Extracellular vesicles containing circMYBL1 induce CD44 in adenoid cystic carcinoma cells and pulmonary endothelial cells to promote lung metastasis.

Adenoid cystic carcinoma (ACC) is a rare malignant epithelial neoplasm that arises in secretory glands and commonly metastasizes to the lungs. MYBL1 is frequently overexpressed in ACC and has been suggested to be a driver of the disease. Here, we identified a circRNA derived from MYBL1 pre-mRNA that accompanied overexpression of MYBL1 in ACC. Overexpression of circMYBL1 was correlated with increased lung metastasis and poor overall survival in ACC patients. Ectopic circMYBL1 overexpression promoted malignant phenotypes and lung metastasis of ACC cells. Mechanistically, circMYBL1 formed a circRNA-protein complex with CCAAT enhancer binding protein beta (CEBPB), which inhibited ubiquitin-mediated degradation and promoted nuclear translocation of CEBPB. In the nucleus, circMYBL1 increased the binding of CEBPB to the CD44 promoter region and enhanced its transcription. In addition, circMYBL1 was enriched in small extracellular vesicles (sEVs) isolated from the plasma of ACC patients. Treatment with sEVs containing circMYBL1 in sEVs enhanced pro-metastatic phenotypes of ACC cells, elevated the expression of CD44 in human pulmonary microvascular endothelial cells (HPMECs), and enhanced the adhesion between HPMECs and ACC cells. Moreover, circMYBL1 encapsulated in sEVs increased the arrest of circulating ACC cells in the lung and enhanced the lung metastatic burden. This data suggests that circMYBL1 is a tumor-promoting circRNA that could serve as a potential biomarker and therapeutic target in ACC.

Integrating Lithium Sulfide as a Single Ionic Conductor Interphase for Stable All-Solid-State Lithium-Sulfur Batteries.

As a very prospective solid-state electrolyte, Li10GeP2S12 (LGPS) exhibits high ionic conductivity comparable to liquid electrolytes. However, severe self-decomposition and Li dendrite propagation of LGPS will be triggered due to the thermodynamic incompatibility with Li metal anode. Herein, by adopting a facile chemical vapor deposition method, an artificial solid electrolyte interphase composed of Li2S is proposed as a single ionic conductor to promote the interface stability of LGPS toward Li. The good electronic insulation coupled with ionic conduction property of Li2S effectively blocks electron transfer from Li to LGPS while enabling smooth passage of Li ions. Meanwhile, the generated Li2S layer remains good interface compatibility with LGPS, which is verified by the stable Li-plating/stripping operation for over 500 h at 0.15 mA cm-2. Consequently, the all-solid-state Li-S batteries (ASSLSBs) with a Li2S layer demonstrate superb capacity retention of 90.8% at 0.2 mA cm-2 after 100 cycles. Even at the harsh condition of 90 °C, the cell can deliver a high reversible capacity of 1318.8 mAh g-1 with decent capacity retention of 88.6% after 100 cycles. This approach offers a new insight for interface modification between LGPS and Li and the realization of ASSLSBs with stable cycle life.

Influence of trimetazidine on myocardial injury in mice with diabetic cardiomyopathy.

