SMAD4 depletion contributes to endocrine resistance by integrating ER and ERBB signaling in HR + HER2- breast cancer.

Endocrine resistance poses a significant clinical challenge for patients with hormone receptor-positive and human epithelial growth factor receptor 2-negative (HR + HER2-) breast cancer. Dysregulation of estrogen receptor (ER) and ERBB signaling pathways is implicated in resistance development; however, the integration of these pathways remains unclear. While SMAD4 is known to play diverse roles in tumorigenesis, its involvement in endocrine resistance is poorly understood. Here, we investigate the role of SMAD4 in acquired endocrine resistance in HR + HER2- breast cancer. Genome-wide CRISPR screening identifies SMAD4 as a regulator of 4-hydroxytamoxifen (OHT) sensitivity in T47D cells. Clinical data analysis reveals downregulated SMAD4 expression in breast cancer tissues, correlating with poor prognosis. Following endocrine therapy, SMAD4 expression is further suppressed. Functional studies demonstrate that SMAD4 depletion induces endocrine resistance in vitro and in vivo by enhancing ER and ERBB signaling. Concomitant inhibition of ER and ERBB signaling leads to aberrant autophagy activation. Simultaneous inhibition of ER, ERBB, and autophagy pathways synergistically impacts SMAD4-depleted cells. Our findings unveil a mechanism whereby endocrine therapy-induced SMAD4 downregulation drives acquired resistance by integrating ER and ERBB signaling and suggest a rational treatment strategy for endocrine-resistant HR + HER2- breast cancer patients.

Iron deficiency anemia and platelet dysfunction: A comprehensive analysis of the underlying mechanisms.

AIMS: This research aimed to study the changes in platelet function and their underlying mechanisms in iron deficiency anemia. MAIN METHODS: Initially, we evaluated platelet function in an IDA mice model. Due to the inability to accurately reduce intracellular Fe2+ concentrations, we investigated the impact of Fe2+ on platelet function by introducing varying concentrations of Fe2+. To probe the underlying mechanism, we simultaneously examined the dynamics of calcium in the cytosol, and integrin αIIbß3 activation in Fe2+-treated platelets. Ferroptosis inhibitors Lip-1 and Fer-1 were applied to determine whether ferroptosis was involved in this process. KEY FINDINGS: Our study revealed that platelet function was suppressed in IDA mice. Fe2+ concentration-dependently facilitated platelet activation and function in vitro. Mechanistically, Fe2+ promoted calcium mobilization, integrin αIIbß3 activation, and its downstream outside-in signaling. Additionally, we also demonstrated that ferroptosis might play a role in this process. SIGNIFICANCE: Our data suggest an association between iron and platelet activation, with iron deficiency resulting in impaired platelet function, while high concentrations of Fe2+ contribute to platelet activation and function by promoting calcium mobilization, αIIbß3 activation, and ferroptosis.

Association of depressive symptoms and sleep disturbances with survival among US adult cancer survivors.

