Depriving Tumor Cells of Ways to Metastasize: Ferroptosis Nanotherapy Blocks Both Hematogenous Metastasis and Lymphatic Metastasis.

Blood and lymph are two main pathways of tumor metastasis; however, hematogenous metastasis and lymphatic metastasis are difficult to inhibit simultaneously. Ferroptosis provides a new breakthrough for metastasis inhibition, but how to effectively trigger ferroptosis in tumor cells remains a major challenge. Metastatic tumor cells are prone to ferroptosis in blood, while they may be protected from ferroptosis in lymph. In this study, a nanoplatform DA/RSL3 was constructed for the intracellular codelivery of the polyunsaturated arachidonic acid (AA) and the GPX4 inhibitor RSL3, which could not only induce ferroptosis but also alleviate ferroptosis resistance. As a result, DA/RSL3 effectively triggered ferroptosis in tumor cells, thereby impairing the ability of tumor cells to metastasize in both blood and lymph. Furthermore, a fucoidan blocking strategy was proposed to maximize the efficacy of DA/RSL3. Fu+DA/RSL3 showed excellent efficacy in 4T1 tumor-bearing mice. This ferroptosis nanotherapy is promising for metastatic cancer treatment.

KRAS mutations upregulate Runx1 to promote occurrence of head and neck squamous cell carcinoma.

Gene mutations play an important role in head and neck squamous cell carcinoma (HNSCC) by not only promoting the occurrence and progression of HNSCC but also affecting sensitivity to treatment and prognosis. KRAS is one of the most frequently mutated oncogenes, which has been reported to have a mutation rate from 1.7% to 12.7% and may lead to poor prognosis in HNSCC, but its role remains unclear. Here, we found that the KRAS mutation can promote HNSCC generation through synergism with 4-Nitroquinoline-1-Oxide(4NQO). Mechanistically, KRAS mutations can significantly upregulate Runx1 to promote oral epithelial cell proliferation and migration and inhibit apoptosis. Runx1 inhibitor Ro 5-3335 can effectively inhibit KRAS-mutated HNSCC progression both in vitro and in vivo. These findings suggest that the KRAS mutation plays an important role in HNSCC and that Runx1 may be a novel therapeutic target for KRAS-mutated HNSCC.

Pathological complete response and prognosis after neoadjuvant chemotherapy in patients with HER2-low breast cancer.

BACKGROUND: The development of novel human epidermal growth factor receptor 2 (HER2) antibody drug conjugates brings encouraging opportunities for the treatment of HER2-low breast cancer. In this study, we investigated the clinical factors and prognosis of HER2-low breast cancer after neoadjuvant chemotherapy (NAC). METHODS: Data from patients diagnosed with HER2-zero or HER2-low breast cancer at a single center between January 2017 and December 2021 who underwent NAC followed by surgery were retrospectively reviewed. HER2 status was detected by immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH), and classified as HER2-zero (IHC 0), HER2-low (IHC 1+ or IHC 2+ and FISH-), and HER2-positive (IHC 3+ or IHC 2+ and FISH+). Baseline characteristics were analyzed and compared between the HER2-low and HER2-zero groups. Survival outcomes were analyzed using the Kaplan-Meier method with the log-rank test and Cox proportional-hazards regression analysis. RESULTS: The sample comprised 132 patients with HER2-zero [n = 62 (47.0 %)] and HER2-low [n = 70 (53.0 %)] breast cancer. Relative to the HER2-zero group, the HER2-low group contained larger proportions of patients with hormone receptor (HR) positivity (37.1 % vs. 75.7 %, P < 0.001) and low nuclear grades and Ki-67 indices (both P < 0.05). The pathological complete response (pCR) rate was significantly lower in the HER2-low group than in the HER2-zero group (20.0 % vs. 37.1 %, P = 0.03). At the final follow-up [median 20 (range 4-66) months], patients with HER2-low status had significantly favorable disease-free survival (DFS) and overall survival (OS) outcomes relative to those with HER2-zero status (87.1 % vs. 71.0 %, P = 0.02 and 94.3 % vs. 82.3 %, P = 0.02, respectively). HER2-low status and pCR were independent prognostic factors for DFS [hazard ratio (HR) = 0.31, 95 % confidence interval (CI) 0.13-0.75, P = 0.009 and HR = 0.08, 95 % CI 0.01-0.67, P = 0.02, respectively]. CONCLUSION: This analysis revealed that HER2-low status is associated significantly with HR positivity and low nuclear grades, Ki-67 indices, and pCR rate. It is also associated with favorable DFS and OS outcomes after NAC. HER2-low status and pCR are independent prognostic factors for DFS.

