Differentiate adrenal lipid-poor adenoma from nodular hyperplasia with CT quantitative parameters: a feasibility study.

OBJECTIVES: To explore the potential of CT quantitative parameters in differentiating adrenal lipid-poor adenoma (LPA) from nodular hyperplasia and evaluate diagnostic performance. MATERIALS AND METHODS: Patients with LPA or nodular hyperplasia who underwent contrast-enhanced CT before adrenalectomy were analyzed retrospectively. The study included 128 patients (83 with LPA and 45 with nodular hyperplasia). Each lesion's unenhanced attenuation, portal-venous phase attenuation (CTp), and the portal-venous phase attenuation of the abdominal aorta were evaluated. We subsequently calculated absolute enhancement [a lesion's portal-venous phase attenuation minus unenhanced attenuation (in HUs)], relative enhancement (absolute enhancement divided by unenhanced attenuation), and the relative enhancement ratio [(absolute enhancement divided by abdominal aorta's portal-venous phase attenuation) ×100%]. Lesion number and size were recorded. Volume was assessed by ITK-snap software and the ratio of lesion volume to ipsilateral adrenal volume (volume ratio) was determined. Intergroup differences were analyzed using Student's t-test and chi-squared test. Logistic regression models were developed, and receiver operating characteristic (ROC) curves were constructed to determine the area under the ROC curve (AUC), sensitivity, and specificity. The model's performance was then compared against radiologists' subjective assessments, and the inter- and intra-reader agreement values among radiologists were calculated. RESULTS: Portal-venous phase attenuation, volume ratio, and lesion number were independent predictors of LPA. The logistic regression model incorporating CTp, volume ratio, and lesion number achieved an AUC of 0.835, with a sensitivity of 73.5% and a specificity of 80.0%. The radiologists' diagnostic specificity and accuracy appeared to be inferior to the model. The inter-reader agreement among radiologists ranged from 0.082 to 0.535, and the intra-reader agreement of two radiologists were 0.734 and 0.583. CONCLUSION: The portal-venous phase CT demonstrated potential in distinguishing LPA from nodular hyperplasia. The diagnostic performance of the model integrating CTp, volume ratio, and lesion number outperformed radiologists in terms of variability and reproducibility.

Single-cell sequencing insights into the transcriptional landscape of Parkinson's disease.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, with an unknown etiology and no specific treatment. Emerging single-cell and single-nucleus RNA sequencing (sc/snRNA-seq) technologies have become instrumental in unravelling cellular heterogeneity and characterizing molecular signatures at single-cell resolution. Single-cell T cell receptor sequencing (scTCR-seq) and single-cell B cell receptor sequencing (scBCR-seq) technologies provide unprecedented opportunities to explore the immune repertoire diversity. These state-of-the-art technologies have been increasingly applied in PD research in the last five years, offering novel insights into the cellular susceptibilities and complex molecular mechanisms underlying PD pathogenesis. Herein we review recent advances in the applications of sc/snRNA-seq, scTCR-seq and scBCR-seq technologies in various PD models. Moreover, we focus on degenerative neurons, activated neuroglial cells, as well as pro-inflammatory immune cells, exploring their unique transcriptional landscapes in PD, as revealed by single-cell sequencing technologies. Finally, we highlight important challenges and the future directions of single-cell experiments in PD research.

Human midbrain organoids: a powerful tool for advanced Parkinson's disease modeling and therapy exploration.

Parkinson's disease (PD) is a neurodegenerative disorder marked by the loss of dopaminergic neurons in the substantia nigra. Despite progress, the pathogenesis remains unclear. Human midbrain organoids (hMLOs) have emerged as a promising model for studying PD, drug screening, and potential treatments. This review discusses the development of hMLOs, their application in PD research, and current challenges in organoid construction, highlighting possible optimization strategies.

The potential of flavonoids to mitigate cellular senescence in cardiovascular disease.

