B cells enhance EphA2 chimeric antigen receptor T cells cytotoxicity against glioblastoma via improving persistence.

Chimeric antigen receptor (CAR) T cell therapy is a powerful adoptive immunotherapy against blood cancers, but the therapeutic effect was not efficient enough on solid tumors. B cells have been reported to play a critical role in regulating memory T differentiation and cytotoxic T development. However, as of yet the influence of such B cells on CAR T cells has not been discussed. In this study, using ephrin type-A receptor 2 (EphA2) specific CAR T cells, we cultured B cells successfully to stimulate CAR T cells in vitro, and investigated the cell differentiation and anti-tumor efficiency. We observed that EphA2-CAR T cells stimulated by B cells performed increased interferon γ (IFN γ) production and upregulated OX40 expression, as well as the enhanced anti-tumor activity and reduced PD-1 expression. The persistence of CAR T cells was enhanced after B cells stimulation for more than 7 days with the increased subset of central memory T cells (TCM). In addition, next generation sequencing was performed to explore the underlying mechanisms. The up-regulated genes clustered in, immune response activation, chemokine signaling pathway, calcium signaling pathway, cGMP-PKG signaling pathway and et al. which contributed to the upregulated anti-glioblastoma (GBM) activity of CAR T cells stimulated by B cell. Furthermore, MEF2C, CD40, SYK and TNFRSF13B were upregulated in CAR T cells after co-culturing with B cells. These genes functionally enriched in promoting lymphocytes proliferation and may contribute to the enhanced persistence of CAR T cells. In conclusion, these results indicated the critical role of B cells in prolonging CAR T cells longevity and enhancing anti-tumor activity, which paves the way for the therapeutic exploitation of EphA2-CAR T cells against GBM in the future.

Carrier-free cryptotanshinone-peptide conjugates self-assembled nanoparticles: An efficient and low-risk strategy for acne vulgaris.

Acne vulgaris ranks as the second most prevalent dermatological condition worldwide, and there are still insufficient safe and reliable drugs to treat it. Cryptotanshinone (CTS), a bioactive compound derived from traditional Chinese medicine Salvia miltiorrhiza, has shown promise for treating acne vulgaris due to its broad-spectrum antimicrobial and significant anti-inflammatory properties. Nevertheless, its local application is hindered by its low solubility and poor skin permeability. To overcome these challenges, a carrier-free pure drug self-assembled nanosystem is employed, which can specifically modify drug molecules based on the disease type and microenvironment, offering a potential for more effective treatment. We designed and synthesized three distinct structures of cationic CTS-peptide conjugates, creating self-assembled nanoparticles. This study has explored their self-assembly behavior, skin permeation, cellular uptake, and both in vitro and in vivo anti-acne effects. Molecular dynamics simulations revealed these nanoparticles form through intermolecular hydrogen bonding and π-π stacking interactions. Notably, self-assembled nanoparticles demonstrated enhanced bioavailability with higher skin permeation and cellular uptake rates. Furthermore, the nanoparticles exhibited superior anti-acne effects compared to the parent drug, attributed to heightened antimicrobial activity and significant downregulation of the MAPK/NF-κB pathway, leading to reduced expression of pro-inflammatory factors including TNF-α, IL-1ß and IL-8. In summary, the carrier-free self-assembled nanoparticles based on CTS-peptide conjugate effectively address the issue of poor skin bioavailability, offering a promising new approach for acne treatment.

Precision mapping of snail habitat in lake and marshland areas: Integrating environmental and textural indicators using Random Forest modeling.

Schistosomiasis japonica continues to pose a significant public health challenge in China, primarily due to the widespread distribution of Oncomelania hupensis, the sole intermediate host of Schistosoma. This study aims to address the constraints of existing remote sensing analyses for identifying snail habitats, which frequently neglect spatial scale and seasonal variations. To this end, we adopt a multi-source data-driven Random Forest approach that integrates bottomland and ground-surface texture data with traditional environmental variables, enhancing the accuracy of snail habitat assessments. We developed four distinct models for the lake and marshland areas of Guichi, China: a baseline model incorporating ground-surface texture, bottomland variables, and environmental variables; Model 1 with only environmental variables; Model 2 adding ground-surface texture and environmental variables; and Model 3 integrating bottomland with environmental variables. The baseline model outperformed the others, achieving a true skill statistic of 0.93, an accuracy of 0.97, a kappa statistic of 0.94, and an area under the curve of 0.99. Our analysis pinpointed critical high-risk snail habitats distributed in a belt-like pattern along major water bodies, near the Yangtze River, QiuPu River, and around Shengjin Lake, Jiuhua River, and Qingtong River. These insights can aid local health authorities in more efficiently allocating limited resources, developing effective snail surveillance and control strategies to combat schistosomiasis. Additionally, this approach can be adapted to localize other endemic hosts with similar ecological characteristics.

