GARNL3 identified as a crucial target for overcoming temozolomide resistance in EGFRvIII-positive glioblastoma.

OBJECT: Amplification of the epidermal growth factor receptor (EGFR) and its active mutant type III (EGFRvIII), frequently occurr in glioblastoma (GBM), contributing to chemotherapy and radiation resistance in GBM. Elucidating the underlying molecular mechanism of temozolomide (TMZ) resistance in EGFRvIII GBM could offer valuable insights for cancer treatment. METHODS: To elucidate the molecular mechanisms underlying EGFRvIII-mediated resistance to TMZ in GBM, we conducted a comprehensive analysis using Gene Expression Omnibus and The cancer genome atlas (TCGA) databases. Initially, we identified common significantly differentially expressed genes (DEGs) and prioritized those correlating significantly with patient prognosis as potential downstream targets of EGFRvIII and candidates for drug resistance. Additionally, we analyzed transcription factor expression changes and their correlation with candidate genes to elucidate transcriptional regulatory mechanisms. Using estimate method and databases such as Tumor IMmune Estimation Resource (TIMER) and CellMarker, we assessed immune cell infiltration in TMZ-resistant GBM and its relationship with candidate gene expression. In this study, we examined the expression differences of candidate genes in GBM cell lines following EGFRvIII intervention and in TMZ-resistant GBM cell lines. This preliminary investigation aimed to verify the regulatory impact of EGFRvIII on candidate targets and its potential involvement in TMZ resistance in GBM. RESULTS: Notably, GTPase Activating Rap/RanGAP Domain Like 3 (GARNL3) emerged as a key DEG associated with TMZ resistance and poor prognosis, with reduced expression correlating with altered immune cell profiles. Transcription factor analysis suggested Epiregulin (EREG) as a putative upstream regulator of GARNL3, linking it to EGFRvIII-mediated TMZ resistance. In vitro experiments confirmed EGFRvIII-mediated downregulation of GARNL3 and decreased TMZ sensitivity in GBM cell lines, further supported by reduced GARNL3 levels in TMZ-resistant GBM cells. CONCLUSION: GARNL3 downregulation in EGFRvIII-positive and TMZ-resistant GBM implicates its role in TMZ resistance, suggesting modulation of EREG/GARNL3 signaling as a potential therapeutic strategy.

The safety and feasibility of mini-invasive Bentall surgery via right anterior mini-thoracotomy.

Background: The right anterior mini-thoracotomy (RAMT) approach has become a popular technique in cardiac surgery and applied in valve surgery. However, there is very limited evidence on the application of RAMT in the Bentall surgery. In the present study, we aimed to evaluate the safety and feasibility of the RAMT approach in Bentall surgery. Methods: A retrospective analysis was performed on 27 patients who underwent Bentall surgery between September 2020 and April 2022 in the First Affiliated Hospital of Xi'an Jiaotong University. Follow-ups were undertaken 1 and 6 months after their operations. The baseline, perioperative, and follow-up results were retrospectively analyzed. Results: A total of 27 male patients aged 48-61 years were included in the study. The operation time ranged from 4.0 to 5.0 hours, with a median of 4.5 hours. The median aortic cross-clamping time was 122 minutes [interquartile range (IQR): 109-145 minutes], and the median cardiopulmonary bypass (CPB) time was 156 minutes (IQR: 143-183 minutes). The median intensive care unit stay was 3 days (IQR: 1.75-4.25 days). The ventilation time ranged from 6.5 to 22.0 hours, with a median of 13.0 hours. The median drainage volume in the first 24 hours was 210 mL. In the following-up data, no deaths or severe complications were observed. Conclusions: The mini-Bentall procedure through an RAMT approach is a feasible and safe approach with few wounds and good clinical results in patients undergoing aortic root replacement.

Potential Role of Tranexamic Acid in Rosacea Treatment: conquering Flushing Beyond Melasma.

