Ultra-reliable quantum dot colliding pulse mode-locked laser as multi-wavelength source for integrated optical interconnects.

For optical interconnect applications, multi-wavelength comb sources require uniform comb spacings and high reliability at high operating temperature. Here, the high-temperature reliability measurements of a InAs quantum dot colliding pulse mode-locked (QD-CPML) laser with 100 GHz comb spacing are systematically investigated. Laser lifetime measurements are performed for over 1600 hours at 80 °C under constant stress current of 150 mA. The mean time to failure (MTTF) of the laser is approximately 38 years (336,203 hours), extracted from the threshold currents extrapolation method. The optical spectral revolutions are also monitored during the aging process, while the grids of comb laser are remarkably stable. The outstanding reliability and spectrum stability make this 100 GHz QD-CPML a promising candidate as a multi-wavelength laser source for datacom and optical I/O applications.

The c-MYC-WDR43 signalling axis promotes chemoresistance and tumour growth in colorectal cancer by inhibiting p53 activity.

Oxaliplatin chemoresistance is a major challenge in the clinical treatment of colorectal cancer (CRC), which is one of the most common malignancies worldwide. In this study, we identified the tryptophan-aspartate repeat domain 43 (WDR43) as a potentially critical oncogenic factor in CRC pathogenesis through bioinformatics analysis. It was found that WDR43 is highly expressed in CRC tissues, and WDR43 overexpression is associated with poor prognosis of CRC patients. WDR43 knockdown significantly inhibits cell growth by arresting cell cycle and enhancing the effect of oxaliplatin chemotherapy both in vitro and in vivo. Mechanistically, upon oxaliplatin stimulation, c-MYC promotes the transcriptional regulation and expression of WDR43. WDR43 enhances the ubiquitination of p53 by MDM2 through binding to RPL11, thereby reducing the stability of the p53 protein, which induces proliferation and chemoresistance of CRC cells. Thus, the overexpression of WDR43 promotes CRC progression, and could be a potential therapeutic target of chemoresistance in CRC.

The role of MRI in the prenatal diagnosis and classification of fetal microtia.

OBJECTIVE: To investigate the role of MRI in the diagnosis and classification of fetal microtia. METHODS: Ninety-five fetuses with suspected microtia based on ultrasound and MRI performed within 1 week were enrolled in this study. The diagnosis based on MRI was compared with postnatal diagnosis. Among the microtia cases suspected on the basis of MRI, mild and severe cases were further classified. In addition, external auditory canal (EAC) atresia was evaluated by MRI in 29 fetuses with a gestational age > 28 weeks, and the accuracy of MRI in the diagnosis and classification of microtia was determined. RESULTS: Of 95 fetuses, 83 were considered to have microtia on the basis of MRI, 81 were confirmed to have microtia, and 14 were found to be normal according to postnatal diagnosis. Among 190 external ears in 95 fetuses, 40 ears were suspected to have mild microtia, and 52 ears were suspected to have severe microtia on the basis of MRI. According to the postnatal diagnosis, mild and severe microtia were confirmed in 43 and 49 ears, respectively. Among the 29 fetuses with a gestational age > 28 weeks, 23 ears were suspected to have EAC atresia according to MRI and 21 ears were ultimately confirmed to have EAC atresia. The accuracy of MRI in diagnosing microtia and EAC atresia was 93.68% and 93.10%, respectively. CONCLUSION: MRI shows good performance in diagnosing fetal microtia and has the potential to evaluate its severity on the basis of classification and EAC status. CLINICAL RELEVANCE STATEMENT: This study was aimed at investigating the role of MRI in the diagnosis and classification of fetal microtia. MRI shows good performance and can help evaluate microtia severity and EAC atresia, thus allowing for better clinical management. KEY POINTS: • MRI is a useful adjunct to prenatal ultrasound. • MRI has a higher accuracy rate than ultrasound in diagnosing fetal microtia. • The accurate classification of fetal microtia and the diagnosis of external auditory canal atresia through MRI may help guide clinical management.

High co-expression of SLC7A11 and GPX4 as a predictor of platinum resistance and poor prognosis in patients with epithelial ovarian cancer.