Macrophages regulate plaque progression in diabetic Apoe-/- mice dependent on Pi4p/Nlrp3 signaling pathway.

BACKGROUND AND AIMS: Atherosclerotic cardiovascular disease complicated by diabetes mellitus (DM) is the leading cause of death in diabetic patients, and it is strongly associated with macrophages and inflammasomes. It has been found that activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome is closely associated with phosphatidylinositol 4-phosphate (PI4P) on the trans-Golgi. However, how PI4P and NLRP3 regulate macrophage function and its role in diabetic atherosclerotic plaques is unclear. METHODS: The expression of Pi4p and Nlrp3-inflammasome-related proteins in atherosclerosis in apolipoprotein E-deficient (Apoe-/-) and Apoe-/- DM mice was investigated. Then, Pi4p levels were affected by shRNA-Pi4kb or cDNA-Sac1 plasmid to investigate the effects of changes in Pi4p-related metabolic enzymes on macrophage function. Finally, genetically modified macrophages were injected into diabetic Apoe-/- mice to explore the effects on atherosclerosis. RESULTS: DM promoted plaque progression in atherosclerotic mice and increased expression of Pi4p and Nlrp3 in plaques. In addition, impaired macrophage function induced by high glucose was reversed by transfected shRNA-Pi4kb or cDNA-Sac1 plasmid. Furthermore, decreased levels of Pi4p reduced plaque area in diabetic Apoe-/- mice. CONCLUSIONS: Our data suggests that Pi4p/Nlrp3 in macrophages play an important role in the exacerbation of atherosclerosis in diabetic mice. Pi4p-related metabolizing enzymes (PI4KB and SAC1) may be a potential therapeutic strategy for diabetic atherosclerosis, and macrophage therapy is also a potential treatment.

Development and Validation of a Predictive Model for Resistance to Platinum-Based Chemotherapy in Patients with Ovarian Cancer through Proteomic Analysis.

Platinum resistance in ovarian cancer poses a significant challenge, substantially impacting patient outcomes. Developing an accurate predictive model is crucial for improving clinical decision-making and guiding treatment strategies. Proteomic data from 217 high-grade serous ovarian cancer (HGSOC) biospecimens obtained from JHU, PNNL, and PTRC were used to construct a prediction model for identifying individuals who are resistant to platinum-based chemotherapy. A total of 6437 common proteins were detected across all data sets, with 26 proteins overlapping between the development cohorts JHU and PNNL. Using LASSO and logistic regression analysis, a six-protein model (P31323_PRKAR2B, Q13309_SKP2, Q14997_PSME4, Q6ZRP7_QSOX2, Q7LGA3_HS2ST1, and Q7Z2Z2_EFL1) was developed, which accurately predicted platinum resistance, with an AUC of 0.964 (95% CI, 0.929-0.999). Internal validation by resampling resulted in a C-index of 0.972 (95% CI 0.894-0.988). External validation performed on the PTRC cohort achieved an AUC of 0.855 (95% CI 0.748-0.963). Calibration curves showed good consistency, and DCA indicated superior clinical utility. The model also performed well in predicting PFS and OS at various time points. Based on these proteins, our predictive model can precisely predict platinum response and survival outcomes in HGSOC patients, which can assist clinicians in promptly identifying potentially platinum-resistant individuals.