Rosacea is a chronic inflammatory skin disease that affects a patient's appearance and quality of life. It mainly affects the midface region and presents as erythema, flushing, telangiectasia, papules, pustules, and rhinophyma. Despite its prevalence, the precise pathophysiology of rosacea remains unknown, and novel pharmacological therapies are currently under investigation. Tranexamic acid (TA) is a synthetic, lysine-like compound that competitively inhibits fibrinogen production by synthesizing fibrinolytic enzymes. In addition to its popular application in hemorrhage treatment, TA has been used to manage a number of skin conditions, including melasma, chronic urticaria, and angioedema. TA is a better option for melasma treatment. However, the role of TA in treating rosacea has not yet been systematically elucidated. In this study, we reviewed all available literature on the use of TA for rosacea treatment. The included articles examined the therapeutic effects of TA in patients with rosacea, including traditional methods such as oral and topical administration and more novel approaches such as intradermal injections, microneedling, and laser-assisted delivery. Several recent clinical studies demonstrated that TA alleviates rosacea symptoms by restoring the permeability barrier, ameliorating the immune reaction, and inhibiting angiogenesis. In this review, we summarized the function and potential application of TA in rosacea treatment, aiming to facilitate the implementation of clinical applications.

The role of transforming growth factor-ß (TGF-ß) in the formation of exhausted CD8 + T cells.

CD8 + T cells exert a critical role in eliminating cancers and chronic infections, and can provide long-term protective immunity. However, under the exposure of persistent antigen, CD8 + T cells can differentiate into terminally exhausted CD8 + T cells and lose the ability of immune surveillance and disease clearance. New insights into the molecular mechanisms of T-cell exhaustion suggest that it is a potential way to improve the efficacy of immunotherapy by restoring the function of exhausted CD8 + T cells. Transforming growth factor-ß (TGF-ß) is an important executor of immune homeostasis and tolerance, inhibiting the expansion and function of many components of the immune system. Recent studies have shown that TGF-ß is one of the drivers for the development of exhausted CD8 + T cells. In this review, we summarized the role and mechanisms of TGF-ß in the formation of exhausted CD8 + T cells and discussed ways to target those to ultimately enhance the efficacy of immunotherapy.

Laser-assisted manipulation of Volta potential pattern on the TC4 surface for improved hBMSCs osteogenesis.

The Ti6Al4V (TC4) alloy, a prevalent biomedical material in orthopedics, still faces limitation of the insufficient osseointegration. To improve the bioactivity of TC4, introducing the electric environment onto the TC4 surface may be an effective way in the view of the necessity of endogenous electric microenvironment in bone regeneration. Herein, a Volta potential pattern was engendered on the TC4 surface via parallel laser patterning, so as to promote the osteogenic differentiation of cells. A 15 W laser successfully transformed the original α + ß dual phase towards radially distributed lath-like martensite phase in the laser treated region. The atomic lattice distortion between the heterogeneous microstructures of the laser treated and untreated regions leads to a significant Volta potential fluctuation on the TC4 surface. The Volta potential pattern as well as the laser-engraved microgrooves respectively induced mutually orthogonal cell alignments. The hBMSCs osteogenic differentiation was significantly enhanced on the laser treated TC4 surfaces in comparison to the surface without the laser treatment. Moreover, a drastic Volta potential gradient on the TC4 surface (treated with 15 W power and 400 µm interval) resulted in the most pronounced osteogenic differentiation tendency compared to other groups. Modulating the electric environment on the TC4 surface by manipulating the phase transformation may provide an effective way in evoking favorable cell response of bone regeneration, thereby improving the bioactivity of TC4 implant.

Prioritizing the multifaceted community and species uniqueness for the conservation of lacustrine fishes in the largest subtropical floodplain, China.

