Biochar and arbuscular mycorrhizal fungi promote rapid-cycling Brassica napus growth under cadmium stress.

PURPOSE: To explore the mechanisms of tolerance of Brassica napus to ultra-high concentration cadmium pollution and the synergistic effects of biochar (BC) and Arbuscular mycorrhizal fungi (AMF) on plant growth under cadmium (Cd) stress. RESULTS: The application of 5 % BC and inoculation with 10 g AMF significantly promoted the growth and development of B. napus. The combined application of BC and AMF (BC1A and BC2A) was better than the single application. At the Cd 200 mg/kg level, BC1A increased the fresh weight and Cd content of the above-ground parts of B. napus by 35.5 % and decreased by 21.20 %. The SOD and POD activities increased by 30.63 % and 73.37 %. The MDA and H2O2 contents decreased by 40.8 % and 69.99 %, soluble sugar content increased by 37.96 %. At the Cd 300 mg/kg level, BC1A increased the fresh weight and Cd content of the above-ground parts of B. napus by 32.8 % and decreased by 15.99 %. The SOD and POD activities increased by 39.06 % and 93.56 %. The MDA and H2O2 contents decreased by 28.39 % and 72.45 %, and the soluble sugar content increased by 21.16 %. Overall, both BC and AMF treatments alone or in combination (BC1A) were able to alleviate Cd stress and promote plant growth, with the combination of biochar and AMF being the most effective. Furthermore, transcriptome analyses indicated that BC may improve cadmium resistance in B. napus by significantly up-regulating the expression of genes related to peroxidase, photosynthesis, and plant MAPK signaling pathways. AMF may alleviate the toxicity of Cd stress on B. napus by up-regulating the expression of genes related to peroxisomes, phytohormone signaling, and carotenoid biosynthesis. The results of the study will provide support for ecological restoration technology in extremely heavy metal-polluted environments and provide some reference for the application and popularization of BC and AMF conjugation technology.

Targeting the Wnt/ß-catenin signal pathway for the treatment of gastrointestinal cancer: Potential for advancement.

Gastrointestinal cancers (GICs) are highly prevalent cancers that threaten human health worldwide. The Wnt/ß-catenin signaling pathway has been reported to play a pivotal role in the carcinogenesis of GICs. Numerous interventions targeting the Wnt/ß-catenin signaling in GICs are currently being tested in clinical trials with promising results. Unfortunately, there are no clinically approved drugs that effectively target this pathway. This comprehensive review aims to evaluate the impact of clinical therapies targeting the Wnt/ß-catenin signaling pathway in GICs. By integrating data from bioinformatics databases and recent literature from the past five years, we examine the heterogeneous expression and regulatory mechanisms of Wnt/ß-catenin pathway genes and proteins in GICs. Specifically, we focus on expression patterns, mutation frequencies, and clinical prognoses to understand their implications for treatment strategies. Additionally, we discuss recent clinical trial efforts targeting this pathway. Understanding the inhibitors currently under clinical investigation may help optimize foundational research and clinical strategies. We hope that elucidating the current status of precision therapeutic stratification for patients targeting the Wnt/ß-catenin pathway will guide future innovations in precision medicine for GICs.

Management of calcific myonecrosis using vacuum sealing drainage: A rare case report and 5-year follow-up.

 Calcific myonecrosis (CM), a rare post-traumatic sequel of the lower limb, is characterized by calcified lesions. A diagnosis of CM can be difficult owing to the longtime span from the emergence of the original trauma to the onset of the symptoms of CM. This case report aimed to feature a case of a 55-year-old gentleman who presented with a progressive painful swelling in the anterolateral aspect of the right lower leg with the initial trauma arising 11 years ago. In the conservative treatment, a fluid-filled mass was formed. The histological examination of the biopsy suggested a diagnosis of CM. The patient underwent a complete debridement operation, after which vacuum sealing drainage was used to manage the space left. Three weeks later, direct wound closure was achieved. Five-year follow-ups showed an excellent outcome without recurrence. Complete surgical debridement combined with primary closure is recommended to manage CM. Cite this article as: Wang C, Hao D, Wang S. Management of calcific myonecrosis using vacuum sealing drainage: A rare case report and 5-year follow-up. Acta Orthop Traumatol Turc., 2024;58(2):135-139.