INTRODUCTION: The prevalence of diabetes mellitus is increasing year by year globally, and diabetic cardiomyopathy (DCM), as the most common complication of type 2 diabetes mellitus, seriously affects the prognosis of patients. Trimetazidine (TMZ), as a drug affecting myocardial energy metabolism, mainly reduces the oxidation rate of ß-oxidation by inhibiting 3-ketoacyl-CoA thiolase (3-KAT), a key enzyme in ß-oxidation of free fatty acid (FFA), so that the energy metabolism substrate of cardiomyocytes preferentially selects glucose rather than fatty acids, increases the content of intracellular adenosine triphosphate (ATP), enhances the contractile function of cardiomyocytes, and improves the state of cellular ischemia and hypoxia. Previous studies have shown that TMZ is closely related to the activation and induction of apoptosis of the MAPK pathway and AMPK pathway, and plays a role in the treatment of diabetic cardiomyopathy, but the specific mechanism is still unclear. OBJECTIVE: This study aims to investigate the impact of TMZ on myocardial damage in mice exhibiting diabetic cardiomyopathy (DCM), and to furnish a laboratory foundation for the clinical treatment of diabetic cardiomyopathy. METHOD: Male db/db mice (6 weeks old, n = 21) and male wild-type (wt) (6 weeks old, n = 20) mice were selected for the study. The wt mice were randomly assigned to the wt group (n = 10) and wt + TMZ group (n = 10), while the remaining db/db mice were randomly allocated to the db/db group (n = 11) and db/db + TMZ group (n = 10). Following 8 weeks of feeding, the wt + TMZ group and db/db + TMZ group received TMZ via gavage, whereas the remaining groups were administered physiological saline. Periodic measurements of blood glucose, blood lipids, and myocardial enzymes were conducted in mice, with samples obtained after the 12th week for subsequent biochemical analysis, myocardial pathology assessment, immunohistochemistry, western blot analysis, and TUNEL staining (TdT-mediated dUTP Nick-End Labeling). RESULT: GLU, TC, TG, LDL-C, and CK-MB levels were significantly higher in db/db mice compared to wt mice (GLU: M ± SD wt 5.94 ± 0.37, db/db 17.63 ± 0.89, p < 0.05, ES = 0.991; TC: M ± SD wt 3.01 ± 0.32, db/db 6.97 ± 0.36, p < 0.05, ES = 0.972; TG: M ± SD wt 0.58 ± 0.2, db/db 1.75 ± 0.14, p < 0.05, ES = 0.920; LDL-C: M ± SD wt 1.59 ± 0.12, db/db 3.87 ± 0.14, p < 0.05, ES = 0.989; CK-MB: M ± SD wt 0.12 ± 0.01, db/db 0.31 ± 0.04, p < 0.05, ES = 0.928). HDL-C levels were significantly lower in db/db mice (M ± SD wt 1.89 ± 0.08, db/db 0.64 ± 0.09, p < 0.05, ES = 0.963). Histopathological analysis confirmed myocardial damage in db/db mice. Treatment with TMZ reduced GLU, TC, TG, LDL-C, and CK-MB levels (p < 0.05, ES > 0.9) and increased HDL-C levels compared to untreated db/db mice. Additionally, TMZ treatment significantly decreased myocardial cell apoptosis (p < 0.05, ES = 0.980). These results demonstrate the efficacy of TMZ in reversing myocardial injury in DCM mice. CONCLUSION: TMZ can mitigate myocardial damage in db/db mice by downregulating the expression of caspase-12, a protein associated with the endoplasmic reticulum stress (ERS) cell apoptosis pathway, consequently diminishing cell apoptosis. This underscores the protective efficacy of TMZ against myocardial damage in mice afflicted with DCM.

Electroacupuncture regulates the P2X7R-NLRP3 inflammatory cascade to relieve decreased sensation on ocular surface of type 2 diabetic rats with dry eye.

Dry eye (DE) is a prevalent ocular surface disease in patients with type 2 diabetes (T2DM). However, current medications are ineffective against decreased sensation on the ocular surface. While electroacupuncture (EA) effectively alleviates decreased sensation on ocular surface of DE in patients with T2DM, the neuroprotective mechanism remains unclear. This study explored the pathogenesis and therapeutic targets of T2DM-associated DE through bioinformatics analysis. It further investigated the underlying mechanism by which EA improves decreased sensation on the ocular surface of DE in rats with T2DM. Bioinformatic analysis was applied to annotate the potential pathogenesis of T2DM DE. T2DM and DE was induced in male rats. Following treatment with EA and fluorometholone, comprehensive metrics were assessed. Additionally, the expression patterns of key markers were studied. Key targets such as NLRP3, Caspase-1, and NOD-like receptor signaling may be involved in the pathogenesis of T2DM DE. EA treatment improved ocular measures. Furthermore, EA potently downregulated P2X7R, NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and Caspase-1 expression within the trigeminal ganglion and spinal trigeminal nucleus caudalis. Targeted P2X7R antagonist (A-438079) and agonist (BzATP) employed as controls to decipher the biochemistry of the therapeutic effects of EA showed an anti-inflammatory effect with A-438079, while BzATP blocked the anti-inflammatory effect of EA. EA relieved DE symptoms and attenuated inflammatory damage to sensory nerve pathways in T2DM rats with DE. These findings suggest a crucial role of EA inhibition of the P2X7R-NLRP3 inflammatory cascade to provide these benefits.