Hydrological variations affect habitat characteristics and fish distribution in floodplain lakes. Assessing the contributions of the local community (i.e., LCBD, community uniqueness) and species to overall ß diversity (i.e., SCBD, species uniqueness) of fish assemblages is valuable for habitat and species conservation planning, particularly from functional and phylogenetic perspectives. We examined the changes in multifaceted LCBD and SCBD of fish across different hydrological periods in the Poyang Lake, China, and analyzed their responsive mechanisms using regression models, based on which the conservation priorities of habitats and species were evaluated. The findings revealed that taxonomic, functional, and phylogenetic LCBD and SCBD were lowest during the wet season compared to the normal and dry seasons, emphasizing the regulatory effects of hydrological regimes on fish assemblages. Taxonomic and functional LCBD were significantly impacted by the mean abundance of migratory fish, highlighting the importance of specific species combinations on community uniqueness. Taxonomic and functional SCBD exhibited positive correlations primarily with mean abundance, suggesting the potential uniqueness of certain common species. Additionally, we identified the river-lake junction (Hukou station) and natural reserve (Xingzi and Nanjishan stations) with high overall community uniqueness as critical habitats. We also emphasized the necessity for increased conservation efforts for species having high overall species uniqueness during different hydrological periods, including Coilia brachygnathus, Ctenopharyngodon idella, Coilia nasus, Saurogobio dabryi, Hypophthalmichthys molitrix, Megalobrama amblycephala, and Parabramis pekinensis. This research underscores the significance of integrating multiple ecological perspectives to manage biodiversity changes and maintain ecological conservation values effectively.

Antioxidant and anti-inflammatory function of Eupatorium adenophora Spreng leaves (EASL) on human intestinal Caco-2 cells treated with tert-butyl hydroperoxide.

Chronic non-communicable diseases (CNCDs) pose a significant public health challenge. Addressing this issue, there has been a notable breakthrough in the prevention and mitigation of NCDs through the use of antioxidants and anti-inflammatory agents. In this study, we aim to explore the effectiveness of Eupatorium adenophora Spreng leaves (EASL) as an antioxidant and anti-inflammatory agent, and its potential applications. To construct a cellular model of oxidative damage and inflammation, Caco-2 cells were treated with tert-butyl hydroperoxide (t-BHP). The biocompatibility of EASL-AE with Caco-2 cells was assessed using the MTT assay, while compatibility was further verified by measuring LDH release and the protective effect against oxidative damage was also assessed using the MTT assay. Additionally, we measured intracellular oxidative stress indicators such as ROS and 8-OHdG, as well as inflammatory pathway signalling protein NFκB and inflammatory factors TNF-α and IL-1ß using ELISA, to evaluate the antioxidant and anti-inflammatory capacity of EASL-AE. The scavenging capacity of EASL-AE against free radicals was determined through the DPPH Assay and ABTS Assay. Furthermore, we measured the total phenolic, total flavonoid, and total polysaccharide contents using common chemical methods. The chemical composition of EASL-AE was analyzed using the LC-MS/MS technique. Our findings demonstrate that EASL-AE is biocompatible with Caco-2 cells and non-toxic at experimental levels. Moreover, EASL-AE exhibits a significant protective effect on Caco-2 cells subjected to oxidative damage. The antioxidant effect of EASL-AE involves the scavenging of intracellular ROS, while its anti-inflammatory effect is achieved by down-regulation of the NFκB pathway. Which in turn reduces the release of inflammatory factors TNF-α and IL-1ß. Through LC-MS/MS analysis, we identified 222 compounds in EASL-AE, among which gentianic acid, procaine and L-tyrosine were the compounds with high antioxidant capacity and may be the effective constituent for EASL-AE with antioxidant activity. These results suggest that EASL-AE is a natural and high-quality antioxidant and anti-inflammatory biomaterial that warrants further investigation. It holds great potential for applications in healthcare and other related fields.

Prognostic value of pulmonary hypertension with a nomogram in acute myocardial infarction patients with reduced left ventricular function.