Remodeling the hepatic immune microenvironment and demolishing T cell traps to enhance immunotherapy efficacy in liver metastasis.

Immune checkpoint inhibitors (ICIs) exhibit compromised therapeutic efficacy in many patients with advanced cancers, particularly those with liver metastases. Much of this incapability can be ascribed as an irresponsiveness resulting from the "cold" hepatic tumor microenvironment that acts as T cell "traps" for which there currently lack countermeasures. We report a novel nanomedicine that converts the hepatic immune microenvironment to a "hot" phenotype by targeting hepatic macrophage-centric T cell elimination. Using the nanomedicine, composed of KIRA6 (an endothelium reticulum stress inhibitor), α-Tocopherol nanoemulsions, and anti-PD1 antibodies, we found its potency in murine models of orthotopic colorectal tumors and hepatic metastases, restoring immune responses and enhancing anti-tumor effects. A post-treatment scrutiny of the immune microenvironment landscape in the liver reveals repolarization of immunosuppressive hepatic macrophages, upregulation of Th1-like effector CD4+ T cells, and rejuvenation of dendritic cells along with CD8+ T cells. These findings suggest adaptations of liver-centric immune milieu modulation strategies to improve the efficacy of ICIs for a variety of "cold" tumors and their liver metastases.

Overexpression of sweetpotato glutamylcysteine synthetase (IbGCS) in Arabidopsis confers tolerance to drought and salt stresses.

Various environmental stresses induce the production of reactive oxygen species (ROS), which have deleterious effects on plant cells. Glutathione (GSH) is an antioxidant used to counteract reactive oxygen species. Glutathione is produced by glutamylcysteine synthetase (GCS) and glutathione synthetase (GS). However, evidence for the GCS gene in sweetpotato remains scarce. In this study, the full-length cDNA sequence of IbGCS isolated from sweetpotato cultivar Xu18 was 1566 bp in length, which encodes 521 amino acids. The qRT-PCR analysis revealed a significantly higher expression of the IbGCS in sweetpotato flowers, and the gene was induced by salinity, abscisic acid (ABA), drought, extreme temperature and heavy metal stresses. The seed germination rate, root elongation and fresh weight were promoted in T3 Arabidopsis IbGCS-overexpressing lines (OEs) in contrast to wild type (WT) plants under mannitol and salt stresses. In addition, the soil drought and salt stress experiment results indicated that IbGCS overexpression in Arabidopsis reduced the malondialdehyde (MDA) content, enhanced the levels of GCS activity, GSH and AsA content, and antioxidant enzyme activity. In summary, overexpressing IbGCS in Arabidopsis showed improved salt and drought tolerance.

METTL14 downregulation drives S100A4+ monocyte-derived macrophages via MyD88/NF-κB pathway to promote MAFLD progression.

Without intervention, a considerable proportion of patients with metabolism-associated fatty liver disease (MAFLD) will progress from simple steatosis to metabolism-associated steatohepatitis (MASH), liver fibrosis, and even hepatocellular carcinoma. However, the molecular mechanisms that control progressive MAFLD have yet to be fully determined. Here, we unraveled that the expression of the N6-methyladenosine (m6A) methyltransferase METTL14 is remarkably downregulated in the livers of both patients and several murine models of MAFLD, whereas hepatocyte-specific depletion of this methyltransferase aggravated lipid accumulation, liver injury, and fibrosis. Conversely, hepatic Mettl14 overexpression alleviated the above pathophysiological changes in mice fed on a high-fat diet (HFD). Notably, in vivo and in vitro mechanistic studies indicated that METTL14 downregulation decreased the level of GLS2 by affecting the translation efficiency mediated by YTHDF1 in an m6A-depedent manner, which might help to form an oxidative stress microenvironment and accordingly recruit Cx3cr1+Ccr2+ monocyte-derived macrophages (Mo-macs). In detail, Cx3cr1+Ccr2+ Mo-macs can be categorized into M1-like macrophages and S100A4-positive macrophages and then further activate hepatic stellate cells (HSCs) to promote liver fibrosis. Further experiments revealed that CX3CR1 can activate the transcription of S100A4 via CX3CR1/MyD88/NF-κB signaling pathway in Cx3cr1+Ccr2+ Mo-macs. Restoration of METTL14 or GLS2, or interfering with this signal transduction pathway such as inhibiting MyD88 could ameliorate liver injuries and fibrosis. Taken together, these findings indicate potential therapies for the treatment of MAFLD progression.