OBJECTIVE: The aim was to assess the expression levels of SLC7A11 and GPX4 in relation to platinum resistance and prognosis in patients with epithelial ovarian cancer (EOC). DESIGN: A retrospective cohort study. SETTING: Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China. POPULATION OR SAMPLE: We included 192 eligible patients from hospital between January 2002 and December 2018. METHODS: We retrospectively analysed the medical records of patients with EOC. Surgical specimens of EOC were stained for SLC7A11 and GPX4. Survival analysis was performed using the Kaplan-Meier and Cox regression methods. MAIN OUTCOME MEASURES: Clinical end points include platinum-free interval (PFI), progression-free survival (PFS) and overall survival (OS). RESULTS: Patients with high co-expression levels of SLC7A11 and GPX4 had a 60-fold higher risk of platinum resistance compared with those with low co-expression (risk ratio, 60.46; 95% confidence interval [CI] 22.76-160.58; p < 0.001). Moreover, high co-expression level of SLC7A11 and GPX4 was an independent prognostic factor for poor OS (p < 0.001, hazard ratio [HR] 4.44, 95% CI, 2.77-7.14) and poor PFS (p < 0.001, HR = 5.73, 95% CI, 3.86-8.73). For in vitro experiments, SLC7A11 and GPX4 expression were both upregulated in platinum-resistant cells compared with their parental ovarian cancer cells, and siRNA-induced SLC7A11 and GPX4 inhibition decreased platinum resistance. CONCLUSIONS: High expression levels of SLC7A11 and GPX4 are associated with platinum resistance in EOC patients. High co-expression of SLC7A11 and GPX4 may be a significant independent prognostic factor and a potential therapeutic target for platinum resistance in EOC patients.

Research Progress on Bacterial Membrane Vesicles and Antibiotic Resistance.

As a result of antibiotic overuse, bacterial antibiotic resistance has become a severe threat to worldwide public health. The development of more effective antimicrobial therapies and alternative antibiotic strategies is urgently required. The role played by bacterial membrane vesicles (BMVs) in antibiotic resistance has become a current focus of research. BMVs are nanoparticles derived from the membrane components of Gram-negative and Gram-positive bacteria and contain diverse components originating from the cell envelope and cytoplasm. Antibiotic stress stimulates the secretion of BMVs. BMVs promote and mediate antibiotic resistance by multiple mechanisms. BMVs have been investigated as conceptually new antibiotics and drug-delivery vehicles. In this article, we outline the research related to BMVs and antibiotic resistance as a reference for the intentional use of BMVs to combat antibiotic resistance.

KVarPredDB: a database for predicting pathogenicity of missense sequence variants of keratin genes associated with genodermatoses.

BACKGROUND: Germline variants of ten keratin genes (K1, K2, K5, K6A, K6B, K9, K10, K14, K16, and K17) have been reported for causing different types of genodermatoses with an autosomal dominant mode of inheritance. Among all the variants of these ten keratin genes, most of them are missense variants. Unlike pathogenic and likely pathogenic variants, understanding the clinical importance of novel missense variants or variants of uncertain significance (VUS) is the biggest challenge for clinicians or medical geneticists. Functional characterization is the only way to understand the clinical association of novel missense variants or VUS but it is time consuming, costly, and depends on the availability of patient's samples. Existing databases report the pathogenic variants of the keratin genes, but never emphasize the systematic effects of these variants on keratin protein structure and genotype-phenotype correlation. RESULTS: To address this need, we developed a comprehensive database KVarPredDB, which contains information of all ten keratin genes associated with genodermatoses. We integrated and curated 400 reported pathogenic missense variants as well as 4629 missense VUS. KVarPredDB predicts the pathogenicity of novel missense variants as well as to understand the severity of disease phenotype, based on four criteria; firstly, the difference in physico-chemical properties between the wild type and substituted amino acids; secondly, the loss of inter/intra-chain interactions; thirdly, evolutionary conservation of the wild type amino acids and lastly, the effect of the substituted amino acids in the heptad repeat. Molecular docking simulations based on resolved crystal structures were adopted to predict stability changes and get the binding energy to compare the wild type protein with the mutated one. We use this basic information to determine the structural and functional impact of novel missense variants on the keratin coiled-coil heterodimer. KVarPredDB was built under the integrative web application development framework SSM (SpringBoot, Spring MVC, MyBatis) and implemented in Java, Bootstrap, React-mutation-mapper, MySQL, Tomcat. The website can be accessed through http://bioinfo.zju.edu.cn/KVarPredDB . The genomic variants and analysis results are freely available under the Creative Commons license. CONCLUSIONS: KVarPredDB provides an intuitive and user-friendly interface with computational analytical investigation for each missense variant of the keratin genes associated with genodermatoses.