Background: Pulmonary hypertension (PH) is a common prognostic factor for acute myocardial infarction (AMI) and its impact may increase when combined with reduced left ventricular function. Methods: This retrospective cohort study enrolled AMI patients with reduced left ventricular function at the First Affiliated Hospital of Xi'an Jiaotong University from January 2018 to January 2022. Basing on the systolic pulmonary artery pressure assessed by echocardiogram, patients were assigned to the PH group and control group. Propensity score matching (PSM) in sex, age and Killip classification was used to match patients between two groups. The primary outcome was defined as 1-year mortality rate, which were obtained from medical records and phone calls. Results: After the PSM, a total of 504 patients were enrolled, with 252 in both groups. No significant difference of the adjusted factors was observed between the two groups. The 1-year mortality rate was significantly higher in the PH group compared with the control group (15.5% vs. 5.3%, P < 0.001). In the cox regression analysis, PH (HR: 2.068, 95% CI: 1.028-4.161, P = 0.042) was identified as an independent risk factor, alongside left ventricular ejection fraction (HR: 0.948; 95% CI: 0.919-0.979; P < 0.001), creatine kinase-MB isoenzymes (HR: 1.002; 95% CI: 1.000-1.003; P = 0.010) and pro-brain natriuretic peptide (HR: 1.000; 95% CI: 1.000-1.000; P = 0.018) for the 1-year mortality in AMI patients with reduced left ventricular function. A nomogram was established using the above factors to predict the 1-year mortality risks in these patients. Conclusion: AMI patients with reduced left ventricular function showed higher 1-year mortality rate when concomitant with PH. Four independent risk factors, including PH, were identified and used to establish a nomogram to predict the 1-year mortality risks in these patients. Clinical Trialsgov ID: NCT06186713.

Diamond with Sp2-Sp3 composite phase for thermometry at Millikelvin temperatures.

Temperature is one of the seven fundamental physical quantities. The ability to measure temperatures approaching absolute zero has driven numerous advances in low-temperature physics and quantum physics. Currently, millikelvin temperatures and below are measured through the characterization of a certain thermal state of the system as there is no traditional thermometer capable of measuring temperatures at such low levels. In this study, we develop a kind of diamond with sp2-sp3 composite phase to tackle this problem. The synthesized composite phase diamond (CPD) exhibits a negative temperature coefficient, providing an excellent fit across a broad temperature range, and reaching a temperature measurement limit of 1 mK. Additionally, the CPD demonstrates low magnetic field sensitivity and excellent thermal stability, and can be fabricated into probes down to 1 micron in diameter, making it a promising candidate for the manufacture of next-generation cryogenic temperature sensors. This development is significant for the low-temperature physics researches, and can help facilitate the transition of quantum computing, quantum simulation, and other related technologies from research to practical applications.

Multi-omics reveals the molecular mechanism of the combined toxic effects of PFOA and 4-HBP exposure in MCF-7 cells and the key player: mTORC1.

With the discovery of evidence that many endocrine-disrupting chemicals (EDCs) in the environment influence human health, their toxic effects and mechanisms have become a hot topic of research. However, investigations into their endocrine-disrupting toxicity under combined binary exposure, especially the molecular mechanism of combined effects, have rarely been documented. In this study, two typical EDCs, perfluorooctanoic acid (PFOA) and 4-hydroxybenzophenone (4-HBP), were selected to examine their combined effects and molecular mechanism on MCF-7 cell proliferation at environmentally relevant exposure concentrations. We have successfully established a model to evaluate the binary combined toxic effects of endocrine disruptors, presenting combined effects in a simple and direct way. Results indicated that the combined effect changed from additive to synergistic from 1.25 × 10-8 M to 4 × 10-7 M. Metabolomics analyses suggested that exposure to PFOA and 4-HBP caused significant alterations in purine metabolism, arginine, and proline metabolism and had superimposed influences on metabolism. Enhanced combined effects were observed in glycine, serine, and threonine metabolic pathways compared to exposure to PFOS and 4-HBP alone. Additionally, the differentially expressed genes (DEGs) are primarily involved in Biological Processes, especially protein targeting the endoplasmic reticulum, and significantly impact the oxidative phosphorylation and thermogenesis-related KEGG pathway. By integrating metabolome and transcriptome analyses, PFOA and 4-HBP regulate purine metabolism, the TCA cycle, and endoplasmic reticulum protein synthesis in MCF-7 cells via mTORC1, which provides genetic material, protein, and energy for cell proliferation. Furthermore, molecular docking confirmed the ability of PFOA and 4-HBP to stably bind the estrogen receptor, indicating that they have different binding pockets. Collectively, these findings will offer new insights into understanding the mechanisms by which EDCs produce combined toxicity.