A foot structure study of new arch flexibility grading system based on three-dimensional arch volume.

PURPOSE: Different arch structures may cause different foot function injuries. In the past, the arch structure and flexibility of the foot were often defined by the height of the arch, and there was no three-dimensional (3D) structure classification method. In order to form a more complete 3D description, we propose a new classification system of arch volume flexibility (AVF), and then use this new classification system to investigate the relationship between the AVF and arch index (AI), and the arch height flexibility (AHF) and AI, respectively. METHODS: It is proposed to recruit 180 young male adults for the test. We obtained arch volume and AI through 3D scanning and obtained the navicular height through manual measurement. Based on these data, we calculated the AHF and the AVF. Using the quintile method, these arches are divided into very stiff, stiff, neutral, flexible, and very flexible. According to AI value, all arches were divided into cavus, rectus, and planus. The distribution of AVF was compared using χ2 goodness of fit test. The spearman correlation test was used to compare the AHF and AVF. A p < 0.05 indicates that the difference is statistically significant. RESULTS: All participants' plantar data was obtained through 3D scanning, but only 159 of them were complete, so only 318 feet had valid data. The left AHF is (21.23 ± 12.91) mm/kN, and the right AHF is (21.71 ± 12.69) mm/kN. The AVF of the left foot arch is (207.35 ± 118.28) mm3/kg, while the right one is (203.00 ± 117.92) mm3/kg, and the total AVF of the arch was (205.17 ± 117.94) mm3/kg. There was no statistical difference in the AVF between the left and right feet for the same participant (n = 159, p = 0.654). In cavus, the percentage of arch with AVF is 21.4% (very stiff), 21.4% (stiff), 14.3% (neutral), 7.1% (flexible), and 35.7% (very flexible). In rectus, the percentage of arch with AVF is 23.9% (very stiff), 19.6% (stiff), 14.7% (neutral), 24.5% (flexible), and 17.2% (very flexible). In planus, the percentage of arch with AVF is 14.9% (very stiff), 20.6% (stiff), 27.0% (neutral), 16.3% (flexible), and 21.3% (very flexible). Moreover, the correlation between AHF and AVF is not significant (p = 0.060). CONCLUSION: In cavus, rectus, and planus, different AVF accounts different percentage, but the difference is not statistically significant. AVF is evenly distributed in the arches of the feet at different heights. We further found the relationship between AHF and AVF is not significant. As a 3D index, AVF may be able to describe the flexibility of the arch more comprehensively than AHF.

Plants of the Genus Zingiber: A Review of Their Ethnomedicine, Phytochemistry and Pharmacology.

Plant of the genus Zingiber (Zingiberaceae) have primarily distributed in subtropical and tropical Asia, South America and Africa. The species of this genus have been widely used as food and in folk with a long history for treating various diseases. Reports related to the phytochemistry and phytochemistry of Zingiber species are numerous, but articles on the summary of the genus Zingiber remain scarce. This review aims at presenting comprehensive information about the genus Zingiber and providing a reference for the future application by systematically reviewing the literature from 1981 to 2020. Currently, a total of 447 phytochemical constituents have been isolated and identified from this genus, in which volatile oils, diarylheptanoids, gingerols, flavonoids and terpenoids are the major components. Gingerols, which are the main functional components, are the spicy and aromatic ingredients in the Zingiber species. Extracts and single compounds from Zingiber plants have been discovered to possess numerous biological functions, such as anti-inflammatory, anticancer, antimicrobial, larvicidal, antioxidant and hypoglycemic activities. This review provides new insights into the ethnomedicine, phytochemistry and pharmacology of the genus Zingiber and brings to the forefront key findings on the functional components of this genus in food and pharmaceutical industries.

Protective Effects of Lixisenatide against Lipopolysaccharide-Induced Inflammation Response in MAC-T Bovine Mammary Epithelial Cells: A Therapeutic Implication in Mastitis.