ALMS1-IT1: A Key Player in the Novel Disulfidptosis-Related LncRNA Prognostic Signature for Head and Neck Squamous Cell Carcinoma.

Disulfidptosis is a newly discovered form of programmed cell death that is induced by disulfide stress. It is closely associated with various cancers, including head and neck squamous cell carcinoma (HNSCC). However, the factors involved in the modulation of disulfidptosis-related genes (DRGs) still remain unknown. In this study, we established and validated a novel risk score model composed of 11 disulfidptosis-related lncRNAs (DRLs) based on 24 DRGs in HNSCC. The results revealed strong correlations between the 11-DRL prognostic signature and clinicopathological features, immune cell infiltration, immune-related functions, and disulfidptosis-associated pathways, including NADPH and disulfide oxidoreductase activities. Furthermore, we studied and verified the involvement of ALMS1-IT1, one of the 11 model DRLs, in the disulfidptosis of HNSCC cell lines. A series of assays demonstrated that ALMS1-IT1 modulated cell death under starvation conditions in a pentose phosphate pathway (PPP)-dependent manner. Knockdown of ALMS1-IT1 inhibited the PPP, contributing to a decline in NADPH levels, which resulted in the formation of multiple intermolecular disulfide bonds between actin cytoskeleton proteins and the collapse of F-actin in the cytoplasm. Therefore, ALMS1-IT1, which is highly expressed in SLC7A11high cells, can be considered a promising therapeutic target for disulfidptosis-focused treatment strategies for cancer and other diseases.

Incidence and predictors of restenosis following successful recanalization of non-acute internal carotid artery occlusion in 252 cases.

BACKGROUND: Data concerning restenosis following successful recanalization of non-acute internal carotid artery occlusion (ICAO) are scarce. This study was conducted to identify the incidence and predictors of restenosis following successful recanalization of non-acute ICAO. METHODS: We reviewed the incidence of restenosis (defined as >70% restenosis or reocclusion) among 252 consecutive patients with successful recanalization of non-acute ICAO. Baseline, imaging, and surgery-related characteristics were analyzed to assess their association with restenosis. A scoring system was developed to identify high-risk patients for restenosis. RESULTS: During a median follow-up of 12.6 months, restenosis occurred in 56 patients (22.2%), including 39 with reocclusion and 17 with >70% restenosis. The cumulative restenosis rate was 18.0% at 12 months and 24.1% at 24 months. The incidence of stroke was higher in patients with restenosis (25.0% vs 1.5%, P<0.01). Multivariate analysis showed occlusion length (5-10 cm vs <5 cm (hazard ratio (HR) 3.15, 95% confidence interval (95% CI) 1.07 to 9.29); ≥ 10 cm vs <5 cm (HR 5.01, 95% CI 1.73 to 14.49)), residual stenosis ≥30% (HR 3.08, 95% CI 1.79 to 5.30), and internal carotid artery (ICA) wall collapse (HR 1.96, 95% CI 1.12 to 3.44) as independent predictors of restenosis. Point scores proportional to model coefficients were assigned, with scores ranging from 0 to 6. Patients scoring 3-6 had a 4.00 times higher chance of developing restenosis (95% CI 2.35 to 6.79) compared with those scoring 0-2. CONCLUSIONS: Nearly one in five patients experienced restenosis following successful recanalization of non-acute ICAO. Occlusion length, residual stenosis ≥30%, and ICA wall collapse were independently associated with restenosis.

Photosensitive Hydrogel with Temperature-Controlled Reversible Nano-Apertures for Single-Cell Protein Analysis.