Aging is one of the most significant factors affecting cardiovascular health, with cellular senescence being a central hallmark. Senescent cells (SCs) secrete a specific set of signaling molecules known as the senescence-associated secretory phenotype (SASP). The SASP has a remarkable impact on age-associated diseases, particularly cardiovascular diseases (CVD). Targeting SCs through anti-aging therapies represents a novel strategy to effectively retard senescence and attenuate disease progression. Accumulating evidence demonstrates that the flavonoids, widely presented in fruits and vegetables worldwide, can delay or treat CVD via selectively eliminating SCs (senolytics) and modulating SASPs (senomorphics). Nevertheless, only sporadic research has illustrated the application of flavonoids in targeting SCs for CVD, which requires further exploration. This review recapitulates the hallmarks and key molecular mechanisms involved in cellular senescence, then summarizes senescence of different types of cardiac cells and describes the mechanisms by which cellular senescence affects CVD development. The discussion culminates with the potential use of flavonoids via exerting their biological effects on cellular senescence to reduce CVD incidence. This summary will provide valuable insights for cardiovascular drug design, development and clinical applications leveraging flavonoids.

ß-resorcylic acid released by Limosilactobacillus reuteri protects against cisplatin-induced ovarian toxicity and infertility.

Chemotherapy-induced premature ovarian insufficiency (CIPOI) triggers gonadotoxicity in women undergoing cancer treatment, leading to loss of ovarian reserves and subfertility, with no effective therapies available. In our study, fecal microbiota transplantation in a cisplatin-induced POI mouse model reveals that a dysbiotic gut microbiome negatively impacts ovarian health in CIPOI. Multi-omics analyses show a significant decrease in Limosilactobacillus reuteri and its catabolite, ß-resorcylic acid , in the CIPOI group in comparison to healthy controls. Supplementation with L. reuteri or ß-RA mitigates cisplatin-induced hormonal disruptions, morphological damages, and reductions in follicular reserve. Most importantly, ß-RA pre-treatment effectively preserves oocyte function, embryonic development, and fetus health, thereby protecting against chemotherapy-induced subfertility. Our results provide evidence that ß-RA suppresses the nuclear accumulation of sex-determining region Y-box 7, which in turn reduces Bcl-2-associated X activation and inhibits granulosa cell apoptosis. These findings highlight the therapeutic potential of targeting the gut-ovary axis for fertility preservation in CIPOI.

Rapid identification of early infections in febrile patients after CD19 target CAR-T cell therapy for B-cell malignancies.

BACKGROUND: CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy stands out as a revolutionary intervention, exhibiting remarkable remission rates in patients with refractory/relapsed (R/R) B-cell malignancies. However, the potential side effects of therapy, particularly cytokine release syndrome (CRS) and infections, pose significant challenges due to their overlapping clinical features. Promptly distinguishing between CRS and infection post CD19 target CAR-T cell infusion (CTI) remains a clinical dilemma. Our study aimed to analyze the incidence of infections and identify key indicators for early infection detection in febrile patients within 30 days post-CTI for B-cell malignancies. METHODS: In this retrospective cohort study, a cohort of 104 consecutive patients with R/R B-cell malignancies who underwent CAR-T therapy was reviewed. Clinical data including age, gender, CRS, ICANS, treatment history, infection incidence, and treatment responses were collected. Serum biomarkers procalcitonin (PCT), interleukin-6 (IL-6), and C-reactive protein (CRP) levels were analyzed using chemiluminescent assays. Statistical analyses employed Pearson's Chi-square test, t-test, Mann-Whitney U-test, Kaplan-Meier survival analysis, Cox proportional hazards regression model, Spearman rank correlation, and receiver operating characteristic (ROC) curve analysis to evaluate diagnostic accuracy and develop predictive models through multivariate logistic regression. RESULTS: In this study, 38 patients (36.5%) experienced infections (30 bacterial, 5 fungal, and 3 viral) within the first 30 days of CAR T-cell infusion. In general, bacterial, fungal, and viral infections were detected at a median of 7, 8, and 9 days, respectively, after CAR T-cell infusion. Prior allogeneic hematopoietic cell transplantation (HCT) was an independent risk factor for infection (Hazard Ratio [HR]: 4.432 [1.262-15.565], P = 0.020). Furthermore, CRS was an independent risk factor for both infection ((HR: 2.903 [1.577-5.345], P < 0.001) and severe infection (9.040 [2.256-36.232], P < 0.001). Serum PCT, IL-6, and CRP were valuable in early infection prediction post-CAR-T therapy, particularly PCT with the highest area under the ROC curve (AUC) of 0.897. A diagnostic model incorporating PCT and CRP demonstrated an AUC of 0.903 with sensitivity and specificity above 83%. For severe infections, a model including CRS severity and PCT showed an exceptional AUC of 0.991 with perfect sensitivity and high specificity. Based on the aforementioned analysis, we proposed a workflow for the rapid identification of early infection during CAR-T cell therapy. CONCLUSIONS: CRS and prior allogeneic HCT are independent infection risk factors post-CTI in febrile B-cell malignancy patients. Our identification of novel models using PCT and CRP for predicting infection, and PCT and CRS for predicting severe infection, offers potential to guide therapeutic decisions and enhance the efficacy of CAR-T cell therapy in the future.