Rationale and Design of the IMPROVE Trial: A Multicenter, Randomized, Controlled, Open-label, Blinded-endpoint Trial Assessing the Efficacy of Remote Ischemic Conditioning in Patients Undergoing Off-Pump Coronary Artery Bypass Grafting.

INTRODUCTION: Despite the appearance of off-pump coronary artery bypass grafting (CABG), ischemia-reperfusion injury (IRI) in the perioperative period still arouses concerns of clinicians. Remote ischemic conditioning (RIC) is the process of repeated ischemia and reperfusion in the peripheral vessels, which is proven to reduce IRI in vital organs. However, the effect of RIC in patients undergoing off-pump CABG is still unclear. METHODS: This IMPROVE trial is a national, multicenter, randomized, controlled, open-label, blinded-endpoint clinical trial designed to assess whether RIC intervention can improve short-term prognosis of patients undergoing off-pump CABG. It plans to enroll 648 patients who will be randomly assigned into a RIC group or control group. Patients in the RIC group will receive four cycles of 5 min of pressurization (about 200 mmHg) and 5 min of rest in the 3 days before and 7 days after the surgery. PLANNED OUTCOMES: The primary outcome is the occurrence of major adverse cardiovascular and cerebrovascular events (MACCE) within the 3-month follow-up. MACCE is defined as all-cause death, myocardial infarction, stroke, and coronary revascularization surgery. CLINICAL TRIAL REGISTRATION: NCT06141525 (ClinicalTrials.gov).

Eosinophil Recovery Time Is Associated with Clinical Outcomes in Patients with Type A Acute Aortic Dissection: a Retrospective Cohort Study.

Type A acute aortic dissection (TA-AAD) patients are prone to life-threatening complications and death. This study aimed to analyze the association between eosinophil (EOS) recovery and clinical outcomes in TA-AAD. A total of 274 patients with TA-AAD were eligible for inclusion, and 54 patients died within 1 month. The patients with poor clinical outcomes showed significantly lower EOS count within 8 days after surgery. The time-dependent ROC analysis showed that EOS recovery days predicted 1-month death with an AUC of 0.886 and a cutoff of 6 days. EOS recovery within 6 days was associated with a lower incidence of postoperative infection, a poorer prognosis, and a lower risk of 1-month and 6-month mortality than those requiring more recovery days. Collectively, postoperative early recovery of EOS predicted lower mortality and better prognosis and may be applied as an effective, rapid, and simple tool for the risk stratification and prognostic prediction of patients with TA-AAD.Clinical trial registration number: NCT05409677.

circKDM1A suppresses bladder cancer progression by sponging miR-889-3p/CPEB3 and stabilizing p53 mRNA.

Circular RNAs (circRNAs) play crucial biological functions in various tumors, including bladder cancer (BCa). However, the roles and underlying molecular mechanisms of circRNAs in the malignant proliferation of BCa are yet unknown. CircKDM1A was observed to be downregulated in BCa tissues and cells. Knockdown of circKDM1A promoted the proliferation of BCa cells and bladder xenograft growth, while the overexpression of circKDM1A exerts the opposite effect. The dual-luciferase reporter assay revealed that circKDM1A was directly bound to miR-889-3p, acting as its molecular sponge to downregulate CPEB3. In turn, the CPEB3 was bound to the CPE signal in p53 mRNA 3'UTR to stabilize its expression. Thus, circKDM1A-mediated CPEB3 downregulation inhibits the stability of p53 mRNA and promotes BCa malignant progression. In conclusion, circKDM1A functions as a tumor suppressor in the malignant proliferation of BCa via the miR-889-3p/CPEB3/p53 axis. CircKDM1A may be a potential prognostic biomarker and therapeutic target of BCa.

Anaerolentibacter hominis gen. nov. sp. nov., Diplocloster hominis sp. nov. and Pilosibacter fragilis gen. nov. sp. nov., isolated from human faeces.