Single cell western blot (scWB) is one of the most important methods for cellular heterogeneity profiling. However, current scWB based on conventional photoactive polyacrylamide hydrogel material suffers from the tradeoff between in-gel probing and separation resolution. Here, a highly sensitive temperature-controlled single-cell western blotting (tc-scWB) method is introduced, which is based on a thermo/photo-dualistic-sensitive polyacrylamide hydrogel, namely acrylic acid-functionalized graphene oxide (AFGO) assisted, N-isopropylacrylamide modified polyacrylamide (ANP) hydrogel. The ANP hydrogel is contracted at high-temperature to constrain protein band diffusion during microchip electrophoretic separation, while the gel aperture is expanded under low-temperature for better antibody penetration into the hydrogel. The tc-scWB method enables the separation and profiling of small-molecule-weight proteins with highly crosslinked gel (12% T) in SDS-PAGE. The tc-scWB is demonstrated on three metabolic and ER stress-specific proteins (CHOP, MDH2 and FH) in four pancreatic cell subtypes, revealing the expression of key enzymes in the Krebs cycle is upregulated with enhanced ER stress. It is found that ER stress can regulate crucial enzyme (MDH2 and FH) activities of metabolic cascade in cancer cells, boosting aerobic respiration to attenuate the Warburg effect and promote cell apoptosis. The tc-scWB is a general toolbox for the analysis of low-abundance small-molecular functional proteins at the single-cell level.

Solvation-Tailored PVDF-Based Solid-State Electrolyte for High-Voltage Lithium Metal Batteries.

Poly(vinylidene fluoride) (PVDF)-based polymer electro-lytes are attracting increasing attention for high-voltage solid-state lithium metal batteries because of their high room temperature ionic conductivity, adequate mechanical strength and good thermal stability. However, the presence of highly reactive residual solvents, such as N, N-dimethylformamide (DMF), severely jeopardizes the long-term cycling stability. Herein, we propose a solvation-tailoring strategy to confine residual solvent molecules by introducing low-cost 3 Šzeolite molecular sieves as fillers. The strong interaction between DMF and the molecular sieve weakens the ability of DMF to participate in the solvation of Li+, leading to more anions being involved in solvation. Benefiting from the tailored anion-rich coordination environment, the interfacial side reactions with the lithium anode and high-voltage NCM811 cathode are effectively suppressed. As a result, the solid-state Li||Li symmetrical cells demonstrates ultra-stable cycling over 5100 h at 0.1 mA cm-2, and the Li||NCM811 full cells achieve excellent cycling stability for more than 1130 and 250 cycles under the charging cut-off voltages of 4.3 V and 4.5 V, respectively. Our work is an innovative exploration to address the negative effects of residual DMF in PVDF-based solid-state electrolytes and highlights the importance of modulating the solvation structures in solid-state polymer electrolytes.

Research Note: Antibiotic resistance and pathogenicity of geese-derived Riemerella anatipestifer isolated from eastern regions of Hebei Province, China.

Riemerella anatipestifer (R. anatipestifer) can cause serositis in multiple poultry species, resulting in significant losses. Although R. anatipestifer-caused infections in ducks have been well established, the literature about this disease in geese is rare. Here, we isolated and identified 56 strains of R. anatipestifer from the eastern regions of Hebei Province, China, and further determined their serotypes, antibiotic resistance, and pathogenicity. A total of 75 strains of causative bacteria were isolated from 70 sick geese with serositis. After Gram staining microscopy, PCR, and 16S rDNA sequence analysis, 56 isolates were identified as members of R. anatipestifer and 19 as Escherichia coli (E. coli). The results of serotyping showed that there were 4 serotypes prevalent in the isolate, including serotype 1 (37/56), serotype 2 (9/56), serotype 11 (8/56), and serotype 13 (2/56). The results of antibiotic susceptibility testing revealed that all 56 R. anatipestifer isolates showed varying degrees of multidrug resistance (MDR). A total of 10 antibiotic resistance genes (ARG) were determined in these isolates. Four isolates of different serotypes were selected for pathogenicity examination, and all were able to reproduce serositis-like symptoms in 15-day-old goslings, with neurological symptoms and a 100% mortality rate. Hemorrhagic congestion of the brain tissue, steatosis of the hepatocytes, and disorganization of some cardiac myofibers were observed in R. anatipestifer-infected geese. All these findings will contribute to our insights into the prevalence characteristics, antibiotic resistance profile, and pathogenicity of R. anatipestifer infection in geese in eastern Hebei Province and provide scientific guidance for the treatment and control of this disease.

Exploring the links of skeletal muscle mitochondrial oxidative capacity, physical functionality, and mental well-being of cancer survivors.