Gut-derived metabolite 3-methylxanthine enhances cisplatin-induced apoptosis via dopamine receptor D1 in a mouse model of ovarian cancer.

Platinum-based chemotherapy failure represents a significant challenge in the management of ovarian cancer (OC) and contributes to disease recurrence and poor prognosis. Recent studies have shed light on the involvement of the gut microbiota in modulating anticancer treatments. However, the precise underlying mechanisms, by which gut microbiota regulates the response to platinum-based therapy, remain unclear. Here, we investigated the role of gut microbiota on the anticancer response of cisplatin and its underlying mechanisms. Our results demonstrate a substantial improvement in the anticancer efficacy of cisplatin following antibiotic-induced perturbation of the gut microbiota in OC-bearing mice. 16S rRNA sequencing showed a pronounced alteration in the composition of the gut microbiome in the cecum contents following exposure to cisplatin. Through metabolomic analysis, we identified distinct metabolic profiles in the antibiotic-treated group, with a notable enrichment of the gut-derived metabolite 3-methylxanthine in antibiotic-treated mice. Next, we employed a strategy combining transcriptome analysis and chemical-protein interaction network databases. We identified metabolites that shared structural similarity with 3-methylxanthine, which interacted with genes enriched in cancer-related pathways. It is identified that 3-methylxanthinesignificantly enhances the effectiveness of cisplatin by promoting apoptosis both in vivo and in vitro. Importantly, through integrative multiomics analyses, we elucidated the mechanistic basis of this enhanced apoptosis, revealing a dopamine receptor D1-dependent pathway mediated by 3-methylxanthine. This study elucidated the mechanism by which gut-derived metabolite 3-methylxanthine mediated cisplatin-induced apoptosis. Our findings highlight the potential translational significance of 3-methylxanthine as a promising adjuvant in conjunction with cisplatin, aiming to improve treatment outcomes for OC patients.IMPORTANCEThe precise correlation between the gut microbiota and the anticancer effect of cisplatin in OC remains inadequately understood. Our investigation has revealed that manipulation of the gut microbiota via the administration of antibiotics amplifies the efficacy of cisplatin through the facilitation of apoptosis in OC-bearing mice. Metabolomic analysis has demonstrated that the cecum content from antibiotic-treated mice exhibits an increase in the levels of 3-methylxanthine, which has been shown to potentially enhance the therapeutic effectiveness of cisplatin by an integrated multiomic analysis. This enhancement appears to be attributable to the promotion of cisplatin-induced apoptosis, with 3-methylxanthine potentially exerting its influence via the dopamine receptor D1-dependent pathway. These findings significantly contribute to our comprehension of the impact of the gut microbiota on the anticancer therapy in OC. Notably, the involvement of 3-methylxanthine suggests its prospective utility as a supplementary component for augmenting treatment outcomes in patients afflicted with ovarian cancer.

The anti-fatigue and sleep-aiding effects vary significantly among different recipes containing Ganoderma lucidum extracts.