BACKGROUND: Depression and sleep disturbances are associated with increased risks of various diseases and mortality, but their impacts on mortality in cancer survivors remain unclear. The objective of this study was to characterize the independent and joint associations of depressive symptoms and sleep disturbances with mortality outcomes in cancer survivors. METHODS: This population-based prospective cohort study included cancer survivors aged ≥ 20 years (n = 2947; weighted population, 21,003,811) from the National Health and Nutrition Examination Survey (NHANES) 2007-2018 cycles. Depressive symptoms and sleep disturbances were self-reported. Depressive symptoms were assessed using the Patient Health Questionnaire 9 (PHQ-9). Death outcomes were determined by correlation with National Death Index records through December 31, 2019. Primary outcomes included all-cause, cancer-specific, and noncancer mortality. RESULTS: During the median follow-up of 69 months (interquartile range, 37-109 months), 686 deaths occurred: 240 participants died from cancer, 146 from heart disease, and 300 from other causes. Separate analyses revealed that compared with a PHQ-9 score (0-4), a PHQ-9 score (5-9) was associated with a greater risk of all-cause mortality (hazard ratio [HR], 1.28; 95% CI, 1.03-1.59), and a PHQ-9 score (≥ 10) was associated with greater risk of all-cause mortality (HR, 1.37; 95% CI, 1.04-1.80) and noncancer mortality (HR, 1.45; 95% CI, 1.01-2.10). Single sleep disturbances were not associated with mortality risk. In joint analyses, the combination of a PHQ-9 score ≥ 5 and no sleep disturbances, but not sleep disturbances, was associated with increased risks of all-cause mortality, cancer-specific mortality, and noncancer mortality. Specifically, compared with individuals with a PHQ-9 score of 0-4 and no sleep disturbances, HRs for all-cause mortality and noncancer mortality in individuals with a PHQ-9 score of 5-9 and no sleep disturbances were 1.72 (1.21-2.44) and 1.69 (1.10-2.61), respectively, and 2.61 (1.43-4.78) and 2.77 (1.27-6.07), respectively, in individuals with a PHQ-9 score ≥ 10 and no sleep disturbances; HRs for cancer-specific mortality in individuals with a PHQ-9 score ≥ 5 and no sleep disturbances were 1.95 (1.16-3.27). CONCLUSIONS: Depressive symptoms were linked to a high risk of mortality in cancer survivors. The combination of a PHQ-9 score (≥ 5) and an absence of self-perceived sleep disturbances was associated with greater all-cause mortality, cancer-specific mortality, and noncancer mortality risks, particularly in individuals with a PHQ-9 score (≥ 10).

UTRN as a potential biomarker in breast cancer: a comprehensive bioinformatics and in vitro study.

Utrophin (UTRN), known as a tumor suppressor, potentially regulates tumor development and the immune microenvironment. However, its impact on breast cancer's development and treatment remains unstudied. We conducted a thorough examination of UTRN using both bioinformatic and in vitro experiments in this study. We discovered UTRN expression decreased in breast cancer compared to standard samples. High UTRN expression correlated with better prognosis. Drug sensitivity tests and RT-qPCR assays revealed UTRN's pivotal role in tamoxifen resistance. Furthermore, the Kruskal-Wallis rank test indicated UTRN's potential as a valuable diagnostic biomarker for breast cancer and its utility in detecting T stage of breast cancer. Additionally, our results demonstrated UTRN's close association with immune cells, inhibitors, stimulators, receptors, and chemokines in breast cancer (BRCA). This research provides a novel perspective on UTRN's role in breast cancer's prognostic and therapeutic value. Low UTRN expression may contribute to tamoxifen resistance and a poor prognosis. Specifically, UTRN can improve clinical decision-making and raise the diagnosis accuracy of breast cancer.

RVX-208, an inducer of Apolipoprotein A-I, inhibits the particle production of hepatitis B virus through activation of cGAS-STING pathway.

BACKGROUND: Previously, we have demonstrated that Apolipoprotein A-I (ApoA-I) could inhibit the secretion of Hepatitis B virus (HBV), suggesting that stimulation of ApoA-I may block particle production. In the present study, we evaluated the anti-HBV effect of RVX-208, a small-molecule stimulator of ApoA-I gene expression. METHODS: RVX-208 was used to treat HepG2.2.15 cell, a HepG2 derived cell line stably producing HBV virus. Real-time PCR was performed to examine the HBV DNA levels. Magnetic particles, which were coated with anti-HBS or anti-HBE antibody, were used to examine the HBsAg and HBeAg levels in the supernatant of cultured HepG2.2.15 cells in combination with the enzyme conjugates that were prepared with horseradish peroxidase labelled anti-HBS or anti-HBE antibody in a double antibody sandwich manner. RNA-seq, immunoblots and real-time PCR were used to analyze the functional mechanism of RVX-208. RESULTS: RVX-208 could elevate the ApoA-I protein levels in HepG2.2.15 cells. In the meantime, RVX-208 significantly repressed HBV DNA, HBsAg and HBeAg levels in the supernatants of HepG2.2.15 cells. RNA-seq data revealed that RVX-208 treatment not only affected the cholesterol metabolism, which is closely related to ApoA-I, but also regulated signalling pathways that are associated with antiviral immune response. Moreover, mechanistic studies demonstrated that RVX-208 could activate cGAS-STING pathway and upregulate the transcription of a series of interferons, pro-inflammatory cytokines and chemokines with antiviral potential that are at the downstream of cGAS-STING pathway. CONCLUSION: Our study demonstrated that RVX-208, an inducer of ApoA-I, could suppress HBV particle production through activation of cGAS-STING pathway.