Effects of cadmium exposure on gut microbiota and antibiotic resistance genes in Haliotis diversicolor abalone.

Heavy metals in soil, water, and industrial production can affect the antibiotic resistance of bacteria. Antibiotic resistance in gut microbiota has been extensively researched. The effects of cadmium (Cd) was investigated on the gut microbiota and antibiotic resistance genes (ARGs) of Haliotis diversicolor, a commercially important abalone species. By exposing H. diversicolor to four concentrations of Cd (0 µg L-1 (control), 6.5 µg L-1 (low), 42.25 µg L-1 (medium), and 274.63 µg L-1 (high)) for 30 and 60 days, 16 types of ARG (aadA-01, aadA-02, cfr, dfrA1, ermB, floR, folA, mecA, sul2, tetB-01, tetC-01, tetD-01, tetG-01, tetM-02, tetQ, vanC-01), and 1213 genus and 27 phylum microbiomes were detected. ARGs can be resistant to aminoglycoside, beta-lactamase, macrolide-lincosamide-streptogramin B, multidrug, florfenicol, macrolide, sulfonamides, tetracyclines, and vancomycin. Cadmium exposure significantly alters the abundance of tetC-01, tetB-01, tetQ, sul2, and aadA-01. About 5% (61) of genus-level microorganisms were significantly affected by Cd exposure. Microbiota alpha and beta diversities in the 60-day 42.25 µg L-1 Cd treatment differed significantly from those in other treatments. In addition, 26 pathogens were detected, and two pathogens (Vibrio and Legionella) were significantly affected by Cd exposure. Significant correlations between pathogens and ARGs increased with increased Cd concentration after 60 days of Cd exposure. Cadmium exposure may cause gut microbiota disturbance in H. diversicolor and increase the likelihood of ARG transfer to pathogens, increasing potential ecological and economic risks.

Toxic effect of chromium on nonspecific immune, bioaccumulation, and tissue structure of Urechis unicinctus.

The contamination of toxic heavy metals in aquatic environments has garnered significant global attention due to its detrimental effects on marine organisms and human health. Hexavalent chromium is a typical environmental and occupational heavy metal pollutant, identified as carcinogenic heavy metal. This study aimed to assess the impact of different Cr (VI) concentrations (0.05-2.5 mg/L) on Urechis unicinctus (U. unicinctus) by investigating bioaccumulation, antioxidant defense system, expression of resistance-related genes, and histological issues. A clear concentration-effect relationship was observed in the bioaccumulation of Cr (VI) in muscle tissues of U. unicinctus. Moreover, exposure to Cr (VI) can alter the activities of lysozyme (LSZ), catalase (CAT), and superoxide dismutase (SOD) to enhance cellular defense mechanisms in U. unicinctus. Likewise, maintained the normal protein structure and functional stability by regulating protein folding. The heat shock cognitive protein (HSC70) gene showed an upward and then downward trend after Cr (VI) exposure. At 12 h, the HSC70 gene expression reached the maximum values of 4.75 and 4.61-fold in the 0.1 and 1.5 mg/L groups, respectively. The organism produced a large number of free radicals, and elevated level of metallothionein (MT) was used to scavenge free radicals and alleviate oxidative stress. Additionally, histopathological examination revealed disorganization in the midgut, atrophic changes in intestinal connective tissue, uneven distribution in respiratory tissues, and irregular shape with a significant reduction in epithelial cells within the gastric cavity. These findings can serve as a valuable reference for elucidating the toxicity mechanisms of heavy metals towards marine benthic organisms and enhancing water environment monitoring strategies.