Aims: This study aims to delve into the anti-fatigue and sleep-aiding effects of various formulations containing Ganoderma lucidum extracts. Materials and methods: PGB [incorporating Ganoderma lucidum extract (GE), broken Ganoderma lucidum spore powder (GB) and Paecilomyces hepiali mycelium (PH)] and GBS [composed of GE, GB, and Ganoderma sinense powder (GS)] were chosen as representative recipes for this study. Mice were treated with these recipes or key components of Ganoderma lucidum for 14 consecutive days. Subsequently, a weight-bearing swimming experiment was conducted to assess the mice's exhaustion time and evaluate the anti-fatigue properties of the recipes. Sleep-aiding effects were analyzed by measuring the sleep latency and duration. Furthermore, levels of blood lactic acid, serum urea nitrogen, hepatic glycogen, muscle glycogen, and malondialdehyde (MDA) were measured in the livers and muscles. Key findings: The anti-fatigue abilities of the tested mice were significantly improved after treatment with PGB and their sleep quality improved as well with GBS treatment. PGB treatment for 14 days could significantly prolong the exhaustion time in weight-bearing swimming (from 10.1 ± 0.5 min to 15.2 ± 1.3 min). Meanwhile, glycogen levels in the livers and muscles were significantly increased, while the levels of serum lactic acid, serum urea nitrogen, and MDA in the livers and muscles were significantly decreased. In contrast, mice treated with GBS for 14 days experienced significant improvements in sleep quality, with shortened sleep latency (from 6.8 ± 0.7 min to 4.2 ± 0.4 min), extended sleep duration (from 88.3 ± 1.4 min to 152.5 ± 9.3 min), and decreased muscle MDA levels. These results indicated that Ganoderma lucidum extracts can be used for anti-fatigue and or aid in sleeping, depending on how they are prepared and administered. Significance: This study provides experimental evidence and theoretical basis for the development of Ganoderma lucidum recipes that are specifically designed to help with anti-fatigue and sleep.

Human genetic associations of the airway microbiome in chronic obstructive pulmonary disease.

Little is known about the relationships between human genetics and the airway microbiome. Deeply sequenced airway metagenomics, by simultaneously characterizing the microbiome and host genetics, provide a unique opportunity to assess the microbiome-host genetic associations. Here we performed a co-profiling of microbiome and host genetics with the identification of over 5 million single nucleotide polymorphisms (SNPs) through deep metagenomic sequencing in sputum of 99 chronic obstructive pulmonary disease (COPD) and 36 healthy individuals. Host genetic variation was the most significant factor associated with the microbiome except for geography and disease status, with its top 5 principal components accounting for 12.11% of the microbiome variability. Within COPD individuals, 113 SNPs mapped to candidate genes reported as genetically associated with COPD exhibited associations with 29 microbial species and 48 functional modules (P < 1 × 10-5), where Streptococcus salivarius exhibits the strongest association to SNP rs6917641 in TBC1D32 (P = 9.54 × 10-8). Integration of concurrent host transcriptomic data identified correlations between the expression of host genes and their genetically-linked microbiome features, including NUDT1, MAD1L1 and Veillonella parvula, TTLL9 and Stenotrophomonas maltophilia, and LTA4H and Haemophilus influenzae. Mendelian randomization analyses revealed a potential causal link between PARK7 expression and microbial type III secretion system, and a genetically-mediated association between COPD and increased relative abundance of airway Streptococcus intermedius. These results suggest a previously underappreciated role of host genetics in shaping the airway microbiome and provide fresh hypotheses for genetic-based host-microbiome interactions in COPD.

Preparation, structural characteristics and pharmacological activity of polysaccharides from Polygala tenuifolia: A review.

Polygala tenuifolia is a traditional Chinese medicine with a long history of application, with the efficacy of suppressing cough, calming asthma, tranquilizing the mind, and benefiting the intellect. It is classified as a top-quality medicine in Shennong's Classic of Materia Medica. Polysaccharide is an important active ingredient in Polygala tenuifolia, which consists of several monosaccharides, including Ara, Gal, Glc, and so on. In this review, the preparation methods, structural characteristics, and biological activities of polysaccharides from Polygala tenuifolia are summarized, and the problems in the current studies are discussed to support further research, development, and utilization.

Helicobacter pylori and Gastrointestinal Cancers: Recent Advances and Controversies.

Helicobacter pylori (H pylori), a gastric bacterium, has been extensively studied for its association with gastritis, peptic ulcers, and gastric cancer. However, recent evidence suggests its potential implications beyond the stomach, linking it to other gastrointestinal malignancies, such as esophageal cancer, liver cancer, pancreatic cancer, gallbladder cancer, and colorectal cancer. In light of the expanding research landscape and the increasing interest in exploring H pylori broader role in gastrointestinal tumorigenesis, this comprehensive review aims to elucidate the relationship between H pylori and gastrointestinal tumors. This review encompasses recent epidemiological studies, research progress, and emerging perspectives, providing a comprehensive assessment of the relationship between H pylori and gastrointestinal tumors. The findings highlight the captivating world of H pylori and its intricate involvement in gastrointestinal malignancies.

Effectiveness of novel ß-lactams for Pseudomonas aeruginosa infection: A systematic review and meta-analysis.