[Spatio-temporal Change in City-level Greenhouse Gas Emissions from Municipal Solid Waste Sector in China During the Last Decade and Its Potential Mitigation].

The waste sector is a significant source of greenhouse gas(GHG) emissions and clarifying its emission trends and characteristics is the premise for formulating GHG emission reduction strategies. Using the IPCC inventory model, the GHG emissions from the municipal solid waste(MSW) sector in China during 2010 to 2020 were estimated. The results showed that GHG emissions increased from 42.5 Mt in 2010 to 75.3 Mt in 2019, then decreased to 72.1 Mt in 2020. MSW landfills were the main source of GHG emissions. Further, with the increase in the proportion of waste incineration, the proportion of GHG incineration increased rapidly from 16.5% in 2010 to 60.1% in 2020. In terms of regional distribution, East and South China were the regions with the highest emissions, and Guangdong, Shandong, Jiangsu, and Zhejiang were the provinces with the largest GHG emissions. Implementing MSW classification, changing the MSW disposal modes from landfilling to incineration, improving the LFG collection efficiency of landfills, and using biological functional materials as the cover soil to strengthen the methane oxidation efficiency are the main measures to achieve GHG emission reduction in waste sectors.

Metal-organic-framework-based pyroptosis nanotuner with long blood circulation for augmented chemotherapy.

Pyroptosis is a proinflammatory form of cell death mediated by members of the gasdermin family, and is a powerful tool against cancer. Herein, a pH-responsive doxorubicin (DOX)-encapsulating zeolitic imidazolate framework-8 (ZIF-8) nanoparticle coated with a carboxybetaine-based zwitterionic polymer (DOX@ZIF-8@PCBMA) was prepared. Furthermore, decitabine (DAC) was loaded to obtain a pyroptosis nanotuner (DOX@ZIF-8@PCBMA-DAC). This nanotuner displayed extended blood circulation and enhanced tumor accumulation. In addition, the ZIF-8 structure and disulfide-crosslinked PCBMA coating endowed DOX@ZIF-8@PCBMA-DAC with acidic-pH- and glutathione-responsive degradation. The nanotuner could robustly activate caspase-3 to induce gasdermin E (GSDME)-dependent pyroptosis via the sustained release of DAC and DOX, contributing to excellent tumor suppression with negligible side effects, which may provide novel insights into traditional chemotherapy.

FGF10 mitigates doxorubicin-induced myocardial toxicity in mice via activation of FGFR2b/PHLDA1/AKT axis.