ZCCHC8 p.P410A disrupts nucleocytoplasmic localization, promoting idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a special kind of chronic interstitial lung disease with insidious onset. Previous studies have revealed that mutations in ZCCHC8 may lead to IPF. The aim of this study is to explore the ZCCHC8 mutations in Chinese IPF patients. METHODS: Here, we enrolled 124 patients with interstitial lung disease from 2017 to 2023 in our hospital. Whole exome sequencing and Sanger sequencing were employed to explore the genetic lesions of these patients. RESULTS: Among these 124 patients, a novel mutation (NM_017612: c.1228 C > G/p.P410A) of Zinc Finger CCHC-Type Containing 8 (ZCCHC8)was identified in a family with IPF and chronic obstructive lung disease. As a component of the nuclear exosome-targeting complex that regulates the turnover of human telomerase RNA, ZCCHC8 mutations have been reported may lead to IPF in European population and American population. Functional study confirmed that the novel mutation can disrupt the nucleocytoplasmic localization of ZCCHC8, which further decreased the expression of DKC1 and RTEL1, and finally reduced the length of telomere and led to IPF and related disorders. CONCLUSIONS: We may first report the ZCCHC8 mutation in Asian population with IPF. Our study broadens the mutation, phenotype, and population spectrum of ZCCHC8 deficiency.

The clinical efficacy and safety of platelet-rich plasma on frozen shoulder: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To systematically review the clinical efficacy (pain, function, quality of life) and safety of platelet-rich plasma (PRP) in the treatment of frozen shoulder through meta-analysis, and provide evidence-based medical evidence for the effectiveness of PRP in the treatment of frozen shoulder. METHODS: A search was conducted on international databases (Pubmed, Web of science, Embase) and Chinese databases (CNKI, Wanfang, VIP) to search the clinical studies on the efficacy of platelet-rich plasma in treating frozen shoulder (adhesive capsulitis/periarthritis/50 shoulder) and their corresponding references published from inception until January 2024. Thoroughly excluded literature not meeting the predetermined inclusion criteria, extracted relevant data from the literature, and input it into RevMan5.4 for meta-analysis. RESULTS: This study ultimately included 14 RCTs, with a total of 1024 patients. The results showed that PRP has significant advantages compared with control groups in VAS (mean difference (MD) =-0.38, 95% confidence interval(CI)(-0.73, -0.03), P = 0.03), UCLA (MD = 3.31, 95% CI (1.02,5.60),P = 0.005), DASH (MD = -4.94,95% CI (-9.34, -0.53),P = 0.03), SPADI (SPADI Total: MD =-16.87, 95% CI (-22.84, -10.91), P < 0.00001; SPADI Pain: MD =-5.38, 95% CI (-7.80, -2.97), P < 0.0001; SPADI Disability: MD =-11.00, 95% CI (-13.61,-8.39), P < 0.00001), and the active and passive Range of Motion (active flexion: MD = 12.70, 95% CI (7.44, 17.95), P < 0.00001; passive flexion: MD = 9.47, 95% CI(3.80, 15.14), P = 0.001; active extension: MD = 3.45, 95% CI(2.39, 4.50), P < 0.00001; active abduction: MD = 13.54, 95% CI(8.42, 18.67), P < 0.00001; passive abduction: MD = 14.26, 95% CI (5.97, 22.56), P = 0.0008; active internal rotation: MD = 5.16, 95% CI (1.84, 8.48), P = 0.002; passive internal rotation: MD = 3.65, 95% CI(1.15, 6.15), P = 0.004; active external rotation: MD = 10.50, 95% CI(5.47, 15.53), P < 0.0001; passive external rotation: MD = 6.00, 95% CI (1.82, 10.19), P = 0.005) except passive extension (MD = 2.25, 95% CI (-0.77, 5.28), P = 0.14). In terms of safety, most studies reported no adverse effects, and only one study reported common complications of joint puncture such as swelling and pain after treatment in both PRP and control groups. Previous studies have shown a risk of osteonecrosis caused by corticosteroids. Therefore, the safety of PRP treatment is more reliable. CONCLUSION: The results showed that PRP was more durable and safer than corticosteroids and other control groups in the treatment of frozen shoulder. STUDY DESIGN: Systematic review. TRIAL REGISTRATION: PROSPERO CRD42022359444, date of registration: 22-09-2022.

Structural Diversity of 2D Molecular Self-Assemblies Arising from Carboxyl Groups Attached to a Molecule: An STM Study at the Liquid-Solid Interface.

Understanding the molecular self-assembly behavior, especially at the microscopic level, sheds light on the rational design of artificial supramolecular systems at surfaces. In this work, scanning tunneling microscopy (STM) and force field simulations were utilized to explore two molecular systems where two and four carboxyl groups are symmetrically modified onto a skeleton. The two target molecules are 4,4'-(ethyne-1,2-diyl) dibenzoic acid (EBA) and 1,1'-ethynebenzene-3,3',5,5,'-tetracarboxylic acid (TCA). The former molecular assembly led to robust close packing, whereas the latter resulted in low-density arrangements that present significant adaption, namely, undergoing phase transformations upon external stimulations, e.g., sensitive to STM-polarity switching and guest molecule incorporations.