Physical impairments following cancer treatment have been linked with the toxic effects of these treatments on muscle mass and strength, through their deleterious effects on skeletal muscle mitochondrial oxidative capacity. Accordingly, we designed the present study to explore relationships of skeletal muscle mitochondrial oxidative capacity with physical performance and perceived cancer-related psychosocial experiences of cancer survivors. We assessed skeletal muscle mitochondrial oxidative capacity using in vivo phosphorus-31 magnetic resonance spectroscopy (31P MRS), measuring the postexercise phosphocreatine resynthesis time constant, τPCr, in 11 post-chemotherapy participants aged 34-70 years. During the MRS procedure, participants performed rapid ballistic knee extension exercise to deplete phosphocreatine (PCr); hence, measuring the primary study outcome, which was the recovery rate of PCr (τPCr). Patient-reported outcomes of psychosocial symptoms and well-being were assessed using the Patient-Reported Outcomes Measurement Information System and the 36-Item Short Form health survey (SF-36). Rapid bioenergetic recovery, reflected through a smaller value of τPCr was associated with worse depression (rho ρ = - 0.69, p = 0.018, and Cohen's d = - 1.104), anxiety (ρ = - 0.61, p = .046, d = - 0.677), and overall mental health (ρ = 0.74, p = 0.010, d = 2.198) scores, but better resilience (ρ = 0.65, p = 0.029), and coping-self efficacy (ρ = 0.63, p = 0.04) scores. This is the first study to link skeletal muscle mitochondrial oxidative capacity with subjective reports of cancer-related behavioral toxicities. Further investigations are warranted to confirm these findings probing into the role of disease status and personal attributes in these preliminary results.

Relationship between circadian eating behavior (daily eating frequency and nighttime fasting duration) and cardiovascular mortality.

BACKGROUND: Knowledge regarding the health impacts of daily eating frequency (DEF) and nighttime fasting duration (NFD) on mortality is very limited. OBJECTIVE: This study aimed to examine whether DEF and NFD are associated with CVD and all-cause mortality. METHODS: This was a prospective cohort study of a nationally representative sample from the United States, including 30,464 adults who participated in the National Health and Nutrition Examination Survey 2003-2014. Using 24-h dietary recall, DEF was assessed by the number of eating episodes, and NFD was calculated by the first and last eating time across a day. Death information was obtained from the National Death Index up to 2019. Weighted Cox proportional hazards regression models were used to assess survival relationships of DEF and NFD with mortality. RESULTS: During 307,686 person-years of follow-up, 4560 deaths occurred, including 1824 CVD cases. After adjustment for confounders, compared to DEF at 4-6 times, participants whose DEF was less than 3 times had greater CVD [hazard-ratio (HR) = 1.33, 95% confidence-interval (CI): 1.06-1.67] and all-cause (HR = 1.16, 95% CI: 1.01-1.33) mortality risks. Furthermore, compared to NFD of 10 to 11 h, participants whose NFD was shorter than 10 h had HRs of 1.30 (95% CI: 1.08-1.55) for CVD mortality and 1.23 (95% CI: 1.08-1.39) for all-cause mortality. NFD longer than 14 h was also related to CVD mortality (HR = 1.37, 95% CI: 1.12-1.67) and all-cause mortality (HR = 1.36, 95% CI: 1.19-1.54). Similar results for the association of NFD and DEF with heart-specific and stroke-specific mortality were observed. CONCLUSION: This study found that DEF less than 3 times and NFD shorter than 10 h or longer than 14 h were independently associated with greater cardiovascular and all-cause mortality.

Dynamic membrane filtration accelerates electroactive biofilms in bioelectrochemical systems.