Doxorubicin is a common chemotherapeutic agent in clinic, but myocardial toxicity limits its use. Fibroblast growth factor (FGF) 10, a multifunctional paracrine growth factor, plays diverse roles in embryonic and postnatal heart development as well as in cardiac regeneration and repair. In this study we investigated the role of FGF10 as a potential modulator of doxorubicin-induced cardiac cytotoxicity and the underlying molecular mechanisms. Fgf10+/- mice and an inducible dominant negative FGFR2b transgenic mouse model (Rosa26rtTA; tet(O)sFgfr2b) were used to determine the effect of Fgf10 hypomorph or blocking of endogenous FGFR2b ligands activity on doxorubicin-induced myocardial injury. Acute myocardial injury was induced by a single injection of doxorubicin (25 mg/kg, i.p.). Then cardiac function was evaluated using echocardiography, and DNA damage, oxidative stress and apoptosis in cardiac tissue were assessed. We showed that doxorubicin treatment markedly decreased the expression of FGFR2b ligands including FGF10 in cardiac tissue of wild type mice, whereas Fgf10+/- mice exhibited a greater degree of oxidative stress, DNA damage and apoptosis as compared with the Fgf10+/+ control. Pre-treatment with recombinant FGF10 protein significantly attenuated doxorubicin-induced oxidative stress, DNA damage and apoptosis both in doxorubicin-treated mice and in doxorubicin-treated HL-1 cells and NRCMs. We demonstrated that FGF10 protected against doxorubicin-induced myocardial toxicity via activation of FGFR2/Pleckstrin homology-like domain family A member 1 (PHLDA1)/Akt axis. Overall, our results unveil a potent protective effect of FGF10 against doxorubicin-induced myocardial injury and identify FGFR2b/PHLDA1/Akt axis as a potential therapeutic target for patients receiving doxorubicin treatment.

Targeted delivery of RNAi to cancer cells using RNA-ligand displaying exosome.

Exosome is an excellent vesicle for in vivo delivery of therapeutics, including RNAi and chemical drugs. The extremely high efficiency in cancer regression can partly be attributed to its fusion mechanism in delivering therapeutics to cytosol without endosome trapping. However, being composed of a lipid-bilayer membrane without specific recognition capacity for aimed-cells, the entry into nonspecific cells can lead to potential side-effects and toxicity. Applying engineering approaches for targeting-capacity to deliver therapeutics to specific cells is desirable. Techniques with chemical modification in vitro and genetic engineering in cells have been reported to decorate exosomes with targeting ligands. RNA nanoparticles have been used to harbor tumor-specific ligands displayed on exosome surface. The negative charge reduces nonspecific binding to vital cells with negatively charged lipid-membrane due to the electrostatic repulsion, thus lowering the side-effect and toxicity. In this review, we focus on the uniqueness of RNA nanoparticles for exosome surface display of chemical ligands, small peptides or RNA aptamers, for specific cancer targeting to deliver anticancer therapeutics, highlighting recent advances in targeted delivery of siRNA and miRNA that overcomes the previous RNAi delivery roadblocks. Proper understanding of exosome engineering with RNA nanotechnology promises efficient therapies for a wide range of cancer subtypes.

Ligand-displaying-exosomes using RNA nanotechnology for targeted delivery of multi-specific drugs for liver cancer regression.

Liver cancer such as hepatocellular carcinoma (HCC) poorly responds to chemotherapeutics as there are no effective means to deliver the drugs to liver cancer. Here we report GalNAc decorated exosomes as cargo for targeted delivery of Paclitaxel (PTX) and miR122 to liver tumors as an effective means to inhibit the HCC. Exosomes (Exos) are nanosized extracellular vesicles that deliver a payload to cancer cells effectively. GalNAc provides Exos targeting ability by binding to the asialoglycoprotein-receptor (ASGP-R) overexpressed on the liver cancer cell surface. A 4-way junction (4WJ) RNA nanoparticle was constructed to harbor 24 copies of hydrophobic PTX and 1 copy of miR122. The 4WJ RNA-PTX complex was loaded into the Exos, and its surface was decorated with GalNAc using RNA nanotechnology to obtain specific targeting. The multi-specific Exos selectively bind and efficiently delivered the payload into the liver cancer cells and exhibited the highest cancer cell inhibition due to the multi-specific effect of miR122, PTX, GalNAc, and Exos. The same was reflected in mice xenograft studies, the liver cancer was efficiently inhibited after systemic injection of the multi-specific Exos. The required effective dose of chemical drugs carried by Exos was significantly reduced, indicating high efficiency and low toxicity. The multi-specific strategy demonstrates that Exos can serve as a natural cargo vehicle for the targeted delivery of anticancer therapeutics to treat difficult-to-treat cancers.

Organoids from patient biopsy samples can predict the response of BC patients to neoadjuvant chemotherapy.

