the differentially expressed genes (DEGs), and a decreasing trend was observed in the EMT score. Network pharmacology analysis revealed that the potential NSCLC-related targets of YFSJ also showed enrichment in EMT-related GO terms and the MAPK pathway. Experimental findings demonstrated that combined YFSJ-treated serum and gefitinib treatment significantly inhibited PC9 cell migration and invasion. In addition, the combined treatment dramatically reduced the tumour volume in an animal model. The effectiveness of the combination treatment surpassed that of gefitinib alone in both cell and animal experiments. RNA sequencing analysis revealed significant enrichment of DEGs in EMT-related GO terms for the gefitinib treatment group, YFSJ treatment group, and combination treatment group compared to the control group. Notably, the negative regulation of EMT showed significant enrichment in the DEGs of the combination treatment group. The MAPK pathway was significantly enriched among the different groups. Moreover, combined treatment with YFSJ and gefitinib may exert synergistic anti-NSCLC effects by inhibiting the p-p38 MAPK/GSK3ß signalling axis, subsequently suppressing downstream EMT processes. CONCLUSION: Combined treatment with YFSJ and gefitinib could enhance the sensitivity of NSCLC cells to gefitinib by suppressing EMT through the EGFR/p-p38 MAPK/GSK3ß signalling axis. YFSJ may serve as an important adjunctive medication for NSCLC patients receiving gefitinib treatment in clinical practice.

Diagnostic value of ultrasound elastography in polycystic ovary syndrome: a systematic review and meta-analysis.

OBJECTIVE: The main purpose of this systematic review and meta-analysis was to investigate the diagnostic value of ultrasound elastography in the evaluation of polycystic ovary syndrome (PCOS). METHODS: A comprehensive and methodical investigation was carried out in the databases of PubMed, EMBASE, Cochrane, Scopus, Web of Science, and China National Knowledge Infrastructure, covering the entire duration of these databases until October 18, 2023. The primary purpose of this research was to evaluate and contrast ovarian tissue elasticity in people with and without PCOS. The elasticity of ovarian tissue was quantified using standardized mean difference (SMD). RESULTS: A total of eight studies were ultimately selected for systematic evaluation and meta-analysis. Five studies used shear wave elastography (SWE) as a diagnostic tool, and it was discovered that women with PCOS had higher levels of ovarian shear wave elasticity than their healthy counterparts. The SMD was determined to be 1.86 kilopascal (95% CI: 1.27 to 2.44). Three studies were conducted using strain elastography (SE) to compare the ovarian strain ratio of patients with PCOS to that of a healthy control group. The SMD for the PCOS group was 2.07 (95% CI: 1.79 to 2.34), which indicated that the ovarian strain ratio was significantly higher in that group. CONCLUSION: This systematic review and meta-analysis found that women with PCOS had stiffer ovarian tissue than women without the disorder. Ultrasound elastography may provide clinicians with value beyond 2D ultrasound in the diagnosis of PCOS.

Screening and identification of an aflatoxin B1-degrading strain from the Qinghai-Tibet Plateau and biodegradation products analysis.

This research aimed to address the issue of aflatoxin B1 (AFB1) contamination, which posed severe health and economic consequences. This study involved exploring unique species resources in the Qinghai-Tibet Plateau, screening strains capable of degrading AFB1. UPLC-Q-Orbitrap HRMS and NMR were employed to examine the degradation process and identify the structure of the degradation products. Results showed that Bacillus amyloliquefaciens YUAD7, isolated from yak dung in the Qinghai-Tibet Plateau, removed 91.7% of AFB1 from TSB-AFB1 medium with an AFB1 concentration of 10 µg/mL (72 h, 37°C, pH 6.8) and over 85% of AFB1 from real food samples at 10 µg/g (72 h, 37°C), exhibiting strong AFB1 degradation activity. Bacillus amyloliquefaciens YUAD7's extracellular secretions played a major role in AFB1 degradation mediated and could still degrade AFB1 by 43.16% after boiling for 20 min. Moreover, B. amyloliquefaciens YUAD7 demonstrated the capability to decompose AFB1 through processes such as hydrogenation, enzyme modification, and the elimination of the -CO group, resulting in the formation of smaller non-toxic molecules. Identified products include C12H14O4, C5H12N2O2, C10H14O2, C4H12N2O, with a structure consisting of dimethoxyphenyl and enoic acid, dimethyl-amino and ethyl carbamate, polyunsaturated fatty acid, and aminomethyl. The results indicated that B. amyloliquefaciens YUAD7 could be a potentially valuable strain for industrial-scale biodegradation of AFB1 and providing technical support and new perspectives for research on biodegradation products.