Mastitis is acute inflammation caused by microbial infections in the mammary glands. This disease is extremely harmful to lactating mothers. The preferred clinical strategy is antibiotic treatment, but this method results in resistance and side effects. Lixisenatide, a kind of glucagon-like peptide-1 (GLP-1) receptor agonist, is typically used for the treatment of type II diabetes. It is unknown whether lixisenatide possesses a beneficial role in mastitis. In the current study, we assessed the protective effects of lixisenatide against lipopolysaccharide (LPS) stimulation in MAC-T bovine mammary epithelial cells (MECs). Our findings show that lixisenatide attenuated LPS-induced oxidative stress by reducing reactive oxygen species (ROS) production and nicotinamide adenine dinucleotide phosphate (NADPH) oxidases-1 (NOX-1) expression in MAC-T MECs. Additionally, lixisenatide inhibited LPS-induced expression and secretion of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and interleukin 1ß (IL-1ß). We also found that lixisenatide suppressed LPS-induced expression of matrix metalloproteinase 2 (MMP-2) and metalloproteinase 9 (MMP-9), and reduced the expression of toll-like receptor 4 (TLR4) (a typical receptor of LPS), its downstream molecule myeloid differentiation factor 88 (MyD88), and the phosphorylation of TGF ß-activated kinase 1 (TAK1). Notably, lixisenatide decreased the nuclear levels of nuclear factor-κB (NF-κB) and its transcriptional activity. These findings suggest that lixisenatide might become a possible therapeutic agent for the treatment of mastitis by weakening oxidative stress and the inflammatory response in MECs.

Study on the diagnosis of gout with xanthine and hypoxanthine.

BACKGROUND: Hyperuricemia is the only biochemical index in the classification of acute gouty arthritis in American Rheumatism Association 1977 and the main basis of clinical diagnosis for most doctors. However, nearly half of the time gout occurs without hyperuricemia, especially in an acute attack，which leads to an urgent need to find a new substitute diadynamic criteria of gout. Xanthine and hypoxanthine, as precursors of uric acid, have been reported to be high in gout patients with hyperuricemia and presumed to be gout biomarkers. OBJECTIVES: To further explore the possibility of xanthine and hypoxanthine to be gout biomarkers as substitutes for uric acid. METHODS: A reversed-phase HPLC-UV method was employed for simultaneous quantitative detection of uric acid (UA), xanthine (X), and hypoxanthine (HX) in gout patients' (with and without hyperuricemia) and healthy persons' serum. RESULTS: The xanthine and hypoxanthine concentrations in gout patients with hyperuricemia and without hyperuricemia are higher than in healthy persons with a P < 0.001. CONCLUSIONS: This study supplements previous researches by confirming that xanthine and hypoxanthine are significantly elevated in gout patients' serum especially in patients' with normouricemia, which supported xanthine and hypoxanthine may have clinical application for the diagnosis of gout.

E-cadherin expression phenotypes associated with molecular subtypes in invasive non-lobular breast cancer: evidence from a retrospective study and meta-analysis.

BACKGROUND: This retrospective study and meta-analysis was designed to explore the relationship between E-cadherin (E-cad) expression and the molecular subtypes of invasive non-lobular breast cancer, especially in early-stage invasive ductal carcinoma (IDC). METHODS: A total of 156 post-operative cases of early-stage IDCs were retrospectively collected for the immunohistochemistry (IHC) detection of E-cad expression. The association of E-cad expression with molecular subtypes of early-stage IDCs was analyzed. A literature search was conducted in March 2016 to retrieve publications on E-cad expression in association with molecular subtypes of invasive non-lobular breast cancer, and a meta-analysis was performed to estimate the relational statistics. RESULTS: E-cad was expressed in 82.7% (129/156) of early-stage IDCs. E-cad expression was closely associated with the molecular types of early-stage IDCs (P < 0.050); moreover, the molecular subtypes were an independent factor influencing E-cad expression in early-stage IDCs. A total of 12 observational studies (including our study) were included in the meta-analysis. The meta-analytical results show a significantly greater risk of E-cad expression loss in triple-negative breast cancer (TNBC) than in other molecular subtypes (TNBC vs. luminal A: RR = 3.45, 95% CI = 2.79-4.26; TNBC vs. luminal B: RR = 2.41, 95% CI = 1.49-3.90; TNBC vs. HER2-enriched: RR = 1.95, 95% CI = 1.24-3.07). CONCLUSIONS: Early-stage IDCs or invasive non-lobular breast cancers with the TNBC molecular phenotype have a higher risk for the loss of E-cad expression than do tumors with non-TNBC molecular phenotypes, suggesting that E-cad expression phenotypes were closely related to molecular subtypes and further studies are needed to clarify the underlying mechanism.