BACKGROUND: Novel ß-lactams have in vitro activity against Pseudomonas aeruginosa (PA), but their clinical performances and the selection criteria for practical use are still not clear. We aimed to evaluate the efficacy of novel ß-lactams for PA infection in various sites and to compare the efficacy of each agent. METHODS: We searched PubMed, Embase, Cochrane Library, and Web of Science for randomized controlled trials that used novel ß-lactams to treat PA infection. The primary outcomes were clinical cure and favorable microbiological response. Subgroup analyses were performed based on drug type, drug resistance of pathogens, and site of infection. Network meta-analysis was carried out within a Bayesian framework. RESULTS: In all studies combined (16 randomized controlled trials), novel ß-lactams indicated comparable performance to other treatment regimens in both outcome measures (relative risk = 1.04; 95% confidence interval 0.94-1.15; P = .43) (relative risk = 0.97; 95% confidence interval 0.81-1.17; P = .76). Subgroup analyses showed that the efficacy of ceftolozane-tazobactam (TOL-TAZ), ceftazidime-avibactam (CAZ-AVI), imipenem-cilastatin-relebactam, and cefiderocol had no apparent differences compared to control groups among different infection sites, drug types and drug resistance of PA. In network meta-analysis, the results showed no statistically significant differences between TOL-TAZ, CAZ-AVI, and cefiderocol. CONCLUSIONS: TOL-TAZ, CAZ-AVI, imipenem-cilastatin-relebactam, and cefiderocol are not inferior to other agents in the treatment of PA infection. Their efficacy is also comparable between TOL-TAZ, CAZ-AVI, and cefiderocol.

Caged xanthone derivatives to promote mitochondria-mediated apoptosis in breast cancer cells.

Caged xanthones represent a class of natural secondary metabolites exhibiting significant potential as antitumor agents. These compounds are characterized by their distinct cage-like structures, which offer novel and compelling frameworks for drug design. Nonetheless, there exists a dearth of research focused on the structural modification of these compounds, particularly in relation to their cage-like architectures. This study aims to address this gap by introducing an innovative synthetic method for constructing a novel caged structure that incorporates a widely employed maleimide group. Drawing upon the well-established synthetic approach for dihydroxanthones previously developed within our research group, we successfully synthesized 13 new caged xanthones using the Diels-Alder reaction. Subsequently, we evaluated their anti-proliferative activity against HepG2, A549, and MDA-MB-231 cell lines. The results revealed that compound 10i exhibited IC50 values of 15.86 µM ± 1.29, 19.27 µM ± 1.58, and 12.96 µM ± 0.09 against these cell lines, respectively. Further investigations into the mechanism of action of 10i demonstrated its ability to induce G2/M cell cycle arrest and initiate mitochondria-mediated apoptosis in breast cancer cells.

Risk and incidence of cardiovascular disease associated with polycystic ovary syndrome.

AIMS: We aimed to evaluate the risk of cardiovascular disease (CVD) in women with polycystic ovary syndrome (PCOS) and estimate the global incidence of PCOS-associated CVD. METHODS AND RESULTS: We conducted a meta-analysis across five databases to evaluate the risk of CVD among women with PCOS. The global incidence of PCOS-associated CVD was calculated by a population attributable fraction modelling using the pooled risk ratio (RR), PCOS prevalence, CVD incidence number, and age-standardized rate (ASIR), from the Global Burden of Diseases 2019. An estimated annual percentage change (EAPC) was used to assess the temporal trend of PCOS-associated CVD. The risk of CVD was significantly increased in women with PCOS for an all-age group (pooled RR 1.51, 95% confidence interval 1.36-1.69) and 10- to 54-year-olds (1.37, 1.17-1.59). Globally, from 1990 to 2019, the PCOS-associated CVD cases in women across the all-age group has raised from 102 530 to 235 560. The most affected regions were East Asia and the Pacific (108 430, 66 090-166 150) in 2019. South Asia has the highest increase trend of PCOS-associated CVD ASIRs (EAPC 2.61%, 2.49-2.73). The annual increase in ASIR in PCOS-CVD incidence for the 10-54 age group (EAPC 0.49%, 0.41-0.56) is faster than that of the all-age group (0.34, 0.27-0.42). The middle- or low-middle sociodemographic index countries experienced higher increase trend of CVD due to PCOS in the past 30 years. CONCLUSION: Women with PCOS have a significantly increased risk of CVD. Efficient measures to enhance its prevention and treatment are important for regions with a high PCOS-associated CVD burden, especially premature CVD in women under 55 years.