COVID-19 mRNA vaccines induce robust levels of IgG but limited amounts of IgA within the oronasopharynx of young children.

Background: Understanding antibody responses to SARS-CoV-2 vaccination is crucial for refining COVID-19 immunization strategies. Generation of mucosal immune responses, including mucosal IgA, could be of potential benefit to vaccine efficacy, yet limited evidence exists regarding the production of mucosal antibodies following the administration of current mRNA vaccines to young children. Methods: We measured the levels of antibodies against SARS-CoV-2 from a cohort of children under 5 years of age undergoing SARS-CoV-2 mRNA vaccination (serially collected, matched serum and saliva samples, N=116) or on convenience samples of children under 5 years of age presenting to a pediatric emergency department (nasal swabs, N=103). Further, we assessed salivary and nasal samples for the ability to induce SARS-CoV-2 spike-mediated neutrophil extracellular traps (NET) formation. Results: Longitudinal analysis of post-vaccine responses in saliva revealed the induction of SARS-CoV-2 specific IgG but not IgA. Similarly, SARS-CoV-2 specific IgA was only observed in nasal samples obtained from previously infected children with or without vaccination, but not in vaccinated children without a history of infection. In addition, oronasopharyngeal samples obtained from children with prior infection were able to trigger enhanced spike-mediated NET formation, and IgA played a key role in driving this process. Conclusions: Despite the induction of specific IgG in the oronasal mucosa, current intramuscular vaccines have limited ability to generate mucosal IgA in young children. These results confirm the independence of mucosal IgA responses from systemic humoral responses following mRNA vaccination and suggest potential future vaccination strategies for enhancing mucosal protection in this young age group.

First total synthesis, antitumor evaluation and target identification of mornaphthoate E: A new tubulin inhibitor template acting on PI3K/Akt signaling pathway.

Mornaphthoate E (MPE) is a prenylated naphthoic acid methyl ester isolated from the roots of a famous Chinese medicinal plant Morinda officinalis and shows remarkable cytotoxicity against several human tumor cell lines. In the current project, the first total synthesis of (±)-MPE was achieved in seven steps and 5.6% overall yield. Then the in vitro anti-tumor activity of MPE was first assessed for both enantiomers in two breast cancer cells, with the levoisomer exerting slightly better potency. The in vivo anti-tumor effect was further verified by applying the racemate in an orthotopic autograft mouse model. Notably, MPE exerted promising anti-metastasis activity both in vitro and in vivo and showed no obvious toxicity on mice at the therapeutic dosage. Mechanistic investigations demonstrated that MPE acted as a tubulin polymerization stabilizer and disturbed the dynamic equilibrium of microtubules via regulating PI3K/Akt signaling. In conclusion, our work has provided a new chemical template for the future design and development of next-generation tubulin-targeting chemotherapies.

The Role of Traditional Chinese Medicine in the Management of Cervical Cancer.

Globally, cervical cancer poses a substantial public health challenge, with low and middle-income countries bearing the highest burden [Rajkhowa, P., D.S. Patil, S.M. Dsouza, P. Narayanan and H. Brand. Evidence on factors influencing HPV vaccine implementation in South Asia: a scoping review. Glob. Public Health 18: 2288269, 2023]. The incidence rate ranks second highest among female malignant tumors in China, following only breast cancer. The prognosis of advanced cervical cancer is extremely poor, with a 5-year progression-free survival (PFS) rate of only 15%, and the treatment of advanced recurrent or metastatic cervical cancer remains a huge challenge. An increasing amount of evidence suggests that traditional Chinese medicine (TCM) can significantly enhance sensitivity to chemotherapeutic drugs, strengthen antitumor effects, and notably improve adverse reactions associated with cancer such as fatigue and bone marrow suppression. In recent years, the therapeutic effects and mechanisms of Chinese herbal medicines, such as the Guizhi-Fuling-decoction, the compound Yangshe granule, Huangqi, and Ginseng, herbal monomers (e.g., Ginsenoside Rh2, Tanshinone IIA, and Tetrandrine), and the related extracts and compound formulations, have received extensive attention for the treatment of cervical cancer. This paper reviews the research progress of TCM in cervical cancer. In addition, we reported a case of an advanced cervical cancer patient with multiple abdominal and pelvic metastasis who initially received chemotherapy, was then treated with TCM alone, and subsequently survived for 22 years. The model of whole-process management with TCM can enable more cancer patients to obtain longer survival periods.