Rapidly progressive malignant glomus tumor of the breast: a case report and review of the literature.

The glomus tumor is a rare neoplasm that is typically found subungually in the extremities and functions as a specialized neurovascular organ. An extremely rare site for glomus tumors is the breast, with only a few reported cases. Breast glomus tumors present with three typical clinical signs: dull pain, focal tenderness, and cold sensitivity. Less than 10% of all glomus tumors are malignant. We herein present a case of a malignant glomus tumor originating in the breast. Distant metastasis was ruled out, and the tumor was completely resected. However, the patient unexpectedly developed rapid systemic metastasis, detected 5 weeks after tumor removal. Despite the administration of analgesics and targeted therapy, the patient died 1 month later. When treating patients with undiagnosed breast tumors, clinicians should pay attention to unexplained and repeatedly reported symptoms and consider the possibility of a rare disease. Our literature search revealed no cases of malignant glomus tumors originating in the breast, making this case the first of its kind.

National age-specific mortality trends for cervical and breast cancers in urban-rural areas of China from 2009 to 2021: a population-based analysis.

BACKGROUND: Cervical and breast cancers are among the top 4 leading causes of cancer-related mortality in women. This study aimed to examine age-specific temporal trends in mortality for cervical and breast cancers in urban and rural areas of China from 2009 to 2021. METHODS: Age-specific mortality data for cervical and breast cancers among Chinese women aged 20-84 years were obtained from China's National Disease Surveillance Points system spanning the years 2009 to 2021. Negative binomial regression models were utilized to assess urban-rural differences in mortality rate ratios, while Joinpoint models with estimated average annual percent changes (AAPC) and slopes were employed to compare temporal trends and the acceleration of mortality rates within different age groups. RESULTS: From 2009 to 2021, there was a relative increase in age-specific mortality associated with the two cancers observed in rural areas compared with urban areas. A rising trend in the screening age of 35-64 [AAPC: 4.0%, 95% confidence interval (CI) 0.5-7.6%, P = 0.026] for cervical cancer was noted in rural areas, while a stable trend (AAPC: - 0.7%, 95% CI - 5.8 to 4.6%, P = 0.78) was observed in urban areas. As for breast cancer, a stable trend (AAPC: 0.3%, 95% CI - 0.3 to 0.9%, P = 0.28) was observed in rural areas compared to a decreasing trend (AAPC: - 2.7%, 95% CI - 4.6 to - 0.7%, P = 0.007) in urban areas. Urban-rural differences in mortality rates increased over time for cervical cancer but decreased for breast cancer. Mortality trends for both cervical and breast cancers showed an increase with age across 4 segments, with the most significant surge in mortality observed among the 35-54 age group across urban and rural areas, periods, and regions in China. CONCLUSIONS: Special attention should be given to women aged 35-54 years due to mortality trends and rural-urban disparities. Focusing on vulnerable age groups and addressing rural-urban differences in the delivery of cancer control programs can enhance resource efficiency and promote health equity.

Study on chemical characterization and sleep-improvement function of Prunella vulgaris L. based on the functional components.

Prunella vulgaris L. (P. vulgaris) has great application value and development prospects in improving sleep. In this study, we continued to evaluate the sleep-improvement function and mechanism of P. vulgaris from both chemical characterization and function based on sleep-improvement functional ingredients, rosmarinic acid and salviaflaside, screened out in the previous stage as the index components. The chemical constituents of P. vulgaris and its phenolic acid fraction were characterized by the UPLC-MSn technology. The quality of the sleep-improvement phenolic acid fraction of P. vulgaris was scientifically evaluated by fingerprints combined with quantitative analysis of rosmarinic acid and salviaflaside. The function of phenolic acid parts of P. vulgaris in improving sleep was verified by different insomnia models including the PCPA-induced insomnia model and surface platform sleep deprivation model. HE staining was used to observe the effect of P. vulgaris on the morphology of nerve cells in different brain regions. In vivo experiments and molecular docking explored the sedative-hypnotic effects of functional ingredients of P. vulgaris. All these results investigated the material basis and mechanism of P. vulgaris to improve sleep from multiple perspectives, which contribute to providing a basis for the development of functional food to improve sleep.