Distraction osteogenesis promotes temporomandibular joint self-remodeling in the treatment of mandibular deviation caused by condylar ankylosis.

Craniofacial deformity and malocclusion are primary concerns following temporomandibular joint ankylosis (TMJa) in growing patients, and they pose even greater challenges in adult patients. The treatment objectives always involve restoring proper jawbone structure, achieving stable occlusion, and attaining satisfactory joint mobility. This report presents a 4-year follow-up of an adult patient with TMJa-induced mandibular deviation, who underwent a combined treatment approach involving distraction osteogenesis (DO) and orthodontic-orthognathic surgery. Orthodontic treatment resulted in favorable occlusion and improved facial esthetics. A new condyle with a reconstructed glenoid fossa in a forward position was established after mandibular DO and the damaged TMJ experienced self-remodeling owing to functional improvement. Thus, this case demonstrates the efficacy of DO in promoting adaptive TMJ self-remodeling with long-term stability when treating mandibular deviation caused by condylar ankylosis in adult patients.

Gender dimorphism in hepatocarcinogenesis-DNA methylation modification regulated X-chromosome inactivation escape molecule XIST.

BACKGROUND: Sex disparities constitute a significant issue in hepatocellular carcinoma (HCC). However, the mechanism of gender dimorphism in HCC is still not completely understood. METHODS: 5-Hydroxymethylcytosine (5hmC)-Seal technology was utilised to detect the global 5hmC levels from four female and four male HCC samples. Methylation of XIST was detected by Sequenom MassARRAY methylation profiling between HCC tissues (T) and adjacent normal liver tissues (L). The role of Tet methylcytosine dioxygenase 2 (TET2) was investigated using diethylnitrosamine (DEN)-administered Tet2-/- female mice, which regulated XIST in hepatocarcinogenesis. All statistical analyses were carried out by GraphPad Prism 9.0 and SPSS version 19.0 software. RESULTS: The results demonstrated that the numbers of 5hmC reads in the first exon of XIST from female HCC tissues (T) were remarkably lower than that in female adjacent normal liver tissues (L). Correspondingly, DNA methylation level of XIST first exon region was significantly increased in female T than in L. By contrast, no significant change was observed in male HCC patients. Compared to L, the expression of XIST in T was also significantly downregulated. Female patients with higher XIST in HCC had a higher overall survival (OS) and more extended recurrence-free survival (RFS). Moreover, TET2 can interact with YY1 binding to the promoter region of XIST and maintain the hypomethylation state of XIST. In addition, DEN-administered Tet2-/- mice developed more tumours than controls in female mice. CONCLUSIONS: Our study provided that YY1 and TET2 could interact to form protein complexes binding to the promoter region of XIST, regulating the methylation level of XIST and then affecting the expression of XIST. This research will provide a new clue for studying sex disparities in hepatocarcinogenesis. HIGHLIGHTS: XIST was significantly downregulated in HCC tissues and had gender disparity. Methylation levels in the XIST first exon were higher in female HCC tissues, but no significant change in male HCC patients. The TET2-YY1 complex regulate XIST expression in female hepatocytes. Other ways regulate XIST expression in male hepatocytes.

Precisely Regulating M2 Subtype Macrophages for Renal Fibrosis Resolution.