Mapping an intelligent algorithm for predicting female adolescents' cervical vertebrae maturation stage with high recall and accuracy.

BACKGROUNDS AND OBJECTIVES: The present study was designed to define a novel algorithm capable of predicting female adolescents' cervical vertebrae maturation stage with high recall and accuracy. METHODS: A total of 560 female cephalograms were collected, and cephalograms with unclear vertebral shapes and deformed scales were removed. 480 films from female adolescents (mean age: 11.5 years; age range: 6-19 years) were used for the model development phase, and 80 subjects were randomly and stratified allocated to the validation cohort to further assess the model's performance. Derived significant predictive parameters from 15 anatomic points and 25 quantitative parameters of the second to fourth cervical vertebrae (C2-C4) to establish the ordinary logistic regression model. Evaluation metrics including precision, recall, and F1 score are employed to assess the efficacy of the models in each identified cervical vertebrae maturation stage (iCS). In cases of confusion and mispredictions, the model underwent modification to improve consistency. RESULTS: Four significant parameters, including chronological age, the ratio of D3 to AH3 (D3:AH3), anterosuperior angle of C4 (@4), and distance between C3lp and C4up (C3lp-C4up) were administered into the ordinary regression model. The primary predicting model that implements the novel algorithm was built and the performance evaluation with all stages of 93.96% for accuracy, 93.98% for precision, 93.98% for recall, and 93.95% for F1-score were obtained. Despite the hybrid logistic-based model achieving high accuracy, the unsatisfactory performance of stage estimation was noticed for iCS3 in the primary cohort (89.17%) and validation cohort (85.00%). Through bivariate logistic regression analysis, the posterior height of C4 (PH4) was further selected in the iCS3 to establish a corrected model, thus the evaluation metrics were upgraded to 95.83% and 90.00%, respectively. CONCLUSIONS: An unbiased and objective assessment of the cervical vertebrae maturation (CVM) method can function as a decision-support tool, assisting in the evaluation of the optimal timing for treatment in growing adults. Our novel proposed logistic model yielded individual formulas for each specific CVM stage and attained exceptional performance, indicating the capability to function as a benchmark for maturity evaluation in clinical craniofacial orthopedics for Chinese female adolescents.

Bacterial Sphingolipids Exacerbate Colitis by Inhibiting ILC3-derived IL-22 Production.

BACKGROUND & AIMS: Gut bacterial sphingolipids, primarily produced by Bacteroidetes, have dual roles as bacterial virulence factors and regulators of the host mucosal immune system, including regulatory T cells and invariant natural killer T cells. Patients with inflammatory bowel disease display altered sphingolipids profiles in fecal samples. However, how bacterial sphingolipids modulate mucosal homeostasis and regulate intestinal inflammation remains unclear. METHODS: We used dextran sodium sulfate (DSS)-induced colitis in mice monocolonized with Bacteroides fragilis strains expressing or lacking sphingolipids to assess the influence of bacterial sphingolipids on intestinal inflammation using transcriptional, protein, and cellular analyses. Colonic explant and organoid were used to study the function of bacterial sphingolipids. Host mucosal immune cells and cytokines were profiled and characterized using flow cytometry, enzyme-linked immunosorbent assay, and Western blot, and cytokine function in vivo was investigated by monoclonal antibody injection. RESULTS: B fragilis sphingolipids exacerbated intestinal inflammation. Mice monocolonized with B fragilis lacking sphingolipids exhibited less severe DSS-induced colitis. This amelioration of colitis was associated with increased production of interleukin (IL)-22 by ILC3. Mice colonized with B fragilis lacking sphingolipids following DSS treatment showed enhanced epithelial STAT3 activity, intestinal cell proliferation, and antimicrobial peptide production. Protection against DSS colitis associated with B fragilis lacking sphingolipids was reversed on IL22 blockade. Furthermore, bacterial sphingolipids restricted epithelial IL18 production following DSS treatment and interfered with IL22 production by a subset of ILC3 cells expressing both IL18R and major histocompatibility complex class II. CONCLUSIONS: B fragilis-derived sphingolipids exacerbate mucosal inflammation by impeding epithelial IL18 expression and concomitantly suppressing the production of IL22 by ILC3 cells.