The negative association between the docosapentaenoic acid intake and the incidence of AMD based on NHANES 2005-2008.

Introduction: Age-related macular degeneration (AMD) is an ophthalmic disease that causes visual impairment and is one of the leading causes of blindness in the elderly. Fatty acids are essential nutrients required by the body and play a cornerstone role in the life activities of the body. Many studies have reported that fatty acids are involved in the development of AMD. To confirm this association, we conducted the present study. Methods: We analyzed the association between all fatty acid intake and AMD using National Health and Nutrition Examination Survey (NHANES) data from 2005-2008. Quantile regression was performed to assess the effect of fatty acids on AMD at different intake levels. Results: After adjusting for covariates, only saturated fatty acids showed no significant difference between AMD patients and non-AMD patients (23.64 g vs. 26.03 g, p = 0.052). Total fat (70.88 g vs. 78.86 g, p = 0.024), monounsaturated fatty acids (25.87 g vs. 28.95 g, p = 0.019), polyunsaturated fatty acids (15.10 g vs. 17.07 g, p = 0.017) showed significant differences between the two groups. When AMD was considered as an outcome, the association between AMD and docosaentaenoic acid (DPA) was negative in the multivariate logic model (model 1: OR = <0.001, 95% CI = <0.001 ~ 0.734; model 2: OR = <0.001, 95% CI = <0.001 ~ 0.002; model 3: OR = <0.001, 95% CI = <0.001 ~ 0.002). In the quantile regression, DPA was shown to be negatively associated with the presence of AMD only in the fourth quartile in model 2 and model 3 (model 2: OR = <0.001, 95% CI = <0.001 ~ 0.927; model 3: OR = <0.001, 95% CI = <0.001 ~ 0.775). Discussion: Therefore, based on above results, we concluded that DPA intake could prevent the development of AMD.

[Retracted] SFRP2 modulates non­small cell lung cancer A549 cell apoptosis and metastasis by regulating mitochondrial fission via Wnt pathways.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the JC1­stained cellular images shown in Fig. 2C on p. 1928 were strikingly similar to data that had already been published in different form in another article written by different authors at different research institutes [Yao S and Yan W: Overexpression of Mst1 reduces gastric cancer cell viability by repressing the AMPK­Sirt3 pathway and activating mitochondrial fission. Onco Targets Ther 11: 8465­8479, 2019]. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 20: 1925­1932, 2019; DOI: 10.3892/mmr.2019.10393].

Deciphering the role of HLF in idiopathic orbital inflammation: integrative analysis via bioinformatics and machine learning techniques.

Idiopathic orbital inflammation, formerly known as NSOI (nonspecific orbital inflammation), is characterized as a spectrum disorder distinguished by the polymorphic infiltration of lymphoid tissue, presenting a complex and poorly understood etiology. Recent advancements have shed light on the HLF (Human lactoferrin), proposing its critical involvement in the regulation of hematopoiesis and the maintenance of innate mucosal immunity. This revelation has generated significant interest in exploring HLF's utility as a biomarker for NSOI, despite the existing gaps in our understanding of its biosynthetic pathways and operational mechanisms. Intersecting multi-omic datasets-specifically, common differentially expressed genes between GSE58331 and GSE105149 from the Gene Expression Omnibus and immune-related gene compendiums from the ImmPort database-we employed sophisticated analytical methodologies, including Lasso regression and support vector machine-recursive feature elimination, to identify HLF. Gene set enrichment analysis and gene set variation analysis disclosed significant immune pathway enrichment within gene sets linked to HLF. The intricate relationship between HLF expression and immunological processes was further dissected through the utilization of CIBERSORT and ESTIMATE algorithms, which assess characteristics of the immune microenvironment, highlighting a noteworthy association between increased HLF expression and enhanced immune cell infiltration. The expression levels of HLF were corroborated using data from the GSE58331 dataset, reinforcing the validity of our findings. Analysis of 218 HLF-related differentially expressed genes revealed statistically significant discrepancies. Fifteen hub genes were distilled using LASSO and SVM-RFE algorithms. Biological functions connected with HLF, such as leukocyte migration, ossification, and the negative regulation of immune processes, were illuminated. Immune cell analysis depicted a positive correlation between HLF and various cells, including resting mast cells, activated NK cells, plasma cells, and CD8 T cells. Conversely, a negative association was observed with gamma delta T cells, naive B cells, M0 and M1 macrophages, and activated mast cells. Diagnostic assessments of HLF in distinguishing NSOI showed promising accuracy. Our investigation delineates HLF as intricately associated with NSOI, casting light on novel biomarkers for diagnosis and progression monitoring of this perplexing condition.