Three Gram-positive, obligately anaerobic bacterial strains, namely CSJ-1T, CSJ-3T, and CSJ-4T, were isolated from faeces of healthy persons. They were characterized through a combination of whole-genome sequencing, phenotypic traits, and metabolomic analysis. The genome sizes of CSJ-1T, CSJ-4T, and CSJ-3T were 3.3, 3.8, and 6.1 Mbp, with DNA G+C contents of 47.2, 48.3, and 48.8 mol%, respectively. Strain CSJ-3T was identified as representing a novel species, Diplocloster hominis (type strain CSJ-3T=CGMCC 1.18033T=JCM 36512T) of the genus Diplocloster. The 16S rRNA gene sequence similarity and whole genome average nucleotide identity (gANI) of CSJ-4T to its closest related species, Diplocloster modestus ASD 4241T, were 98.3 and 91.4 %, respectively. Comparative analysis of 16S rRNA gene sequences showed 91.6 % similarity between CSJ-1T and its closest phylogenetic neighbour, Catenibacillus scindens DSM 106146T, and 93.3 % similarity between CSJ-4T and its closest relative strain, Clostridium fessum SNUG30386T. Based on the polyphasic taxonomic results, we proposed two novel genera and three novel species. Strain CSJ-1T was identified as representing a novel species of novel genus, Anaerolentibacter hominis gen. nov. sp. nov. (type strain CSJ-1T=CGMCC 1.18046T=JCM 36511T) of the family Lachnospiraceae, and strain CSJ-4T was identified as representing a novel species of novel genus Pilosibacter fragilis gen. nov. sp. nov. (type strain CSJ-4T=CGMCC 1.18026T= JCM 36513T) of the family Clostridiaceae.

DIMINISHED EXPRESSION OF GLS IN CD4 + T CELLS SERVES AS A PROGNOSTIC INDICATOR ASSOCIATED WITH CUPROPTOSIS IN SEPTIC PATIENTS.

ABSTRACT: Objectives: Sepsis is defined as a life-threatening disease associated with a dysfunctional host immune response. Stratified identification of critically ill patients might significantly improve the survival rate. The present study sought to probe molecular markers associated with cuproptosis in septic patients to aid in stratification and improve prognosis. Methods: We studied expression of cuproptosis-related genes (CRGs) using peripheral blood samples from septic patients. Further classification was made by examining levels of expression of these potential CRGs in patients. Coexpression networks were constructed using the Weighted Gene Coexpression Network Analysis (WGCNA) method to identify crucial prognostic CRGs. Additionally, we utilized immune cell infiltration analysis to further examine the immune status of septic patients with different subtypes and its association with the CRGs. scRNA-seq data were also analyzed to verify expression of key CRGs among specific immune cells. Finally, immunoblotting, flow cytometry, immunofluorescence, and CFSE analysis were used to investigate possible regulatory mechanisms. Results: We classified septic patients based on CRG expression levels and found significant differences in prognosis and gene expression patterns. Three key CRGs that may influence the prognosis of septic patients were identified. A decrease in GLS expression was subsequently verified in Jurkat cells, accompanied by a reduction in O-GlcNAc levels, and chelation of copper by tetrathiomolybdate could not rescue the reduction in GLS and O-GLcNAc levels. Moreover, immoderate chelation of copper was detrimental to mitochondrial function, cell viability, and cell proliferation, as well as the immune status of the host. Conclusion: We have identified novel molecular markers associated with cuproptosis, which could potentially function as diagnostic indicators for septic patients. The reversible nature of the observed alterations in FDX1 and LIAS was demonstrated through copper chelation, whereas the correlation between copper and the observed changes in GLS requires further investigation.

Desulfovibrio desulfuricans and its derived metabolites confer resistance to FOLFOX through METTL3.