Endothelial cell-derived extracellular vesicles modulate the therapeutic efficacy of mesenchymal stem cells through IDH2/TET pathway in ARDS.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a severe and fatal disease. Although mesenchymal stem cell (MSC)-based therapy has shown remarkable efficacy in treating ARDS in animal experiments, clinical outcomes have been unsatisfactory, which may be attributed to the influence of the lung microenvironment during MSC administration. Extracellular vesicles (EVs) derived from endothelial cells (EC-EVs) are important components of the lung microenvironment and play a crucial role in ARDS. However, the effect of EC-EVs on MSC therapy is still unclear. In this study, we established lipopolysaccharide (LPS) - induced acute lung injury model to evaluate the impact of EC-EVs on the reparative effects of bone marrow-derived MSC (BM-MSC) transplantation on lung injury and to unravel the underlying mechanisms. METHODS: EVs were isolated from bronchoalveolar lavage fluid of mice with LPS - induced acute lung injury and patients with ARDS using ultracentrifugation. and the changes of EC-EVs were analysed using nanoflow cytometry analysis. In vitro assays were performed to establish the impact of EC-EVs on MSC functions, including cell viability and migration, while in vivo studies were performed to validate the therapeutic effect of EC-EVs on MSCs. RNA-Seq analysis, small interfering RNA (siRNA), and a recombinant lentivirus were used to investigate the underlying mechanisms. RESULTS: Compared with that in non-ARDS patients, the quantity of EC-EVs in the lung microenvironment was significantly greater in patients with ARDS. EVs derived from lipopolysaccharide-stimulated endothelial cells (LPS-EVs) significantly decreased the viability and migration of BM-MSCs. Furthermore, engrafting BM-MSCs pretreated with LPS-EVs promoted the release of inflammatory cytokines and increased pulmonary microvascular permeability, aggravating lung injury. Mechanistically, LPS-EVs reduced the expression level of isocitrate dehydrogenase 2 (IDH2), which catalyses the formation of α-ketoglutarate (α-KG), an intermediate product of the tricarboxylic acid (TCA) cycle, in BM-MSCs. α-KG is a cofactor for ten-eleven translocation (TET) enzymes, which catalyse DNA hydroxymethylation in BM-MSCs. CONCLUSIONS: This study revealed that EC-EVs in the lung microenvironment during ARDS can affect the therapeutic efficacy of BM-MSCs through the IDH2/TET pathway, providing potential strategies for improving the therapeutic efficacy of MSC-based therapy in the clinic.

Exploring Dynamic Changes in HIV-1 Molecular Transmission Networks and Key Influencing Factors: Cross-Sectional Study.