Bioelectrochemical systems (BES) have emerged as a dual-function technology for treating wastewater and recovering energy. A vital element of BES is the rapid formation and maintenance of electroactive biofilms (EABs). Previous attempts to accelerate EAB formation and improve electroactivities focused on enhancing the bacterial adhesion process while neglecting the rate-limiting step of the bacterial transport process. Here, we introduce membrane filtration into BES, establishing a dynamic membrane filtration system that enhances overall performance. We observed that optimal membrane flux considerably reduced the startup time for EAB formation. Specifically, EABs established under a 25 L m-2 h-1 flux (EAB25 LMH) had a formation time of 43.8 ± 1.3 h, notably faster than the 51.4 ± 1.6 h in the static state (EAB0 LMH). Additionally, EAB25 LMH exhibited a significant increase in maximum current density, approximately 2.2 times higher than EAB0 LMH. Pearson correlation analysis indicated a positive relationship between current densities and biomass quantities and an inverse correlation with startup time. Microbial analysis revealed two critical findings: (i) variations in maximum current densities across different filtration conditions were associated with redox-active substances and biomass accumulation, and (ii) the incorporation of a filtration process in EAB formation enhanced the proportion of viable cells and encouraged a more diverse range of electroactive bacteria. Moreover, the novel electroactive membrane demonstrated sustained current production and effective solid-liquid separation during prolonged operation, indicating its potential as a viable alternative in membrane-based systems. This approach not only provides a new operational model for BES but also holds promise for expanding its application in future wastewater treatment solutions.

Boosting a practical Li-CO2 battery through dimerization reaction based on solid redox mediator.

Li-CO2 batteries offer a promising avenue for converting greenhouse gases into electricity. However, the inherent challenge of direct electrocatalytic reduction of inert CO2 often results in the formation of Li2CO3, causing a dip in output voltage and energy efficiency. Our innovative approach involves solid redox mediators, affixed to the cathode via a Cu(II) coordination compound of benzene-1,3,5-tricarboxylic acid. This technique effectively circumvents the shuttle effect and sluggish kinetics associated with soluble redox mediators. Results show that the electrochemically reduced Cu(I) solid redox mediator efficiently captures CO2, facilitating Li2C2O4 formation through a dimerization reaction involving a dimeric oxalate intermediate. The Li-CO2 battery employing the Cu(II) solid redox mediator boasts a higher discharge voltage of 2.8 V, a lower charge potential of 3.7 V, and superior cycling performance over 400 cycles. Simultaneously, the successful development of a Li-CO2 pouch battery propels metal-CO2 batteries closer to practical application.

NAT10/CEBPB/vimentin signalling axis promotes adenoid cystic carcinoma malignant phenotypes in vitro.

OBJECTIVE: To explore the biological function and mechanisms of CEBPB and NAT10-mediated N4-acetylcytidine (ac4c) modification in salivary adenoid cystic carcinoma (SACC). MATERIALS AND METHODS: CEBPB and NAT10 were knocked down in SACC-LM cells by siRNA transfection and overexpressed in SACC-83 cells by plasmid transfection. Malignant phenotypes were evaluated using CCK-8, Transwell migration and colony formation assays. Real-time PCR, western blotting, ChIP and acRIP were used to investigate the molecular mechanisms involved. RESULTS: We found that CEBPB was highly expressed in SACC tissues and correlated with lung metastasis and unfavourable prognosis. Gain- and loss-of-function experiments revealed that CEBPB promoted SACC malignant phenotypes. Mechanistically, CEBPB exerted its oncogenic effect by binding to the vimentin gene promoter region to enhance its expression. Moreover, NAT10-mediated ac4c modification led to stabilization and overexpression of CEBPB in SACC cells. We also found that NAT10, the only known human enzyme responsible for ac4C modification, promoted SACC cell migration, proliferation and colony formation. Moreover, CEBPB overexpression restored the inhibitory effect of NAT10 knockdown on malignant phenotypes. CONCLUSIONS: Our study reveals the critical role of the newly identified NAT10/CEBPB/vimentin axis in SACC malignant progression, and the findings may be applied to improve treatment for SACC.

The impact of the HER2-low status on conditional survival in patients with breast cancer.

Introduction: With recent advances in breast cancer (BC) treatment, the disease-free survival (DFS) of patients is increasing and the risk factors for recurrence and metastasis are changing. However, a dynamic approach to assessing the risk of recurrent metastasis in BC is currently lacking. This study aimed to develop a dynamically changing prediction model for recurrent metastases based on conditional survival (CS) analysis. Methods: Clinical and pathological data from patients with BC who underwent surgery at the Affiliated Hospital of Qingdao University between August 2011 and August 2022 were retrospectively analysed. The risk of recurrence and metastasis in patients with varying survival rates was calculated using CS analysis, and a risk prediction model was constructed. Results: A total of 4244 patients were included in this study, with a median follow-up of 83.16 ± 31.59 months. Our findings suggested that the real-time DFS of patients increased over time, and the likelihood of DFS after surgery correlated with the number of years of prior survival. We explored different risk factors for recurrent metastasis in baseline patients, 3-year, and 5-year disease-free survivors, and found that low HER2 was a risk factor for subsequent recurrence in patients with 5-year DFS. Based on this, conditional nomograms were developed. The nomograms showed good predictive ability for recurrence and metastasis in patients with BC. Conclusion: Our study showed that the longer patients with BC remained disease-free, the greater their chances of remaining disease-free again. Predictive models for recurrence and metastasis risk based on CS analysis can help improve the confidence of patients fighting cancer and help doctors personalise treatment and follow-up plans.