BACKGROUND: Chemoresistance is a critical factor contributing to poor prognosis in clinical patients with cancer undergoing postoperative adjuvant chemotherapy. The role of gut microbiota in mediating resistance to tumour chemotherapy remains to be investigated. METHODS: Patients with CRC were categorised into clinical benefit responders (CBR) and no clinical benefit responders (NCB) based on chemotherapy efficacy. Differential bacterial analysis using 16S rRNA sequencing revealed Desulfovibrio as a distinct microbe between the two groups. Employing a syngeneic transplantation model, we assessed the effect of Desulfovibrio on chemotherapy by measuring tumour burden, weight, and Ki-67 expression. We further explored the mechanisms underlying the compromised chemotherapeutic efficacy of Desulfovibrio using metabolomics, western blotting, colony formation, and cell apoptosis assays. FINDINGS: In comparison, Desulfovibrio was more abundant in the NCB group. In vivo experiments revealed that Desulfovibrio colonisation in the gut weakened the efficacy of FOLFOX. Treatment with Desulfovibrio desulfuricans elevates serum S-adenosylmethionine (SAM) levels. Interestingly, SAM reduced the sensitivity of CRC cells to FOLFOX, thereby promoting the growth of CRC tumours. These experiments suggest that SAM promotes the growth and metastasis of CRC by driving the expression of methyltransferase-like 3 (METTL3). INTERPRETATION: A high abundance of Desulfovibrio in the intestines indicates poor therapeutic outcomes for postoperative neoadjuvant FOLFOX chemotherapy in CRC. Desulfovibrio drives the manifestation of METTL3 in CRC, promoting resistance to FOLFOX chemotherapy by increasing the concentration of SAM. FUNDING: This study is supported by Wuxi City Social Development Science and Technology Demonstration Project (N20201005).

Mild magnetic hyperthermia-activated immuno-responses for primary bladder cancer therapy.

Surgical intervention followed by chemotherapy is the principal treatment strategy for bladder cancer, which is hindered by significant surgical risks, toxicity from chemotherapy, and high rates of recurrence after surgery. In this context, a novel approach using mild magnetic hyperthermia therapy (MHT) for bladder cancer treatment through the intra-bladder delivery of magnetic nanoparticles is presented for the first time. This method overcomes the limitations of low magnetic thermal efficiency, inadequate tumor targeting, and reduced therapeutic effectiveness associated with the traditional intravenous administration of magnetic nanoparticles. Core-shell Zn-CoFe2O4@Zn-MnFe2O4 (MNP) nanoparticles were developed and further modified with hyaluronic acid (HA) to enhance their targeting ability toward tumor cells. The application of controlled mild MHT using MNP-HA at temperatures of 43-44 °C successfully suppressed the proliferation of bladder tumor cells and tumor growth, while also decreasing the expression levels of heat shock protein 70 (HSP70). Crucially, this therapeutic approach also activated the body's innate immune response involving macrophages, as well as the adaptive immune responses of dendritic cells (DCs) and T cells, thereby reversing the immunosuppressive environment of the bladder tumor and effectively reducing tumor recurrence. This study uncovers the potential immune-activating mechanism of mild MHT in the treatment of bladder cancer and confirms the effectiveness and safety of this strategy, indicating its promising potential for the clinical management of bladder cancer with a high tendency for relapse.

Evaluating the fire resistance and durability of cotton textiles treated with a phosphoramide phosphorus ester phosphate ammonium flame retardant.

The phosphoramide phosphorus ester phosphate ammonium (PPEPA) flame retardant was synthesized by phosphorus oxychloride and ethanolamine, and its structure was characterized by nuclear magnetic resonance and Fourier transform infrared spectroscopy (FTIR). Cotton textiles treated with 20 wt% PPEPA (CT-PPEPA3) would have high durability and flame retardance. The limiting oxygen index (LOI) of CT-PPEPA3 was found to be 46.5 %, while after undergoing 50 laundering cycles (LCs) following the AATCC 61-2013 3 A standard, the LOI only decreased to 31.4 %. Scanning electron microscopy and X-ray diffraction analyses suggested the penetration of PPEPA molecules into the interior of cotton fibers, resulting in a minor alteration of the cellulose crystal structure. The excellent durability, FTIR, and energy-dispersive X-ray of CT-PPEPA3 provided evidence for the formation of -N-P(=O)-O-C- and -O-P(=O)-O-C- covalent bonds between the PPEPA molecules and cellulose. The -N-P(=O)-O-C- bond exhibited a p-π conjugation effect, leading to enhanced stability and improved durability of the flame-retardant cotton textiles. Vertical flame, thermogravimetric, and cone calorimetry tests demonstrated that the CT-PPEPA3 underwent condensed-phase and synergistic flame retardation. Additionally, these finished cotton textiles retained adequate breaking strength and softness, making them suitable for various applications. In conclusion, the incorporation of the -N-P(=O)-ONH4 group into the phosphorus ester phosphate ammonium flame retardant demonstrated effective enhancement of the fire resistance and durability of treated cotton textiles.