BACKGROUND: The HIV-1 molecular network is an innovative tool, using gene sequences to understand transmission attributes and complementing social and sexual network studies. While previous research focused on static network characteristics, recent studies' emphasis on dynamic features enhances our understanding of real-time changes, offering insights for targeted interventions and efficient allocation of public health resources. OBJECTIVE: This study aims to identify the dynamic changes occurring in HIV-1 molecular transmission networks and analyze the primary influencing factors driving the dynamics of HIV-1 molecular networks. METHODS: We analyzed and compared the dynamic changes in the molecular network over a specific time period between the baseline and observed end point. The primary factors influencing the dynamic changes in the HIV-1 molecular network were identified through univariate analysis and multivariate analysis. RESULTS: A total of 955 HIV-1 polymerase fragments were successfully amplified from 1013 specimens; CRF01_AE and CRF07_BC were the predominant subtypes, accounting for 40.8% (n=390) and 33.6% (n=321) of the specimens, respectively. Through the analysis and comparison of the basic and terminal molecular networks, it was discovered that 144 sequences constituted static molecular networks, and 487 sequences contributed to the formation of dynamic molecular networks. The findings of the multivariate analysis indicated that the factors occupation as a student, floating population, Han ethnicity, engagement in occasional or multiple sexual partnerships, participation in anal sex, and being single were independent risk factors for the dynamic changes observed in the HIV-1 molecular network, and the odds ratio (OR; 95% CIs) values were 2.63 (1.54-4.47), 1.83 (1.17-2.84), 2.91 (1.09-7.79), 1.75 (1.06-2.90), 4.12 (2.48-6.87), 5.58 (2.43-12.80), and 2.10 (1.25-3.54), respectively. Heterosexuality and homosexuality seem to exhibit protective effects when compared to bisexuality, with OR values of 0.12 (95% CI 0.05-0.32) and 0.26 (95% CI 0.11-0.64), respectively. Additionally, the National Eight-Item score and sex education experience were also identified as protective factors against dynamic changes in the HIV-1 molecular network, with OR values of 0.12 (95% CI 0.05-0.32) and 0.26 (95% CI 0.11-0.64), respectively. CONCLUSIONS: The HIV-1 molecular network analysis showed 144 sequences in static networks and 487 in dynamic networks. Multivariate analysis revealed that occupation as a student, floating population, Han ethnicity, and risky sexual behavior were independent risk factors for dynamic changes, while heterosexuality and homosexuality were protective compared to bisexuality. A higher National Eight-Item score and sex education experience were also protective factors. The identification of HIV dynamic molecular networks has provided valuable insights into the characteristics of individuals undergoing dynamic alterations. These findings contribute to a better understanding of HIV-1 transmission dynamics and could inform targeted prevention strategies.

Crohn's disease treatment and memory T-cell subset changes: insights from a case series.

Background: Crohn's disease (CD) is a chronic inflammatory bowel disease with significant morbidity, affecting millions worldwide. The intricacies of immune responses in CD, especially post-treatment, remain a vital area of exploration. While memory T (Tm)-cell subsets play a pivotal role in adaptive immunity, their specific function in patients with CD after treatment is not well-understood. This study aims to investigate the effect and function of Tm-cell subsets in these patients, addressing a crucial knowledge gap in the context of CD therapeutics. Methods: A total of eight patients diagnosed with CD were selected based on predefined inclusion criteria. All patients were treated with either anti-inflammatory agents, immunosuppressive drugs, or a combination of both. For comparison, healthy donors were enrolled based on exclusion of autoimmune or inflammatory diseases. Peripheral blood mononuclear cells (PBMCs) and lymphocytes were isolated from blood and lymph node tissue respectively. The phenotype and cytokine production of T lymphocytes from both CD patients and healthy donors were analyzed using flow cytometry. Statistical comparisons of the outcomes between CD patients and healthy donors were made using Mann-Whitney test (two-tailed) and Student t-test. Results: Post-treatment CD patients exhibited an altered T cell distribution with a notable increase in CD8+ T cells in PBMCs (P=0.0005), and altered frequencies of CD4+ and CD8+ T cells in mesenteric lymph nodes (MLNs). Tm cells showed decreased interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) production, with significant alterations in the frequency of IFN-γ-producing CD8+ stem cell-like Tm (Tscm) cells in lesions of the MLNs from patients with CD (CD-M-Lys) compared to healthy MLNs from patients with CD (N-M-Lys) (P=0.0152). Differences in tissue-resident Tm (Trm)-cell subset frequencies were observed between the MLNs and small intestinal mucosa in CD patients. Conclusions: The treatments with anti-inflammatory agents and/or immunosuppressive drugs have a significant effect on the frequency and function of Tm-cell subsets. Clinically, these findings suggest a potential therapeutic avenue in modulating Tm-cell responses, which might be particularly beneficial for conditions where immune response modulation is crucial. Further clinical studies are warranted to explore the full therapeutic implications of these findings.

Dextran Macroinitiator for Synthesis of Polysaccharide-b-Polypeptide Block Copolymers via NCA Ring-Opening Polymerization.