Macrophages are central to the pathogenesis of kidney disease and serve as an effective therapeutic target for kidney injury and fibrosis. Among them, M2-type macrophages have double-edged effects regarding anti-inflammatory effects and tissue repair. Depending on the polarization of the M2 subtypes (M2a or M2c) in the diseased microenvironment, they can either mediate normal tissue repair or drive tissue fibrosis. In renal fibrosis, M2a promotes disease progression through macrophage-to-myofibroblast transition (MMT) cells, while M2c possesses potent anti-inflammatory functions and promotes tissue repair, and is inhibited. The mechanisms underlying this differentiation are complex and are currently not well understood. Therefore, in this study, we first confirmed that M2a-derived MMT cells are responsible for the development of renal fibrosis and demonstrated that the intensity of TGF-ß signaling is a major factor determining the differential polarization of M2a and M2c. Under excessive TGF-ß stimulation, M2a undergoes a process known as MMT cells, whereas moderate TGF-ß stimulation favors the polarization of M2c phenotype macrophages. Based on these findings, we employed targeted nanotechnology to codeliver endoplasmic reticulum stress (ERS) inhibitor (Ceapin 7, Cea or C) and conventional glucocorticoids (Dexamethasone, Dex or D), precisely modulating the ATF6/TGF-ß/Smad3 signaling axis within macrophages. This approach calibrated the level of TGF-ß stimulation on macrophages, promoting their polarization toward the M2c phenotype and suppressing excessive MMT polarization. The study indicates that the combination of ERS inhibitor and a first-line anti-inflammatory drug holds promise as an effective therapeutic approach for renal fibrosis resolution.

A Free-Standing Polymer Polypyrrole/Cellulose Composite Film via Spatial-Confined Interfacial Electrodeposition for Flexible Supercapacitors.

As a kind of energy storage device, a flexible supercapacitor has the characteristics of high capacity, fast charge/discharge rate, good stability, portability and softness. Conductive polymer polypyrrole (PPy) can be used as an electrode material for supercapacitors due to its environmental friendliness, simple synthesis process, good conductivity and potential for large-scale production. However, pristine PPy inevitably suffers from structural rupture due to repeated doping/de-doping during charge and discharge processes, which in turn impairs its cycle stability. In general, compounding with flexible substrates like soft carbon materials, cellulose or nylon fabric, is a good strategy to weaken the inner stress and restrain the structure pulverization of PPy. Herein, cellulose is utilized as a soft substrate to compound with PPy based on the electrochemical oxidation of polypyrrole. The interfacial electrodeposition method can successfully obtain a smooth, uniform and flexible PPy/cellulose composite film, which shows good conductivity. The assembled symmetric supercapacitor with PPy/cellulose film has an optimized specific capacitance of 256.1 mF cm-2, even after 10,000 cycles at a current density of 1 mA cm-2. Furthermore, there is no significant capacitance loss even after 180° bending of the device. This work provides a new means to prepare flexible, low-cost, environmentally friendly and high-performance electrode materials for energy conversion and storage systems.

Extreme environments and human health: From the immune microenvironments to immune cells.

Exposure to extreme environments causes specific acute and chronic physiological responses in humans. The adaptation and the physiological processes under extreme environments predominantly affect multiple functional systems of the organism, in particular, the immune system. Dysfunction of the immune system affected by several extreme environments (including hyperbaric environment, hypoxia, blast shock, microgravity, hypergravity, radiation exposure, and magnetic environment) has been observed from clinical macroscopic symptoms to intracorporal immune microenvironments. Therefore, simulated extreme conditions are engineered for verifying the main influenced characteristics and factors in the immune microenvironments. This review summarizes the responses of immune microenvironments to these extreme environments during in vivo or in vitro exposure, and the approaches of engineering simulated extreme environments in recent decades. The related microenvironment engineering, signaling pathways, molecular mechanisms, clinical therapy, and prevention strategies are also discussed.

Rational Design and Development of Selective BRD7 Bromodomain Inhibitors and Their Activity in Prostate Cancer.

Bromodomain-containing proteins are readers of acetylated lysine and play important roles in cancer. Bromodomain-containing protein 7 (BRD7) is implicated in multiple malignancies; however, there are no selective chemical probes to study its function in disease. Using crystal structures of BRD7 and BRD9 bromodomains (BDs) bound to BRD9-selective ligands, we identified a binding pocket exclusive to BRD7. We synthesized a series of ligands designed to occupy this binding region and identified two inhibitors with increased selectivity toward BRD7, 1-78 and 2-77, which bind with submicromolar affinity to the BRD7 BD. Our binding mode analyses indicate that these ligands occupy a uniquely accessible binding cleft in BRD7 and maintain key interactions with the asparagine and tyrosine residues critical for acetylated lysine binding. Finally, we validated the utility and selectivity of the compounds in cell-based models of prostate cancer.