Studies have reported that cardiovascular disease (CVD) is the leading cause of mortality for women. Meanwhile, women with polycystic ovary syndrome (PCOS) substantially elevate the risk of CVD. However, no studies have quantified the impact of PCOS on the overall CVD burden. This study performed a meta-analysis to assess the risk of CVD in an all-age group and 10- to 54-year-old women, living with PCOS with 17 articles, and estimated the burdens of PCOS-associated CVD burden globally, in 7 World Bank­defined regions, and in 204 countries, from 1990 to 2019, using population attributable fraction (PAF) modelling. Our study implicated that women in all-age group and 10 to 54 years old with PCOS face a 1.51-fold and 1.37-fold increased risk of CVD compared to those without, respectively. Globally, ∼0.85% of CVD new cases in 2019 were associated with PCOS, corresponding to a more than two-fold increase in PCOS-associated CVD cases from 1990. However, the burden of PCOS-associated CVD varies widely by region; for instance, nearly 1.49% of CVD new cases were attributed to PCOS in North America. Meanwhile, the East Asia and Pacific region had the highest PCOS-associated new CVD case, and South Asia experienced the highest increase in age-standardized incidence rates of CVD due to PCOS. Notably, we found higher worldwide PAFs and an annual increase in ASIR than that in all-age group women. This result suggests that premature CVDs in women with PCOS under 55 years deserve more attention.

Genetically predicted telomere length and the risk of 11 hematological diseases: a Mendelian randomization study.

OBJECTIVE: Previous studies have demonstrated that various hematologic diseases (HDs) induce alterations in telomere length (TL). The aim of this study is to investigate whether genetically predicted changes in TL have an impact on the risk of developing HDs. METHODS: GWAS data for TL and 11 HDs were extracted from the database. The R software package "TwoSampleMR" was employed to conduct a two-sample Mendelian randomization (MR) analysis, in order to estimate the influence of TL changes on the risk of developing the 11 HDs. RESULTS: We examined the effect of TL changes on the risk of developing the 11 HDs. The IVW results revealed a significant causal association between genetically predicted longer TL and the risk of developing acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MANTLE), and hodgkin lymphoma (HODGKIN). However, there was no significant causal relationship observed between TL changes and the risk of developing chronic myeloid leukemia (CML), diffuse large b-cell lymphoma (DLBCL), marginal zone b-cell lymphoma (MARGINAL), follicular lymphoma (FOLLICULAR), monocytic leukemia (MONOCYTIC), and mature T/NK-cell lymphomas (TNK). CONCLUSIONS: The MR analysis revealed a positive association between genetically predicted longer TL and an increased risk of developing ALL, AML, CLL, MANTLE, and HODGKIN. This study further supports the notion that cells with longer TL have greater proliferative and mutational potential, leading to an increased risk of certain HDs.

Accumulation of circulating myeloid-derived suppressor cell subsets: predicting poor clinical efficacy and prognosis through T cell suppression in non-Hodgkin's lymphoma.

Myeloid-derived suppressor cells (MDSCs) are implicated in the regulation of immune responses closely associated with poor clinical outcomes in cancer. However, the MDSC subtypes in non-Hodgkin's lymphoma (NHL) have not been systematically investigated. So, we investigated the percentage of MDSC subsets in 78 newly diagnosed NHL patients by flow cytometry. The results showed that all MDSC subsets increased in NHL patients compared with healthy donors. Notably, MDSCs, monocytic MDSCs, and CD14 + CD66b + MDSCs significantly increased in NHL patients compared with those with lymphadenitis donors. polymorphonuclear MDSCs (PMN-MDSCs), early-stage MDSCs (e-MDSCs), and the International Prognostic Index were independent risk factors for poor clinical efficacy and were involved in constructing the nomogram for predicting clinical efficacy. Progression-free survival (PFS) was significantly shorter in patients with high level of MDSC subsets, and PMN-MDSCs emerged as an independent prognostic factor for PFS. PMN-MDSCs, e-MDSCs, and the International Prognostic Index were involved in constructing the nomogram for predicting PFS. Patients with a higher percentage of MDSCs, PMN-MDSCs, e-MDSCs, and CD14 + CD66b + MDSCs experienced a shorter overall survival compared with those with lower percentages. In addition, research on mechanisms found that T cell function was suppressed and mediated by the expansion of MDSCs via involving arginase-1 and interleukin-10 in vitro and in vivo. In conclusion, our study demonstrates that the increased circulating MDSC subsets predict poor clinical efficacy and prognosis in NHL, potentially involving T cell suppression through MDSC subset expansion. These findings indicate the potential of MDSC subsets as comprehensive diagnostic, prognostic biomarkers, and therapeutic targets for NHL.