PROPOSE: Neoadjuvant chemotherapy has been widely used in locally advanced and inflammatory breast cancer. Generally, complete pathological response after neoadjuvant chemotherapy treatment predicts survival. Studies have shown that patient-derived organoids can be used in cancer research and drug development. Therefore, we aimed to generate a living organoid biobank from biopsy samples to predict the response of patients to neoadjuvant chemotherapy. METHOD: We generated a living organoid biobank from locally advanced breast cancer patients receiving neoadjuvant chemotherapy. When the patient received neoadjuvant chemotherapy, the organoids were treated with similar drugs, thereby simulating the situation of the patient receiving treatment. RESULT: We successfully constructed organoids from breast cancer biopsies, demonstrating that organoids can be generated from a small sample of tissue. The phenotype of breast cancer organoid often agreed with the original breast cancer according to the blinded histopathological analysis of H&E stain tissue and organoid sections. In addition, our data confirm that the patient's response to chemotherapy closely matches the organoids' response to drugs. CONCLUSION: Our data indicate that patient-derived organoids can be used to predict the clinical response of breast cancer patients to neoadjuvant chemotherapy in vitro and to screen drugs that have different effects on different patients. Key messageComplete pathological response (pCR) after adjuvant chemotherapy can predict, survival, therefore, predicting patient response to neoadjuvant chemotherapy is critical.Patient-derived organoids (PDOs) matched the original tumour in terms of histopathology, hormone receptor levels and HER2 receptor status.Patient-derived organoids can predict the responsiveness of patient to neoadjuvant chemotherapy.

MED16 Promotes Tumour Progression and Tamoxifen Sensitivity by Modulating Autophagy through the mTOR Signalling Pathway in ER-Positive Breast Cancer.

Recent studies have shown that the mediator complex (MED) plays a vital role in tumorigenesis and development, but the role of MED16 (mediator complex subunit 16) in breast cancer (BC) is not clear. Increasing evidence has shown that the mTOR pathway is important for tumour progression and therapy. In this study, we demonstrated that the mTOR signalling pathway is regulated by the expression level of MED16 in ER+ breast cancer. With the analysis of bioinformatics data and clinical specimens, we revealed an elevated expression of MED16 in luminal subtype tumours. We found that MED16 knockdown significantly inhibited cell proliferation and promoted G1 phase cell cycle arrest in ER+ BC cell lines. Downregulation of MED16 markedly reduced the sensitivity of ER+ BC cells to tamoxifen and increased the stemness and autophagy of ER+ BC cells. Bioinformatic analysis of similar genes to MED16 were mainly enriched in autophagy, endocrine therapy and mTOR signalling pathways, and the inhibition of mTOR-mediated autophagy restored sensitivity to tamoxifen by MED16 downregulation in ER+ BC cells. These results suggest an important role of MED16 in the regulation of tamoxifen sensitivity in ER+ BC cells, crosstalk between the mTOR signalling pathway-induced autophagy, and together, with the exploration of tamoxifen resistance, may indicate a new therapy option for endocrine therapy-resistant patients.

Moxidectin induces autophagy arrest in colorectal cancer.

Colorectal cancer (CRC) is a cancer with a high morbidity and mortality worldwide. Hence, developing new therapeutic drugs for CRC is very important. Moxidectin (MOX) has shown good anti-glioblastoma effect both in vitro and in vivo. This study aimed to elucidate the anti-CRC effect of MOX and its potential mechanism by investigating the influence of MOX on the viability, apoptosis, necrosis and autophagy of colorectal cancer cells (HCT15 and SW620) and its underlying mechanisms. It was found that MOX can induce autophagy arrest, promote autophagy initiation, inhibit autophagic flux and cell proliferation, simultaneously PI3K-Akt-mTOR signaling pathway and microtubule acetylation. Furthermore, MOX suppressed the growth of xenograft tumors, which was consistent with the in vitro results.

Cuprotosis-Related Genes: Predicting Prognosis and Immunotherapy Sensitivity in Pancreatic Cancer Patients.