Synthesis of polysaccharide-b-polypeptide block copolymers represents an attractive goal because of their promising potential in delivery applications. Inspired by recent breakthroughs in N-carboxyanhydride (NCA) ring-opening polymerization (ROP), we present an efficient approach for preparation of a dextran-based macroinitiator and the subsequent synthesis of dextran-b-polypeptides via NCA ROP. This is an original approach to creating and employing a native polysaccharide macroinitiator for block copolymer synthesis. In this strategy, regioselective (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) oxidation of the sole primary alcohol located at the C-6 position of the monosaccharide at the nonreducing end of linear dextran results in a carboxylic acid. This motif is then transformed into a tetraalkylammonium carboxylate, thereby generating the dextran macroinitiator. This macroinitiator initiates a wide range of NCA monomers and produces dextran-b-polypeptides with a degree of polymerization (DP) of the polypeptide up to 70 in a controlled manner (D < 1.3). This strategy offers several distinct advantages, including preservation of the original dextran backbone structure, relatively rapid polymerization, and moisture tolerance. The dextran-b-polypeptides exhibit interesting self-assembly behavior. Their nanostructures have been investigated by dynamic light scattering (DLS) and transmission electron microscopy (TEM), and adjustment of the structure of block copolymers allows self-assembly of spherical micelles and worm-like micelles with varied diameters and aspect ratios, revealing a range of diameters from 60 to 160 nm. Moreover, these nanostructures exhibit diverse morphologies, including spherical micelles and worm-like micelles, enabling delivery applications.

Bioengineered vascular grafts with a pathogenic TGFBR1 variant model aneurysm formation in vivo and reveal underlying collagen defects.

Thoracic aortic aneurysm (TAA) is a life-threatening vascular disease frequently associated with underlying genetic causes. An inadequate understanding of human TAA pathogenesis highlights the need for better disease models. Here, we established a functional human TAA model in an animal host by combining human induced pluripotent stem cells (hiPSCs), bioengineered vascular grafts (BVGs), and gene editing. We generated BVGs from isogenic control hiPSC-derived vascular smooth muscle cells (SMCs) and mutant SMCs gene-edited to carry a Loeys-Dietz syndrome (LDS)-associated pathogenic variant (TGFBR1A230T). We also generated hiPSC-derived BVGs using cells from a patient with LDS (PatientA230T/+) and using genetically corrected cells (Patient+/+). Control and experimental BVGs were then implanted into the common carotid arteries of nude rats. The TGFBR1A230T variant led to impaired mechanical properties of BVGs, resulting in lower burst pressure and suture retention strength. BVGs carrying the variant dilated over time in vivo, resembling human TAA formation. Spatial transcriptomics profiling revealed defective expression of extracellular matrix (ECM) formation genes in PatientA230T/+ BVGs compared with Patient+/+ BVGs. Histological analysis and protein assays validated quantitative and qualitative ECM defects in PatientA230T/+ BVGs and patient tissue, including decreased collagen hydroxylation. SMC organization was also impaired in PatientA230T/+ BVGs as confirmed by vascular contraction testing. Silencing of collagen-modifying enzymes with small interfering RNAs reduced collagen proline hydroxylation in SMC-derived tissue constructs. These studies demonstrated the utility of BVGs to model human TAA formation in an animal host and highlighted the role of reduced collagen modifying enzyme activity in human TAA formation.

Dietary intake and glutamine-serine metabolism control pathologic vascular stiffness.

Perivascular collagen deposition by activated fibroblasts promotes vascular stiffening and drives cardiovascular diseases such as pulmonary hypertension (PH). Whether and how vascular fibroblasts rewire their metabolism to sustain collagen biosynthesis remains unknown. Here, we found that inflammation, hypoxia, and mechanical stress converge on activating the transcriptional coactivators YAP and TAZ (WWTR1) in pulmonary arterial adventitial fibroblasts (PAAFs). Consequently, YAP and TAZ drive glutamine and serine catabolism to sustain proline and glycine anabolism and promote collagen biosynthesis. Pharmacologic or dietary intervention on proline and glycine anabolic demand decreases vascular stiffening and improves cardiovascular function in PH rodent models. By identifying the limiting metabolic pathways for vascular collagen biosynthesis, our findings provide guidance for incorporating metabolic and dietary interventions for treating cardiopulmonary vascular disease.

Optimization of 3D printing supply chain in the era of live streaming e-commerce.