Multi-Omics Reveals the Genetic and Metabolomic Architecture of Chirality Directed Stem Cell Lineage Diversification.

Chirality-directed stem-cell-fate determination involves coordinated transcriptional and metabolomics programming that is only partially understood. Here, using high-throughput transcriptional-metabolic profiling and pipeline network analysis, the molecular architecture of chirality-guided mesenchymal stem cell lineage diversification is revealed. A total of 4769 genes and 250 metabolites are identified that are significantly biased by the biomimetic chiral extracellular microenvironment (ECM). Chirality-dependent energetic metabolism analysis has revealed that glycolysis is preferred during left-handed ECM-facilitated osteogenic differentiation, whereas oxidative phosphorylation is favored during right-handed ECM-promoted adipogenic differentiation. Stereo-specificity in the global metabolite landscape is also demonstrated, in which amino acids are enriched in left-handed ECM, while ether lipids and nucleotides are enriched in right-handed ECM. Furthermore, chirality-ordered transcriptomic-metabolic regulatory networks are established, which address the role of positive feedback loops between key genes and central metabolites in driving lineage diversification. The highly integrated genotype-phenotype picture of stereochemical selectivity would provide the fundamental principle of regenerative material design.

Week-long normoglycaemia in diabetic mice and minipigs via a subcutaneous dose of a glucose-responsive insulin complex.

Glucose-responsive formulations of insulin can increase its therapeutic index and reduce the burden of its administration. However, it has been difficult to develop single-dosage formulations that can release insulin in both a sustained and glucose-responsive manner. Here we report the development of a subcutaneously injected glucose-responsive formulation that nearly does not trigger the formation of a fibrous capsule and that leads to week-long normoglycaemia and negligible hypoglycaemia in mice and minipigs with type 1 diabetes. The formulation consists of gluconic acid-modified recombinant human insulin binding tightly to poly-L-lysine modified by 4-carboxy-3-fluorophenylboronic acid via glucose-responsive phenylboronic acid-diol complexation and electrostatic attraction. When the insulin complex is exposed to high glucose concentrations, the phenylboronic acid moieties of the polymers bind rapidly to glucose, breaking the complexation and reducing the polymers' positive charge density, which promotes the release of insulin. The therapeutic performance of this long-acting single-dose formulation supports its further evaluation and clinical translational studies.

Associations between antibiotic exposure and abnormal cardiac enzyme profiles in older Chinese adults.

Biomonitoring methods can be used to measure exposure to antibiotics in the general population; however, epidemiological data on the associations between urinary antibiotic levels and the cardiac profiles of enzymes lactate dehydrogenase, creatine kinase, and creatine kinase isoenzyme in older adults remain sparse. We investigated these associations in 990 individuals from the Cohort of Elderly Health and Environment Controllable Factors. Antibiotic residues in urine samples were analyzed using high-performance liquid chromatography-tandem mass spectrometry. Urinary levels of 34 antibiotics were measured. The participants' cardiac enzyme profiles were influenced by sex, age, marital status, education level, cohabitation status, physical activity, dietary structure, body mass index, depression presence and salt, sugar, and oil consumption (P < 0.05). Oxytetracycline, tetracycline, doxycycline, sulfaclozine, and, florfenicol concentrations were negatively associated with the risk of having an abnormal cardiac enzyme profile. Older adults exposed to higher concentrations of norfloxacin had a higher risk of LDH anomalies. After antibiotics were classified, we identified associations between exposure to chloramphenicols, sulfonamides, or veterinary antibiotics and a lower risk of having an abnormal cardiac enzyme profile. Obtaining an accurate epidemiological profile of antibiotic exposure is indispensable for the prevention and detection of cardiac enzyme profile abnormalities in older adults.