Urchin-Like Amorphous Ni2B Alloys: Efficient Antibacterial Materials and Catalysts for Hydrous Hydrazine Decomposition to Produce H2.

Urchin-like amorphous Ni2B alloys were successfully prepared for the first time from a mixture of Ni(NH3)6(2+) and polyvinyl alcohol (PVA) via a solution plasma process (SPP). The as-synthesized samples were characterized by X-ray powder diffraction (XRD), inductively coupled plasma atomic emission spectrometry (ICP-AES) X-ray photoelectron spectroscopy (XPS), scanning transmission electron microscopy (STEM), selected-area electron diffraction patterns (SAED) and nitrogen adsorption-desorption isotherms. In the performance test, the obtained Ni-B urchins showed great antibacterial activities, comparable with those of amikacin and kanamycin, especially towards Pseudomonas aeruginosa (P. aeruginosa). Meanwhile, the magnetic properties of Ni-B urchins are enhanced in comparison with those of conventional Ni-B. During hydrous hydrazine (N2H4) decomposition, the dehydrogenation performance of Ni-B urchins is superior to those of Raney Ni and conventional Ni-B. The enhanced catalytic performance of Ni-B urchins is attributed to their high surface area of active species nickel and the enhanced intrinsic activity resulting from their unique structure.

Combination of SF1126 and gefitinib induces apoptosis of triple-negative breast cancer cells through the PI3K/AKT-mTOR pathway.

To investigate the apoptotic mechanism of triple-negative breast cancer (TNBC) cells induced by gefitinib and PI3K inhibitor SF1126. MDA-MB-231, MDA-MB-436, and MCF-7 cells were incubated with 0.1 µmol/l gefitinib, 1 µmol/l gefitinib, 10 µmol/l gefitinib, 1 µmol/l SF1126, 0.1 µmol/l gefitinib+1 µmol/l SF1126, 1 µmol/l gefitinib+1 µmol/l SF1126, and 10 µmol/l gefitinib+1 µmol/l SF1126. Then, cell viability and survival were determined using an 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay and Hoechst staining. The apoptosis-related factors and phosphoinositide-3-kinase/protein kinase B, the mammalian target of rapamycin (PI3K/AKT-mTOR) signaling pathway-related factors were detected by western blot. For TNBC cells, cell viability or survival was not significantly inhibited by gefitinib or SF1126 alone; however, marked cell apoptosis was noted in the gefitinib and SF1126 combination groups, and this effect was dose dependent. Also, the expressions of apoptosis markers, such as cleaved caspase-3, Bcl-2/Bax, were altered by the gefitinib and SF1126 combination. Moreover, phosphorylated AKT (p-AKT) and 70 kDa ribosomal protein S6-kinase (p-p70S6K) were also inhibited by the gefitinib and SF1126 combination, which may be responsible for the apoptosis. Gefitinib combined with SF1126 could induce cell apoptosis in TNBC cells and this effect was mediated through the EGFR-PI3K-AKT-mTOR-p70S6K pathway. Our studies have set the stage for future clinical trials of TNBC therapy by the combination of gefitinib and SF1126.

Anti-aging effect of estrogen on telomerase activity in ovariectomised rats--animal model for menopause.

OBJECTIVE: The aim of this study was to investigate the anti-aging effects of exogenous estrogen on telomerase activity in ovariectomized female Sprague-Dawley rats. METHODS: Thirty-three 12-week-old female rats were divided into three groups: the ovariectomized-Treated group (Treated, n = 11), the ovariectomized control group (OVX, n = 11) and the Sham-operated group (Sham, n = 11). The rats in the Treated group were given 0.21 mg/kg estradiol valerate intragastric administration while other two groups were given the amount of physiological saline daily. All of the animals were euthanized 12 weeks after treatment, and abdominal aortic blood samples were taken to assess the level of estradiol (E2), follicle stimulating hormone (FSH). Telomerase activity and telomerase reverse transcriptase (TERT) mRNA expression in the heart, liver, brain tissues of all rats were measured by reverse transcriptional polymerase chain reaction (RT-PCR) and competitive enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared to the OVX and Sham group, telomerase activity and TERT mRNA levels were significantly increased in the heart, liver and brain tissues of rats in the Treated group (p < 0.05). The telomerase expression was significantly higher in the heart than in liver and brain tissues in the Treated group (p < 0.05). CONCLUSION: Based on the findings in the ovariectomized female rats model, exogenous estrogen can significantly up-regulate telomerase activity and TERT mRNA expression to exert the effects of anti-aging.