The Application of Nanoparticle-Based Imaging and Phototherapy for Female Reproductive Organs Diseases.

Various female reproductive disorders affect millions of women worldwide and bring many troubles to women's daily life. Let alone, gynecological cancer (such as ovarian cancer and cervical cancer) is a severe threat to most women's lives. Endometriosis, pelvic inflammatory disease, and other chronic diseases-induced pain have significantly harmed women's physical and mental health. Despite recent advances in the female reproductive field, the existing challenges are still enormous such as personalization of disease, difficulty in diagnosing early cancers, antibiotic resistance in infectious diseases, etc. To confront such challenges, nanoparticle-based imaging tools and phototherapies that offer minimally invasive detection and treatment of reproductive tract-associated pathologies are indispensable and innovative. Of late, several clinical trials have also been conducted using nanoparticles for the early detection of female reproductive tract infections and cancers, targeted drug delivery, and cellular therapeutics. However, these nanoparticle trials are still nascent due to the body's delicate and complex female reproductive system. The present review comprehensively focuses on emerging nanoparticle-based imaging and phototherapies applications, which hold enormous promise for improved early diagnosis and effective treatments of various female reproductive organ diseases.

Targeting CD44 Variant 5 with an Antibody-Drug Conjugate Is an Effective Therapeutic Strategy for Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is the second most frequent type of primary liver cancer. ICC is among the deadliest malignancies, highlighting that novel treatments are urgently needed. Studies have shown that CD44 variant isoforms, rather than the CD44 standard isoform, are selectively expressed in ICC cells, providing an opportunity for the development of an antibody-drug conjugate (ADC)-based targeted therapeutic strategy. In this study, we observed the specific expression of CD44 variant 5 (CD44v5) in ICC tumors. CD44v5 protein was expressed on the surface of most ICC tumors (103 of 155). A CD44v5-targeted ADC, H1D8-DC (H1D8-drug conjugate), was developed that comprises a humanized anti-CD44v5 mAb conjugated to the microtubule inhibitor monomethyl auristatin E (MMAE) via a cleavable valine-citrulline-based linker. H1D8-DC exhibited efficient antigen binding and internalization in cells expressing CD44v5 on the cell surface. Because of the high expression of cathepsin B in ICC cells, the drug was preferentially released in cancer cells but not in normal cells, thus inducing potent cytotoxicity at picomolar concentrations. In vivo studies showed that H1D8-DC was effective against CD44v5-positive ICC cells and induced tumor regression in patient-derived xenograft models, whereas no significant adverse toxicities were observed. These data demonstrate that CD44v5 is a bona fide target in ICC and provide a rationale for the clinical investigation of a CD44v5-targeted ADC-based approach. SIGNIFICANCE: Elevated expression of CD44 variant 5 in intrahepatic cholangiocarcinoma confers a targetable vulnerability using the newly developed antibody-drug conjugate H1D8-DC, which induces potent growth suppressive effects without significant toxicity.

Neutrophil hitchhiking for drug delivery to the bone marrow.

Pharmaceuticals have been developed for the treatment of a wide range of bone diseases and disorders, but suffer from problematic delivery to the bone marrow. Neutrophils are naturally trafficked to the bone marrow and can cross the bone marrow-blood barrier. Here we report the use of neutrophils for the targeted delivery of free drugs and drug nanoparticles to the bone marrow. We demonstrate how drug-loaded poly(lactic-co-glycolic acid) nanoparticles are taken up by neutrophils and are then transported across the bone marrow-blood barrier to boost drug concentrations in the bone marrow. We demonstrate application of this principle to two models. In a bone metastasis cancer model, neutrophil delivery is shown to deliver cabazitaxel and significantly inhibit tumour growth. In an induced osteoporosis model, neutrophil delivery of teriparatide is shown to significantly increase bone mineral density and alleviate osteoporosis indicators.