Based on TCGA, GTEx, and TIMER databases and various bioinformatics analysis methods, the potential biological roles of cuprotosis-related genes in pancreatic cancer were deeply explored, and a predictive model for pancreatic cancer patients was constructed. We downloaded the RNA-Seq data and clinicopathological and predictive data of 179 pancreatic cancer tissues and 332 adjacent normal tissues from TCGA and GTEx databases. The differential expression of cuprotosis-related genes in pancreatic cancer tissue and adjacent normal tissue was analyzed, and the LASSO regression algorithm was used to construct a prediction model and verify the validity of the model prediction. Based on the LASSO regression algorithm, a predictive model composed of three genes LIPT1, LIAS, and DLAT was screened. The corresponding survival curves showed that the constructed prediction model could significantly distinguish the prognosis of pancreatic cancer patients, and the prognosis of patients in the high-risk group was worse (P = 0.00557). The ROC curve showed that the area under the curve of the predictive model for predicting the 4-, 5-, and 6-year survival rates in pancreatic cancer was 0.816, 0.836, and 0.956, respectively. The AUC value of this risk model was significantly higher than 0.7, which could more accurately predict the prognosis of pancreatic cancer patients. This study determined a risk-scoring model of cuprotosis-related genes, which can provide an essential basis for judging the prognosis of pancreatic cancer patients.

The Relationship Between Vitamin D and Activity of Daily Living in the Elderly.

Objective: To analyze the association between vitamin D and the performance of activity of daily living in the elderly. Methods: A total of 94 patients over the age of 65 were eligible to participate if they had undergone a bone mineral density test and if they were in a stable health condition. Subjects were further divided into two groups according to activity of daily living (ADL): the score over 40 of the patients as the high ADL group and the below as the low ADL group. Results: According to univariate analysis, the mean of total hip T score, serum creatinine/cystatin C ratio (CCR), and vitamin D were significantly different between the two groups (P=0.024, 0.008, 0.010). Multivariate ORs showed that the CCR (OR: 0.948; 95%CI: 0.910-0.989; P=0.013) and vitamin D (OR: 865; 95%CI: 0.752-0.994; P=0.047) were inversely associated with having low ADL. Furthermore, on multiple linear regression analysis, the Barthel ADL index was related to geriatric nutritional risk index (GNRI), CCR and vitamin D but independent of patients' age with the slope of 0.732, 0.539, and 0.689 separately, reflected the stronger relative within the variables. Conclusion: We demonstrated that there is a negative correlation of CCR and vitamin D with having low ADL in elderly population. Monitoring the trend of serum vitamin D and CCR, may have a role in the early detection of low ADL with loss of muscle mass and strength in the population of the elderly.

Development and Validation of a Novel PPAR Signaling Pathway-Related Predictive Model to Predict Prognosis in Breast Cancer.

This study is aimed at exploring the potential mechanism of the PPAR signaling pathway in breast cancer (BRCA) and constructing a novel prognostic-related risk model. We used various bioinformatics methods and databases to complete our exploration in this research. Based on TCGA database, we use multiple extension packages based on the R language for data conversion, processing, and statistics. We use LASSO regression analysis to establish a prognostic-related risk model in BRCA. And we combined the data of multiple online websites, including GEPIA, ImmuCellAI, TIMER, GDSC, and the Human Protein Atlas database to conduct a more in-depth exploration of the risk model. Based on the mRNA data in TCGA database, we conducted a preliminary screening of genes related to the PPAR signaling pathway through univariate Cox analysis, then used LASSO regression analysis to conduct a second screening, and successfully established a risk model consisting of ten genes in BRCA. The results of ROC curve analysis show that the risk model has good prediction accuracy. We can successfully divide breast cancer patients into high- and low-risk groups with significant prognostic differences (P = 1.92e - 05) based on this risk model. Combined with the clinical data in TCGA database, there is a correlation between the risk model and the patient's N, T, gender, and fustat. The results of multivariate Cox regression show that the risk score of this risk model can be used as an independent risk factor for BRCA patients. In particular, we draw a nomogram that can predict the 5-, 7-, and 10-year survival rates of BRCA patients. Subsequently, we conducted a series of pancancer analyses of CNV, SNV, OS, methylation, and immune infiltration for this risk model gene and used GDSC data to investigate drug sensitivity. Finally, to gain insight into the predictive value and protein expression of these risk model genes in breast cancer, we used GEO and HPA databases for validation. This study provides valuable clues for future research on the PPAR signaling pathway in BRCA.