This study examines the effects of the rising live streaming e-commerce on the 3DP supply chain, employing system dynamics to develop separate models for pure polymer and polymer-metal mixed printing. The analysis focuses on optimizing the 3DP supply chain configuration. Results indicate that, based solely on printing time, cost, and quality metrics, Corporate-live-3DP services are optimal for live commerce scenarios. However, despite this, Private-live-3DP maintains a substantial consumer base in practice, as evidenced by literature data and case studies. Both models pose significant challenges to conventional supply chains, necessitating adaptation. For Corporate-live-3DP, optimization strategies may include technology advancements, digital transformation, agile manufacturing, global network optimization, innovative management, collaborative R&D, fine-tuned inventory control, quality system upgrades, talent development, and organizational restructuring. Conversely, Private-live-3DP can be optimized through consolidation of private 3D printing resources, demand prediction and order optimization, supply chain collaboration platforms, quality management extensions, inventory strategy adjustments, increased transparency, regulatory compliance, and risk mitigation measures.

High-fat diet during early life reshapes the gut microbiome and is associated with the disrupted mammary microenvironment in later life in mice.

The influence of gut microbiota on gut health is well-documented, but it remains obscure for extraintestinal diseases such as breast cancer. Moreover, it is entirely unknown how gut dysbiosis during early life contributes to breast tumorigenesis later in life. In this study, we hypothesized that a high-fat diet during early life leads to alterations in the gut microbiome and is associated with disruptions in the mammary microenvironment. Female C57BL/6 mice were fed a low-fat diet (10% kcal fat) or a high-fat diet (HF, 60% kcal fat) for 8 weeks from the age of 4 to 12 weeks, which is equivalent to human childhood and adolescence. Twelve mice were sacrificed immediately after the 8-week feeding, the remainder were euthanized after switching to a normal lifecycle-supporting diet for an additional 12 weeks; the gut microbiome was then sequenced. The 8-week HF diet feeding altered the beta-diversity (Bray & Jaccard P < .01), and the difference remained significant after switching the diet (Bray & Jaccard P < .05). Immediately after HF feeding, a greater number of microbial taxa (>50) were altered, and about half of the taxa (25) remained significantly changed after switching the diet. The abundance of Alistipes, Bilophila, and Rikenellaceae stood out as significantly associated with multiple metabolic and inflammatory biomarkers in mammary tissue, including aromatase, Ccl2, and Cox2. In conclusion, an 8-week early-life HF feeding reshaped the gut microbiome, which connected with disrupted mammary microenvironments.

Association of Preoperative Immune Checkpoint Inhibitor Therapy With Cardiopulmonary Instability and Organ Injury After High-Risk Surgery.

OBJECTIVES: To assess the relationship between prior exposure to immune checkpoint inhibitors (ICIs) and the risk of postoperative complications in cancer patients. DESIGN: Single-center retrospective cohort study. INTERVENTIONS: The main exposure was treatment with an FDA-approved ICI within 6 months before surgery. MEASUREMENTS AND MAIN RESULTS: Exposure to ICIs and covariates was determined from the electronic health record. The primary outcome was a composite of postoperative complications, including prolonged pressor or oxygen dependence, kidney injury, or myocardial injury. Secondary outcomes included each subcomponent of the primary outcome. Of 7674 subjects with cancer admitted to the ICU after surgery, 247 were exposed to one or more ICIs in the 6 months before surgery. After propensity score matching, 197 ICI-exposed subjects were matched to 777 nonexposed. The composite outcome occurred in 70 of 197 (35.5%) ICI-exposed subjects and 251 of 777 (32.3%) nonexposed. There was no difference between exposed and nonexposed groups in the primary composite outcome (odds ratio [OR], 1.12; 95% CI, 0.80-1.58) by conditional logistic regression. Risk of the secondary outcome of prolonged pressor dependence was significantly higher in ICI-exposed subjects (OR, 1.64; 95% CI, 1.01-2.67). Risks of oxygen dependence (OR, 1.13; 95% CI, 0.75-1.73), kidney injury (OR, 1.15; 95% CI, 0.77-1.71), and myocardial injury (OR, 1.76; 95% CI, 1.00-3.10) were not significantly different. There was no difference between groups in the time to hospital discharge alive (p = 0.62). CONCLUSIONS: Exposure to ICIs within 6 months before high-risk surgery was not associated with the composite outcome of cardiopulmonary instability or organ injury in patients with cancer. The potential for an association with the secondary outcomes of cardiac instability and injury is worthy of future study.