Self-assembly of nano/micro-structured Fe3O4 microspheres among 3D rGO/CNTs hierarchical networks with superior lithium storage performances.

Nano/micro-structured Fe3O4 microspheres among three-dimensional (3D) reduced graphene oxide (rGO)/carbon nanotubes (CNTs) hierarchical networks (the ternary composite is denoted as rGCFs) have been synthesized using a facile, self-assembled and one-pot hydrothermal approach. The rGCFs composite exhibits superior lithium storage performances: initial discharge and charge capacities of 1452 and 1036 mAh g(-1), respectively, remarkable rate capability at current densities from 100 mA g(-1) to 10 A g(-1) and outstanding cycling performance up to 200 cycles. The highly enhanced electrochemical performances of rGCFs depend heavily on the robust 3D rGO/CNTs hierarchical networks, the stable nano/microstructures of active Fe3O4 microspheres and the positive synergistic effects of building components. The systematic structure characterizations and electrochemical investigations provide insightful understanding towards the relationship between structure/morphology and lithium storage performances, which may pave the way for the rational design of composite materials with desirable goals.

Conditional survival of male breast cancer.

BACKGROUND: The incidence of male breast cancer has been increasing in recent years; however, the long-term survival outcomes of diagnosed patients remain uncertain. This study was designed to evaluate the conditional survival of male breast cancer patients and to predict the future survival of patients through the conditional nomogram, to provide important suggestions for clinical decision-making. METHODS: Retrospective data from the SEER database included 3600 male breast cancer patients, divided into training and validation groups (7 : 3 ratio). Overall survival rates were calculated using Kaplan-Meier analysis. Conditional survival analysis described survival at specific years. Time-dependent multivariate Cox analysis identified prognostic factors' impact. The conditional survival nomogram model predicted real-time survival rates. RESULTS: Over time, the 5-year real-time survival rate of patients gradually improved, increasing from 70.5 to 74.8, 79.4, 85.8, and 92.9% (respectively, representing 5-year survival rates of 1-4 years after diagnosis). In addition, the improvement in conditional survival rate CS5 showed a nonlinear trend. After 5 years of diagnosis, age, tumor size, and tumor stage had a sustained impact on patient prognosis. Finally, a conditional survival nomogram was constructed to predict the 10-year survival rate in real time. CONCLUSION: Five years after diagnosis, the conditional survival rate of male patients with breast cancer has improved, but it is not nonlinear. In the first 5 years after diagnosis, patients with older age, larger tumor size, poorer tumor stage, and distant metastasis should be actively followed up and treated to improve their long-term survival.

Enhancing biohydrogen production from xylose through natural FeS2 ore: Mechanistic insights.

In this study, we investigated the advantages of utilizing natural FeS2 ore in the context of dark fermentative hydrogen production within a fermentation system employing heat-treated anaerobic granular sludge with xylose as the carbon source. The results demonstrated a significant improvement in both hydrogen production and the maximum rate, with increases of 2.58 and 4.2 times, respectively. Moreover, the presence of FeS2 ore led to a reduction in lag time by more than 2-3 h. The enhanced biohydrogen production performance was attributed to factors such as the intracellular NADH/NAD+ ratio, redox-active components of extracellular polymeric substances, secreted flavins, as well as the presence of hydrogenase and nitrogenase. Furthermore, the FeS2 ore served as a direct electron donor and acceptor during biohydrogen production. This study shed light on the underlying mechanisms contributing to the improved performance of biohydrogen production from xylose during dark fermentation through the supplementation of natural FeS2 ore.

Longitudinal relationship between grip strength and cognitive function in a European population older than 50 years: A cross-lagged panel model.

OBJECTIVES: The aim of this study was to investigate the dynamic longitudinal relationship between grip strength and cognitive function. METHODS: 6175 participants aged ≥50 years were included in the study using three waves of follow-up data from the Survey of Health, Ageing, and Retirement in Europe in 2015 (T1), 2017 (T2) and 2019 (T3). Cognitive function was assessed using numeracy, verbal fluency, immediate recall, delayed recall and total. The cross-lagged panel model was used for analysis. RESULTS: There was a correlation between grip strength and cognitive function. Standardized path coefficient from numeracy T1 to grip strength T2 was 0.017 (p = 0.003), and from numeracy T2 to grip strength T3 was 0.014 (p = 0.012). Standardized path coefficient from grip strength T1 to numeracy T2 was 0.096 (p < 0.001), and from grip strength T2 to numeracy T3 was 0.113 (p < 0.001). Other indicators of cognitive function had similar relationships with grip strength. CONCLUSIONS: The study found a statistically significant longitudinal and bidirectional relationship between grip strength and cognitive function in a sample of people aged ≥50 years from several European countries.