Conditional survival in breast cancer With recent advances in breast cancer (BC) treatment, the disease-free survival of patients is increasing and the risk factors for recurrence and metastasis are changing. One of the key risk factor is the human epidermal growth factor receptor 2 (HER2). However, the recent advent of anti-HER2 antibody-drug conjugates (ADC) has challenged the traditional binary classification based on HER2. Patients in the traditional HER2-negative group can now be further classified as HER2-low (ISH-negative with IHC1 or IHC2) or HER2-0 (ISH-negative and IHC-0). Does this categorisation also have some value for the prognosis of BC? To figure this out, we retrospectively analysed the clinical and pathological data of BC patients who underwent surgery at the Affiliated Hospital of Qingdao University between August 2011 and August 2022. The risk of recurrence and metastasis in patients with varying survival rates was calculated using conditional survival analysis, and a risk prediction model was constructed.Our findings suggested that the real-time disease-free survival (DFS) of patients increased over time, and the likelihood of DFS after surgery correlated with the number of years of prior survival. Conditional nomograms were developed for baseline patients, 3-year and 5-year disease-free survivors. The nomograms showed good predictive ability for recurrence and metastasis in patients with BC.

Prognostic value and distribution pattern of tumor infiltrating lymphocytes and their subsets in distant metastases of advanced breast cancer.

BACKGROUND: There are significant correlations between the levels of tumor infiltrating lymphocytes (TILs) and the prognosis of primary breast cancer. While little is known about immunological mechanisms in the distant metastasis of advanced breast cancer. PATIENTS AND METHODS: A total of 106 patients with advanced metastatic breast cancer were enrolled in this study between 2016 and 2022. Hematoxylin and eosin staining and immunohistochemistry were used to assess the densities of stromal TILs (sTILs), intratumoral TILs (iTILs) and invasive marginal TILs (imTILs) and CD4+, CD8+, CD20+, FOXP3+ TILs in the primary tumor and metastasis (bone, lung, liver, and distant lymph node) of advanced breast cancer. RESULTS: Higher levels of sTILs at metastatic sites were associated with better progression-free survival (PFS), postmetastasis survival (PMS) and overall survival (OS) (p = .026, .001 and .005, respectively). The levels of iTILs were significantly lower than those of sTILs and imTILs in both primary tumor (p< .001, both) and metastasis (p< .001, both). The level of CD4+ T cells was higher than those of CD8+ T cells and CD20+ B cells in both primary tumor (p < .001) and metastasis (p < .001). The levels of sTILs (p=0. 001) and imTILs (p< .001) in the primary tumor were generally higher than those in the metastasis. CONCLUSION: The levels of TILs and their subsets can predict the survival and prognosis of patients with advanced breast cancer. The distributions of TILs and their subsets are similar between the primary tumor and metastasis. The metastases have a lower degree of lymphocytes infiltration than its corresponding primary tumor.

Single-Cell Study Unveils Lead Lifespan in Blood Cell Populations Follows a Universal Lognormal Distribution with Individual Skewness.

Lead is a widespread environmental hazard that can adversely affect multiple biological functions. Blood cells are the initial targets that face lead exposure. However, a systematic assessment of lead dynamics in blood cells at single-cell resolution is still absent. Herein, C57BL/6 mice were fed with lead-contaminated food. Peripheral blood was harvested at different days. Extracted red blood cells and leukocytes were stained with 19 metal-conjugated antibodies and analyzed by mass cytometry. We quantified the time-lapse lead levels in 12 major blood cell subpopulations and established the distribution of lead heterogeneity. Our results show that the lead levels in all major blood cell subtypes follow lognormal distributions but with distinctively individual skewness. The lognormal distribution suggests a multiplicative accumulation of lead with stochastic turnover of cells, which allows us to estimate the lead lifespan of different blood cell populations by calculating the distribution skewness. These findings suggest that lead accumulation by single blood cells follows a stochastic multiplicative process.