Chicken Meal as a Fishmeal Substitute: Effects on Growth, Antioxidants, and Digestive Enzymes in Lithobates catesbeianus.

In pursuit of sustainable aquaculture, this study was performed to evaluate chicken meal as a substitute for fishmeal in bullfrog diets. Three experimental groups were established: a control group (FM) with 20% fishmeal, a CM50 group with 50% replacement (10% fishmeal), and a CM100 group with 100% replacement (0 fishmeal). Bullfrogs were fed for 56 days. The CM50 group exhibited significant increases in total weight gain and survival rate and a notable decrease in feed coefficient (p < 0.05). However, the CM100 group showed contrary effects. Increasing chicken meal substitution correlated with decreased amino acid content in muscle. Notably, the CM50 group demonstrated enhanced activities of antioxidant enzymes (CAT, T-AOC) and elevated gene expression levels (cat, sod, gst, etc.) in muscle and the intestine (p < 0.05), improved intestinal morphology, enhanced digestive enzyme activities (amylase, lipase), and reduced expression of inflammatory factors (il-1ß, il-8, il-17, etc.). Conversely, the CM100 group's indicators regressed to levels similar to or worse than those of the FM group. Therefore, a 50% substitution of fishmeal with chicken meal effectively promoted bullfrog survival, protected the intestines, and enhanced antioxidant capacity, supporting its potential as a fishmeal alternative. However, the adverse outcomes of the CM100 strategy, including growth retardation and reduced amino acid content in muscle, indicate that complete replacement is unsuitable.

Mycoplasma genitalium membrane lipoprotein induces GAPDH malonylation in urethral epithelial cells to regulate cytokine response.

Membrane lipoproteins serve as primary pro-inflammatory virulence factors in Mycoplasma genitalium. Membrane lipoproteins primarily induce inflammatory responses by activating Toll-like Receptor 2 (TLR2); however, the role of the metabolic status of urethral epithelial cells in inflammatory response remains unclear. In this study, we found that treatment of uroepithelial cell lines with M. genitalium membrane lipoprotein induced metabolic reprogramming, characterized by increased aerobic glycolysis, decreased oxidative phosphorylation, and increased production of the metabolic intermediates acetyl-CoA and malonyl-CoA. The metabolic shift induced by membrane lipoproteins is reversible upon blocking MyD88 and TRAM. Malonyl-CoA induces malonylation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and malonylated GAPDH could dissociate from the 3' untranslated region of TNF-α and IFN-γ mRNA. This dissociation greatly reduces the inhibitory effect on the translation of TNF-α and IFN-γ mRNA, thus achieving fine-tuning control over cytokine secretion. These findings suggest that GAPDH malonylation following M. genitalium infection is an important inflammatory signal that plays a crucial role in urogenital inflammatory diseases.

The treatment landscape of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) tumors are biologically aggressive breast cancer. On the molecular level, TNBC is a highly heterogeneous disease; more biotechnologies are gradually being used to advance the understanding of TNBC subtypes and help establish more targeted therapies. Multiple TNBC target-related agents are already approved by the Food and Drug Administration for clinical use, including PI3K/AKT/mTOR inhibitors, PRAP inhibitors, and antibody-drug conjugates. Some innovative approaches, like peptide strategies, also promise to treat TNBC. Currently, the interplay between TNBC tumors and their tumor microenvironment provides a promising prospect for improving the efficacy of immunotherapy. In this review, we summarize the prevalent TNBC subtype methodologies, discuss the evolving therapeutic strategies, and propose new therapeutic possibilities based on existing foundational theories, with the attempt to serve as a reference to further advance tailoring treatment of TNBC.

The mitochondrial division inhibitor Mdivi-1 protected organ function and extended the treatment window in rats with uncontrolled haemorrhagic shock.