Prognostic and Clinical Significance of Human Leukocyte Antigen Class I Expression in Breast Cancer: A Meta-Analysis.

BACKGROUND: The value of human leukocyte antigen (HLA; also known as major histocompatibility complex) class I expression for the prediction of breast cancer survival outcomes remains unclear. We conducted a meta-analysis to explore the prognostic significance of this expression. MATERIALS AND METHODS: We searched electronic databases to identify reports on associations of HLA class I protein or mRNA expression with survival outcomes and clinicopathological factors in the breast cancer context. Pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were used to conduct a quantitative meta-analysis. RESULTS: The sample comprised eight studies involving 3590 patients. Only the classical HLA class Ia (HLA-ABC) molecules studies were included in this meta-analysis. Elevated HLA class I protein expression was found to be significantly related to better disease-free survival (DFS) (HR 0.58, 95% CI 0.35-0.95, P = 0.03), particularly among patients with triple-negative breast cancer (TNBC) (HR 0.31, 95% CI 0.18-0.52, P < 0.001), but not to overall survival. It was also associated with estrogen receptor (ER) negativity (OR 1.71, 95% CI 1.24-2.35, P = 0.001), progesterone receptor (PR) negativity (OR 1.49, 95% CI 1.22-1.81, P < 0.001), human epidermal growth factor receptor 2 (HER2) positivity (OR 1.51, 95% CI 1.18-1.94, P = 0.001), TNBC (OR 1.68, 95% CI 1.15-2.45, P < 0.01), high Ki-67 indices (OR 2.06, 95% CI 1.62-2.61, P < 0.001), and high nuclear grades (OR 2.67, 95% CI 2.17-3.29, P < 0.001). CONCLUSION: This meta-analysis demonstrated that enhanced HLA class I protein expression is significantly associated with the better DFS of patients with breast cancer, especially TNBC, as well as with ER and PR negativity, HER2 positivity, TNBC, and high Ki-67 indices and nuclear grades. The immune target HLA class I may serve as a prognostic indicator for breast cancer.

Differential expression of plasma­derived exosomal miRNAs in polycystic ovary syndrome as a circulating biomarker.

Identifying biomarkers with high sensitivity and stability is helpful for the timely and accurate diagnosis, and effective management of polycystic ovary syndrome (PCOS), a long-term, progressive endocrine disorder. Circulating microRNAs (miRNAs/miRs) are being increasingly recognized as promising biomarkers given the stability and enrichment of miRNAs in exosomes. The high sensitivity of the reverse transcription-quantitative PCR (RT-qPCR) has enabled accurate quantification of miRNAs and small fragments, present in a low abundance, in the circulation. In the present study, the potential of miRNAs in the diagnosis of PCOS was evaluated. Exosomal miRNAs were extracted and screened, and three miRNAs (miR-4488, miR-151a-5p, and miR-223-3p) were found to be differentially expressed between the PCOS group and age-matched controls by sequencing analysis. RT-qPCR was performed on a clinically confirmed PCOS cohort (n=107) and a non-PCOS control cohort (n=101) from South China to validate the PCOS-related RNA sequencing results. miR-151a-5p and miR-4488 expression levels were significantly upregulated, and miR-223-3p expression was downregulated in the PCOS cohort compared with the control cohort (P<0.05). The areas under the receiver operating characteristic curve were 0.889, 0.871, and 0.664 for miR-4488, miR-151a-5p, and miR-223-3p, respectively. Combining anti-Müllerian hormone levels with the three miRNAs resulted in an AUC of 0.967, and higher sensitivity and specificity. These results suggest that miRNAs may prove useful in the early diagnosis and effective management of PCOS, and that these three miRNAs may be involved in the pathogenesis of PCOS. In addition, bioinformatics analysis showed that these three exosomal miRNAs were involved in key signaling pathways related to cancer.

Curbing Exosome Communications via Introducing Artificial Membrane Receptors for Metastatic Pancreatic Cancer Therapy.