Loss of PFKFB4 induces cell cycle arrest and glucose metabolism inhibition by inactivating MEK/ERK/c-Myc pathway in cervical cancer cells.

6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) was reported to be necessary for tumour growth in several cancers. However, the function of PFKFB4 in cervical cancer has not been clearly elucidated. Bioinformatics analysis was applied to detect the expression of PFKFB4 in cervical cancer and the association with survival prognosis. The effect of PFKFB4 on cervical cancer cells growth, cycle, invasion, migration and glucose metabolism was investigated by loss-of-function approaches in vitro. The association between PFKFB4 and MEK/ERK/c-Myc pathway was identified by western blot assay. We found that PFKFB4 was highly expressed in cervical cancer samples and its overexpression led to a poor prognosis of cervical cancer patients. Knock down of PFKFB4 reduced cell growth, blocked cell cycle, inhibited cell invasion and migration, and blocked glucose metabolism in cervical cancer cells. Our findings afforded a theoretical basis for further research on the treatment of cervical cancer based on the control of PFKFB4 expression. Impact StatementWhat is already known on this subject? PFKFB4 was overexpressed in several kinds of cancers and its requirement for tumour growth has been confirmed in cancers such as glioma and breast cancer. However, the function of PFKFB4 in cervical cancer cells has not been clearly elucidated. A bioinformatics study showed that PFKFB4 was a member of a six-gene signature associated with glycolysis to predict the prognosis of patients with cervical cancer. However, the relationship between PFKFB4 and glucose metabolism in cervical cancer has not been revealed.What do the results of this study add? Our results showed that PFKFB4 was highly expressed in cervical cancer samples and its overexpression led to a poor prognosis of cervical cancer patients. Moreover, the administration of si-PFKFB4 significantly reduced cell growth ability, blocked cell cycle, restrained the mobility and suppressed the glucose metabolism in cervical cancer cells partially by inactivating MEK/ERK/c-Myc pathway.What are the implications of these findings for clinical practice and/or further research? Our findings afforded a theoretical basis for further research on the treatment of cervical cancer based on the control of PFKFB4 expression.

Platelet-Derived TGF (Transforming Growth Factor)-ß1 Enhances the Aerobic Glycolysis of Pulmonary Arterial Smooth Muscle Cells by PKM2 (Pyruvate Kinase Muscle Isoform 2) Upregulation.

BACKGROUND: Metabolic reprogramming is a hallmark of pulmonary arterial hypertension. Platelet activation has been implicated in pulmonary arterial hypertension (PAH), whereas the role of platelet in the pathogenesis of PAH remains unclear. METHODS: First, we explored the platelet function of semaxanib' a inhibitor of VEGF receptor (SU5416)/hypoxia mice and monocrotaline-injected rats PAH model. Then we investigated pulmonary arterial smooth muscle cell aerobic glycolysis after being treated with platelet supernatant. TGF (transforming growth factor)-ßRI, pyruvate kinase muscle 2, and other antagonists were applied to identify the underlying mechanism. In addition, platelet-specific deletion TGF-ß1 mice were exposed to chronic hypoxia and SU5416. Cardiopulmonary hemodynamics, vascular remodeling, and aerobic glycolysis of pulmonary arterial smooth muscle cell were determined. RESULTS: Here, we demonstrate that platelet-released TGF-ß1 enhances the aerobic glycolysis of pulmonary arterial smooth muscle cells after platelet activation via increasing pyruvate kinase muscle 2 expression. Mechanistically, platelet-derived TGF-ß1 regulate spyruvate kinase muscle 2 expression through mTOR (mammalian target of rapamycin)/c-Myc/PTBP-1(polypyrimidine tract binding protein 1)/hnRNPA-1(heterogeneous nuclear ribonucleoprotein A1) pathway. Platelet TGF-ß1 deficiency mice are significantly protected from SU5416 plus chronic hypoxia-induced PAH, including attenuated increases in right ventricular systolic pressure and less pulmonary vascular remodeling. Also, in Pf4cre+ Tgfb1fl/fl mice, pulmonary arterial smooth muscle cells showed lower glycolysis capacity and their pyruvate kinase muscle 2 expression decreased. CONCLUSIONS: Our data demonstrate that TGF-ß1 released by platelet contributes to the pathogenesis of PAH and further highlights the role of platelet in PAH.