AIM: To elucidate whether the application of the mitochondrial division inhibitor Mdivi-1 can protect organ function and prolong the treatment window for traumatic hemorrhagic shock. METHODS: Before definitive haemostasis treatment, Mdivi-1 (0.25 mg/kg, 0.5 mg/kg and 1 mg/kg) was administered to uncontrolled haemorrhagic shock (UHS) model rats. Lactate Ringer's solution plus hydroxyethyl starch (130/0.4) was used as a control. The effects of Mdivi-1 on blood loss, fluid demand, survival time, vital organ function, myocardial mitochondrial structure, and mitochondrial function of the heart, liver, kidney and intestine, and oxidative stress at 1 hour after hypotensive resuscitation (50-60 mmHg) were investigated. In addition, we investigated the effect of varying doses of Mdivi-1 on the maintenance time of hypotensive resuscitation without definitive haemostasis and the beneficial effect of Mdivi-1 after prolonging the duration of hypotensive resuscitation to 2 hours. RESULTS: Compared to conventional resuscitative fluid, Mdivi-1 significantly reduced blood loss and fluid demand, improved important organ functions during hypotensive resuscitation, improved animal survival and reduced the incidence of early death. Mdivi-1 significantly alleviated oxidative stress injury, reduced mitochondrial damage and restored myocardial mitochondrial structure and mitochondrial function of the heart, liver, kidney and intestine. In addition, Mdivi-1 increased the maintenance time of hypotensive resuscitation and improved rat survival after the duration of hypotensive resuscitation was prolonged to 2 h. CONCLUSIONS: Mdivi-1 significantly prolonged the treatment window for traumatic hemorrhagic shock to 2 hours in UHS model rats. The underlying mechanism may be that Mdivi-1 inhibits excessive mitochondrial fission and oxidative stress and improves the structure and function of mitochondria.

A Low-Frequency Oscillation Suppression Method for Regional Interconnected Power Systems with High-Permeability Wind Power.

With the integration of large-scale wind power into the power grid, the impact on system stability, especially the issue of low-frequency oscillations caused by small disturbances, is becoming increasingly prominent. Therefore, this paper proposes a damping quantitative analysis method for regional interconnected power systems incorporating large-scale wind power. Using the cross-entropy particle swarm optimization (CE-PSO) algorithm, the control parameters of wind turbines are optimized to suppress low-frequency oscillations in interconnected systems. The method begins with the state equation of the interconnected power system in two regions; it deduces the characteristic polynomial of the interconnected system, including wind farms, and takes into account the influence of wind power integration on the electrical connectivity of the system. Subsequently, the influence of wind turbine control parameters on the system is quantified, and a quantitative analysis model of the impact of wind power integration on system damping characteristics is constructed. Based on this, an optimization model for wind turbine control parameters is established, and the CE-PSO algorithm is utilized to achieve suppression of low-frequency oscillations in interconnected power grids with wind power integration. Finally, the accuracy and effectiveness of the proposed method are verified through a typical electromagnetic transient simulation model of the two-region interconnected power system.

Endoplasmic Reticulum Membrane Protein Complex Regulates Cancer Stem Cells and is Associated with Sorafenib Resistance in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, underscoring the need for novel therapeutic targets. This study aimed to elucidate the role of endoplasmic reticulum membrane protein complex subunit 1 (EMC1) in HCC progression and its therapeutic potential. Methods: Publicly available sequencing data and biopsy specimens were analyzed to assess EMC's clinical value and functions in HCC. In vitro experiments validated EMC functions, and multiplex immunofluorescence analysis examined EMC-associated sorafenib resistance mechanisms. EMC1 expression was knocked down in HCC cell lines, followed by cell viability, wound healing, and transwell migration assays. Tumor growth and response to sorafenib treatment were evaluated in mouse models. Metabolomic analysis assessed changes in the TCA cycle. Results: EMC genes were aberrantly expressed in HCC, and high EMC1 expression correlated with poorer survival rates. EMC1 disruption enhanced HCC cells' sensitivity to sorafenib, reducing cell viability, increasing apoptosis, and decreasing tumor size and weight. EMC1 maintained cancer cell stemness and promoted M2 macrophage infiltration. Metabolomic analysis revealed significant changes in the TCA cycle, indicating EMC1's role in HCC metabolic reprogramming. Importantly, EMC1 is highly associated with sorafenib resistance, potentially linked to CTNNB1 mutation or activation. Conclusion: EMC1 plays a critical role in regulating the sorafenib resistance in HCC. Targeting EMC1 may improve HCC treatment efficacy.