The size-dependence and reversibility of polystyrene nanoplastics-induced lipid accumulation in mice: Possible roles of lysosomes.

Nanoplastics (NPs) continue to accumulate in global aquatic and terrestrial systems, posing a potential threat to human health through the food chain and/or other pathways. Both in vivo and in vitro studies have confirmed that the liver is one of the main organs targeted for the accumulation of NPs in living organisms. However, whether exposure to NPs induces size-dependent disorders of liver lipid metabolism remains controversial, and the reversibility of NPs-induced hepatotoxicity is largely unknown. In this study, the effects of long-term exposure to environmentally relevant doses of polystyrene nanoplastics (PS-NPs) on lipid accumulation were investigated in terms of autophagy and lysosomal mechanisms. The findings indicated that hepatic lipid accumulation was more pronounced in mice exposed to 100 nm PS-NPs compared to 500 nm PS-NPs. This effect was effectively alleviated after 50 days of self-recovery for 100 nm and 500 nm PS-NPs exposure. Mechanistically, although PS-NPs exposure activated autophagosome formation through ERK (mitogen-activated protein kinase 1)/mTOR (mechanistic target of rapamycin kinase) signaling pathway, the inhibition of Rab7 (RAB7, member RAS oncogene family), CTSB (cathepsin B), and CTSD (cathepsin D) expression impaired lysosomal function, thereby blocking autophagic flux and contributing to hepatic lipid accumulation. After termination of PS-NPs exposure, lysosomal exocytosis was responsible for the clearance of PS-NPs accumulated in lysosomes. Furthermore, impaired lysosomal function and autophagic flux inhibition were effectively alleviated. This might be the main reason for the alleviation of PS-NPs-induced lipid accumulation after recovery. Collectively, we demonstrate for the first time that lysosomes play a dual role in the persistence and reversibility of hepatotoxicity induced by environmental relevant doses of NPs, which provide novel evidence for the prevention and intervention of liver injury associated with nanoplastics exposure.

Exposure to haloacetic acid disinfection by-products and male steroid hormones: An epidemiological and in vitro study.

Haloacetic acids (HAAs) are ubiquitous in drinking water and have been associated with impaired male reproductive health. However, epidemiological evidence exploring the associations between HAA exposure and reproductive hormones among males is scarce. In the current study, the urinary concentrations of dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA), the internal exposure markers of HAAs, as well as sex hormones (testosterone [T], progesterone [P], and estradiol [E2]) were measured among 449 Chinese men. Moreover, in vitro experiments, designed to simulate the real-world scenarios of human exposure, were conducted to assess testosterone synthesis in the Leydig cell line MLTC-1 and testosterone metabolism in the hepatic cell line HepG2 in response to low-dose HAA exposure. The DCAA and TCAA urinary concentrations were found to be positively associated with urinary T, P, and E2 levels (all p < 0.001), but negatively associated with the ratio of urinary T to E2 (p < 0.05). Combined with in vitro experiments, the results suggest that environmentally-relevant doses of HAA stimulate sex hormone synthesis and steroidogenesis pathway gene expression in MLTC-1 cells. In addition, the inhibition of the key gene CYP3A4 involved in the testosterone phase Ⅰ catabolism, and induction of the gene UGT2B15 involved in testosterone phase Ⅱ glucuronide conjugation metabolism along with the ATP-binding cassette (ABC) transport genes (ABCC4 and ABCG2) in HepG2 cells could play a role in elevation of urinary hormone excretion upon low-dose exposure to HAAs. Our novel findings highlight that exposure to HAAs at environmentally-relevant concentrations is associated with increased synthesis and excretion of sex hormones in males, which potentially provides an alternative approach involving urinary hormones for the noninvasive evaluation of male reproductive health following exposure to DBPs.