Tumor-derived exosomes (TDEs) carry various biomolecular cargos and play crucial roles in metastasis. TDEs migrate to distal organs for intercellular communication and induce the formation of pre-metastatic niches (PMNs) to support tumor implantation and proliferation. Precise interference in the bioprocess of TDEs is expected to be efficacious for suppressing tumor metastasis. However, targeting both TDEs and the primary tumor is challenging. Here, based on metabolic glycoengineering and bio-orthogonal click chemistry, a two-step delivery strategy is designed to overcome this. During the first step, the tetraacetylated N-azidoacetyl-d-mannosamine-loaded nanoparticle responds to the metabolic activity of tumor cells in the primary tumor, tagging both tumor cells and TDEs with azide groups; dibenzyl-cyclootyne-modified nanoparticles then can, as the second step, specifically react with tumor cells and TDEs through a bio-orthogonal click reaction. This strategy not only inhibits tumor growth in pancreatic cancer models but also curbs the communicative role of TDEs in inducing liver PMNs and metastasis by tracking and downregulating the exosomal macrophage migration inhibitory factor.

Systemic Inflammation Markers Associated with Bone Mineral Density in perimenopausal and Postmenopausal Women.

Objective: The aim of this research was to determine whether systemic inflammatory indicators, including aggregate index of systemic inflammation (AISI), neutrophils lymphocyte to platelet ratio (NLPR), systemic immune-inflammation index (SII), and systemic inflammation response index (SIRI), are related to bone mineral density (BMD) in perimenopausal and postmenopausal women. Methods: One hundred and eighty-one perimenopausal and 390 postmenopausal women were enrolled in this cross-sectional study. Continuous variables by analysis of variance and Kruskal Wallis test for comparing the clinical characteristics. Linear regression analysis was conducted to investigate the associations between inflammatory indicators with BMD. The comparison between the subgroups was performed using the nonparametric test and the T-test. Results: AISI, NLPR, SII, and SIRI quartile values were inversely associated with BMD in menopausal women (P = 0.021; P = 0.047; P < 0.001; P < 0.001, respectively). After adjusting for confounding factors, four inflammatory indicators remained significantly associated with BMD (all P for trend <0.001). Analysis according to menopausal status demonstrated that AISI, SII, and SIRI were significantly correlated with mean femoral neck BMD in postmenopausal women (P for trend = 0.015, 0.004, and 0.001), but not significantly associated with BMD in perimenopausal women (P for trend = 0.248, 0.054, and 0.352) after adjustment for covariates. Conclusion: The quartile values of AISI, SII, and SIRI were inversely associated with BMD in postmenopausal women, following adjustment for individual variables, hormone profiles and glucolipid metabolism profiles. AISI, SII, and SIRI have potential to be important tools for screening and prevention of bone loss in menopausal women in future clinical practice.

Responses of Bacillus sp. under Cu(II) stress in relation to extracellular polymeric substances and functional gene expression level.

The production and composition of extracellular polymeric substances (EPS), as well as the EPS-related functional resistance genes and metabolic levels of Bacillus sp. under Cu(II) stress, were investigated. EPS production increased by 2.73 ± 0.29 times compared to the control when the strain was treated with 30 mg L-1 Cu(II). Specifically, the polysaccharide (PS) content in EPS increased by 2.26 ± 0.28 g CDW-1 and the PN/PS (protein/polysaccharide) ratio value increased by 3.18 ± 0.33 times under 30 mg L-1 Cu(II) compared to the control. The increased EPS secretion and higher PN/PS ratio in EPS strengthened the cells' ability to resist the toxic effect of Cu(II). Differential expression of functional genes under Cu(II) stress was revealed by Gene Ontology pathway enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. The enriched genes were most obviously upregulated in the UMP biosynthesis pathway, the pyrimidine metabolism pathway, and the TCS metabolism pathway. This indicates an enhancement of EPS regulation-related metabolic levels and their role as a defense mechanism for cells to adapt to Cu(II) stress. Additionally, seven copper resistance genes were upregulated while three were downregulated. The upregulated genes were related to the heavy metal resistance, while downregulated genes were related to cell differentiation, indicating that the strain had initiated an obvious resistance to Cu(II) despite its severe cell toxicity. These results provided a basis for promoting EPS-regulated associated functional genes and the application of gene-regulated bacteria in heavy metal-containing wastewater treatment.