Association between Serum Free Fatty Acids to HDL-Cholesterol Ratio and Nonalcoholic Fatty Liver Disease: a Cross-Sectional Study.

BACKGROUND: This cross-sectional study aimed to investigate the association between serum free fatty acids and high-density lipoprotein-cholesterol ratio (FHR) and nonalcoholic fatty liver disease (NAFLD) in a Chinese population. METHODS: A total of 760 NAFLD subjects and 379 healthy controls who took their annual health checkups were enrolled during 2019. Fasting blood samples were obtained from the population. NAFLD was diagnosed based on hepatic ultrasound examination. RESULTS: Serum FHR (*100) in NAFLD subjects was significantly higher than that in controls. We found that the serum FHR in NAFLD participants was positively correlated with BMI, DBP, WBC, HGB, ALT, AST, GGT, TG, FPG, UA, and hsCRP. Univariate and multivariate logistic regression analysis showed that FHR was independently associated with the presence of NAFLD. The area under curve (AUC) of the receiver operating characteristic (ROC) curve of FHR for NAFLD was 0.781 with the 95% confidence interval from 0.753 to 0.810. The optimal cutoff point of FHR for predicting NAFLD was 41.14 with 78.8% sensitivity and 77.3%, respectively. CONCLUSIONS: FHR was significantly associated with NAFLD and may serve as an effective indicator in NAFLD patients.

Nucleoside transporter-guided cytarabine-conjugated liposomes for intracellular methotrexate delivery and cooperative choriocarcinoma therapy.

Gestational trophoblastic tumors seriously endanger child productive needs and the health of women in childbearing age. Nanodrug-based therapy mediated by transporters provides a novel strategy for the treatment of trophoblastic tumors. Focusing on the overexpression of human equilibrative nucleoside transporter 1 (ENT1) on the membrane of choriocarcinoma cells (JEG-3), cytarabine (Cy, a substrate of ENT1)-grafted liposomes (Cy-Lipo) were introduced for the targeted delivery of methotrexate (Cy-Lipo@MTX) for choriocarcinoma therapy in this study. ENT1 has a high affinity for Cy-Lipo and can mediate the endocytosis of the designed nanovehicles into JEG-3 cells. The ENT1 protein maintains its transportation function through circulation and regeneration during endocytosis. Therefore, Cy-Lipo-based formulations showed high tumor accumulation and retention in biodistribution studies. More importantly, the designed DSPE-PEG2k-Cy conjugation exhibited a synergistic therapeutic effect on choriocarcinoma. Finally, Cy-Lipo@MTX exerted an extremely powerful anti-choriocarcinoma effect with fewer side effects. This study suggests that the overexpressed ENT1 on choriocarcinoma cells holds great potential as a high-efficiency target for the rational design of active targeting nanotherapeutics.

A comprehensive evaluation of computational tools to identify differential methylation regions using RRBS data.

DNA methylation plays a vital role in transcription regulation. Reduced representation bisulfite sequencing (RRBS) is becoming common for analyzing genome-wide methylation profiles at the single nucleotide level. A major goal of RRBS studies is to detect differentially methylated regions (DMRs) between different biological conditions. The previous tools to predict DMRs lack consistency. Here, we simulated RRBS datasets with significant attributes of real sequencing data under a wide range of scenarios, and systematically evaluated seven DMR detection tools in terms of type I error rate, precision/recall (PR), and area under ROC curve (AUC) using different methylation levels, sequencing coverage depth, length of DMRs, read length, and sample sizes. DMRfinder, methylSig, and methylKit were our preferred tools for RRBS data analysis, in terms of their AUC and PR curves. Our comparison highlights the different applicability of DMR detection tools and provides information to guide researchers towards the advancement of sequence-based DMR analysis.

Serum Thyroid Hormones Levels are Significantly Associated with Nonalcoholic Fatty Liver Disease in Euthyroid Chinese Population.