Therapeutic potential of miRNAs in placental extracellular vesicles in ovarian and endometrial cancer.

There is a cross-link between the placenta and cancer development, as the placenta is grown as a highly invasive tumour-like organ. However, placental development is strictly controlled. Although the underlying mechanism of this control is largely unknown, it is now well-recognised that extracellular vesicles (EVs) released from the placenta play an important role in controlling placenta proliferation and invasion, as placental EVs have shown their effect on regulating maternal adaptation. Better understanding the tumour-like mechanism of the placenta could help to develop a therapeutic potential in cancers. In this study, by RNA sequencing of placental EVs, 20 highly expressed microRNAs (miRNAs) in placental EVs were selected and analysed for their functions on ovarian and endometrial cancer. There were up to seven enriched miRNAs, including miRNA-199a-3p, miRNA-143-3p, and miRNA-519a-5p in placental EVs showing effects on the inhibition of ovarian and endometrial cancer cell proliferation and migration, and promotion of cancer cell death, reported in the literature. Most of these miRNAs have been reported to be downregulated in ovarian and endometrial cancer. Transfection of ovarian and endometrial cancer cells with mimics of miRNA-199a-3p, miRNA-143-3p, and miRNA-519a-5p significantly reduced the cell viability. Our findings could provide strategies for using these naturally occurring miRNAs to develop a novel method to treat ovarian and endometrial cancer in the future.

Effects of intravenous glucocorticoids on postoperative delirium in adult patients undergoing major surgery: a systematic review and meta-analysis with trial sequential analysis.

BACKGROUND: The effects of intravenous glucocorticoids on postoperative delirium (POD) in adult patients undergoing major surgery remain controversial. Therefore, we conducted this meta-analysis to assess whether intravenous glucocorticoids can decrease POD incidence in the entire adult population undergoing major surgery and its association with patients age, type of surgery, and type of glucocorticoid. METHODS: We searched the relevant literature published before November 3, 2023, through Cochrane Library, PubMed, Embase, and Web of Science. The primary outcome was POD incidence. The risk ratio for the primary outcome was calculated using the Mantel-Haenszel method. The secondary outcomes included 30-day mortality, length of hospital stay, ICU duration, mechanical ventilation duration, and occurrence of glucocorticoid-related adverse effects (e.g., infection and hyperglycemia). This meta-analysis was registered in PROSPERO: CRD42022345997. RESULTS: We included eight randomized controlled studies involving 8972 patients. For the entire adult population undergoing major surgery, intravenous glucocorticoids reduced the POD incidence (risk ratio = 0.704, 95% confidence interval, 0.519-0.955; P = 0.024). However, subgroups defined by type of surgery showed differential effects of glucocorticoids on POD. Intravenous glucocorticoids can not reduce POD incidence in adult patients undergoing cardiac surgery (risk ratio = 0.961, 95% confidence interval, 0.769-1.202; P = 0.728), with firm evidence from trial sequential analysis. However, in major non-cardiac surgery, perioperative intravenous glucocorticoid reduced the incidence of POD (risk ratio = 0.491, 95% confidence interval, 0.338-0.714; P < 0.001), which warrants further studies due to inconclusive evidence by trial sequence analysis. In addition, the use of glucocorticoids may reduce the mechanical ventilation time (weighted mean difference, -1.350; 95% confidence interval, -1.846 to -0.854; P < 0.001) and ICU duration (weighted mean difference = -7.866; 95% confidence interval, -15.620 to -0.112; P = 0.047). CONCLUSIONS: For the entire adult population undergoing major surgery, glucocorticoids reduced the POD incidence. However, the effects of glucocorticoids on POD appear to vary according to the type of surgery. In patients receiving major non-cardiac surgery, glucocorticoid may be an attractive drug in the prevention of POD, and further studies are needed to draw a definitive conclusion. In cardiac surgery, intravenous glucocorticoids have no such effect.