A novel pyroptosis-related signature predicts prognosis and response to treatment in breast carcinoma.

BACKGROUND: Pyroptosis is a new form of programmed cell death (PCD), also known as cellular inflammatory necrosis. Its discovery has resulted in a novel approach to the progression and medication resistance of breast cancer (BC). However, there is still a significant gap in the investigation of pyroptosis-related genes in BC. METHODS: The mRNA expression profiles and clinical data of BC patients were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Then, using the TCGA cohort, we created a predictive multigene signature including pyroptosis-related genes and verified it using the two GEO cohorts. A pyroptosis-related gene signature was created by combining several bioinformatics and statistical methodologies to predict patient prognosis and responses to immunotherapy and chemotherapy. Furthermore, a nomogram based on the gene signature and clinicopathological markers was created to better classify the risk and quantify the risk assessment of individual patients. RESULTS: A pyroptosis-related gene signature consisting of 15 genes was established. The pyroptosis-related gene signature classified the patients into two groups: high-risk and low-risk. When combined with clinical variables, the risk score was discovered to be an independent predictor of overall survival (OS) in BC patients. Some immunological pathways and genes were linked to pyroptosis, according to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) evaluations. Patients in the high-risk group had a worse prognosis and were not very sensitive to immunotherapy. However, several chemotherapeutic agents were predicted to have greater potential for patients in the high-risk group. Finally, a nomogram was developed that included a classifier based on the 15 pyroptosis-related genes, tumor stage, age, and histologic grade. This nomogram demonstrated good classification capacity and might help with clinical decision-making in BC.

A proposed scoring system for facial port-wine stain evaluation: Facial port-wine stain area and severity index.

BACKGROUND: Port-wine stain (PWS) is a congenital capillary malformation that often occurs on the face. Feasible and quantitative evaluation of facial port-wine stain (FPWS) can significantly impact its clinical management and aid in future research. AIM: To develop and validate an easy-to-use scoring system for FPWS evaluation. METHODS: A facial port-wine stain area and severity index (FSASI) scoring system was proposed. To determine the FSASI score, the face was divided into four regions: forehead, right malar, left malar, and perioral. The severity of FPWS in each region was evaluated by three factors: percentage of the area affected, lesion color, and thickness. To evaluate the intra- and inter-rater reliability of FSASI, two separate FSASI assessments on 111 clinical pictures were conducted by each rater in a one-week interval, and the results from 6 independent raters at different time points were compared. Validity of the FSASI scores was assessed by comparing it with physician global assessment (PGA) and traditional classification data. Validity of the area and color elements of FSASI was also determined. The changes in FSASI scores after vascular-targeted photodynamic therapy (V-PDT) were analyzed to evaluate the treatment effect. RESULTS: The FSASI scoring system showed good intra- and inter-rater reliability (ICC >0.75, p < 0.001) and was found to be comparable to PGA scores (Spearman's r = 0.752-0.907, p < 0.001) and traditional classification data (Spearman's r = 0.426-0.662, p < 0.001). Efficacy analysis indicated that FSASI scores decreased after V-PDT treatment. CONCLUSION: The results of this study demonstrated the reliability and validity of FSASI, which may be applied to assess the severity of FPWS and to evaluate treatment effects in clinical practice and research.