PFKFB4 facilitates palbociclib resistance in oestrogen receptor-positive breast cancer by enhancing stemness.

BACKGROUND: ER+ breast cancer (ER+ BC) is the most common subtype of BC. Recently, CDK4/6 inhibitors combined with aromatase inhibitors have been approved by FDA as the first-line therapy for patients with ER+ BC, and showed promising therapeutic efficacy in clinical treatment. However, resistance to CDK4/6 inhibitors is frequently observed. A better understanding of the drug resistance mechanism is beneficial to improving therapeutic strategies by identifying optimal combinational treatments. METHODS: Western blotting, qPCR, flow cytometry and a series of cell experiments were performed to evaluate the phenotype of MCF-7/R cells. RNA sequencing, non-targeted metabolomics, shRNA knockdown and tumour cell-bearing mouse models were used to clarify the drug resistance mechanism. RESULTS: Here, we found that ER+ BC cells have shown an adaptive resistance to palbociclib-induced cell cycle arrest by activating an alternative signal pathway, independent of the CDK4/6-RB signal transduction. Continuing treatment of palbociclib evoked cellular senescence of ER+ BC cells. Subsequently, the senescence-like phenotype promoted stemness of ER+ BC cells, accompanied by increased chemoresistance and tumour-initiating potential. Based on transcriptome analysis, we found that PFKFB4 played an important role in stemness transformation and drug resistance. A close correlation was determined between PFKFB4 expression by ER+ BC cells and cell senescence and stemness. Mechanistically, metabolomic profiling revealed that PFKFB4 reprogramed glucose metabolism and promoted cell stemness by enhancing glycolysis. Strikingly, diminishing PFKFB4 levels improved drug sensitivity and overcame chemoresistance during palbociclib treatment in ER+ BC. CONCLUSIONS: These findings not only demonstrated the novel mechanism underlying which ER+ BC cells resisted to palbociclib, but also provided a possible therapeutic strategy in the intervention of ER+ BC to overcome drug resistance.

Development and Clinical Validation of a Novel 5 Gene Signature Based on Fatty Acid Metabolism-Related Genes in Oral Squamous Cell Carcinoma.

Background/Aim: Lipid metabolism disorders play a crucial role in tumor development and progression. The aim of the study focused on constructing a novel prognostic model of oral squamous cell carcinoma (OSCC) patients using fatty acid metabolism-related genes. Methods: Microarray test and data from The Cancer Genome Atlas (TCGA) were used to identify differentially expressed genes related to fatty acid metabolism. The quantitative real-time polymerase chain reaction (qRT-PCR) was then used to validate the expression of targeted fatty acid metabolism genes. A risk predictive scoring model of fatty acid metabolism-related genes was generated using a multivariate Cox model. The efficacy of this model was assessed by time-dependent receiver operating characteristic curve (ROC). Results: 14 fatty acid metabolism-related genes were identified by microarray test and TCGA database analysis and then confirmed by PCR. Finally, a 5 gene signature (ACACB, FABP3, PDK4, PPARG, and PLIN5) was constructed and a RiskScore was calculated for each patient. Compared to the high RiskScore group, the low RiskScore group had better overall survival (OS) (p = 0.02). The RiskScore derived from a 5 gene signature was a prognostic factor (HR: 3.73, 95% CI: 1.38, 10.09) for OSCC patients. The predictive classification efficiencies of RiskScore were evaluated and the area under the curve (AUC) values for 1, 3, and 5 years were 0.613, 0.652, and 0.681, respectively. Then we compared the predictive performance of the prognostic model with or without the RiskScore. The 5 gene-derived RiskScore can improve the predictive performance with AUC values of 0.760, 0.803, and 0.830 for 1, 3, and 5 years OS in prognostic model including the RiskScore. While the predicted AUC values of the model without RiskScore for 1, 3, and 5 years OS were 0.699, 0.715, and 0.714, respectively. Conclusion: We developed a predictive score model using 5 fatty acid metabolism-related genes, which could be a potential prognostic indicator in OSCC.