BACKGROUND: Thyroid hormones play an essential role in metabolic homeostasis. Previous studies have demon-strated a close relationship between thyroid abnormalities and metabolic disorders. This retrospective cross-sectional study was to investigate whether significant differences of circulating thyroid profiles exist and to explore the potential of serum thyroid hormones in reflecting advanced fibrosis in subjects with Nonalcoholic Fatty Liver Disease (NAFLD). METHODS: Abdominal ultrasonography was performed to diagnose NAFLD. For all the participants including 522 NAFLD patients and 415 gender- and age-matched controls recruited, demographic, clinical data and thyroid functions were recorded. Fasting serum thyroid hormones including free triiodothyronine (FT3), free thyroxine (FT4), total thyroxine (TT4), total triiodothyronine (TT3), and thyroid-stimulating hormone (TSH) were evaluated. RESULTS: Serum FT3 levels in subjects with NAFLD were significantly reduced, while TSH was increased compared to that in controls. The NAFLD subjects with metabolic syndrome (MS) had significantly lower FT3 and FT4 levels and higher TSH levels than the non-MS group. Serum TSH levels were positively associated with the risk for NAFLD, while FT3 levels were inversely correlated with NAFLD. Among thyroid hormones, low serum FT4 was the only independent predictor of reflecting advanced fibrosis in NAFLD participants. CONCLUSIONS: An altered thyroid profile not only can be significantly associated with an increased incidence of NAFLD, but also had clinical predictive value for assessing significant fibrosis.

Roles of Mifepristone on the Regulation of Cytotoxic Lymphocytes and Regulatory T Cells.

OBJECTIVE: To investigate the immunologic function of mifepristone, which acts as a contraceptive drug at the level of the decidua. SETTING: In our hospital, 60 women (less than 63 days of amenorrhea) volunteered to terminate their pregnancies by the uterine suction evacuation method. Immunohistochemically, the transcription factor forkhead box P3 and granzyme B staining were performed to identify regulatory T cells and cytotoxic lymphocytes (CLs) in all operational subjects. CD8 (cytotoxic T cells marker) and CD56 (natural killer cells marker) staining were further performed in order to characterize the CLs subpopulations. RESULT: A significantly increased number of CLs was found in the decidua treated with mifepristone. CONCLUSION: Mifepristone increases the expression of CLs in the decidua, and it provides new insights into the immunologic function of mifepristone as a drug used for pregnancy termination.

Sonoporation: Applications for Cancer Therapy.

Therapeutic efficacy of both traditional chemotherapy and gene therapy in cancer is highly dependent on the ability to deliver drugs across natural barriers, such as the vessel wall or tumor cell membranes. In this regard, sonoporation induced by ultrasound-guided microbubble (USMB) destruction has been widely investigated in the enhancement of therapeutic drug delivery given it can help overcome these natural barriers, thereby increasing drug delivery into cancer. In this chapter we discuss challenges in current cancer therapy and how some of these challenges could be overcome using USMB-mediated drug delivery. We particularly focus on recent advances in delivery approaches that have been developed to further improve therapeutic efficiency and specificity of various cancer treatments. An example of clinical translation of USMB-mediated drug delivery is also shown.

Three-dimensional Dynamic Contrast-enhanced US Imaging for Early Antiangiogenic Treatment Assessment in a Mouse Colon Cancer Model.

PURPOSE: To evaluate feasibility and reproducibility of three-dimensional (3D) dynamic contrast material-enhanced (DCE) ultrasonographic (US) imaging by using a clinical matrix array transducer to assess early antiangiogenic treatment effects in human colon cancer xenografts in mice. MATERIALS AND METHODS: Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care at Stanford University. Three-dimensional DCE US imaging with two techniques (bolus and destruction-replenishment) was performed in human colon cancer xenografts (n = 38) by using a clinical US system and transducer. Twenty-one mice were imaged twice to assess reproducibility. Seventeen mice were scanned before and 24 hours after either antiangiogenic (n = 9) or saline-only (n = 8) treatment. Data sets of 3D DCE US examinations were retrospectively segmented into consecutive 1-mm imaging planes to simulate two-dimensional (2D) DCE US imaging. Six perfusion parameters (peak enhancement [PE], area under the time-intensity curve [AUC], time to peak [TTP], relative blood volume [rBV], relative blood flow [rBF], and blood flow velocity) were measured on both 3D and 2D data sets. Percent area of blood vessels was quantified ex vivo with immunofluorescence. Statistical analyses were performed with the Wilcoxon rank test by calculating intraclass correlation coefficients and by using Pearson correlation analysis. RESULTS: Reproducibility of both 3D DCE US imaging techniques was good to excellent (intraclass correlation coefficient, 0.73-0.86). PE, AUC, rBV, and rBF significantly decreased (P ≤ .04) in antiangiogenic versus saline-treated tumors. rBV (r = 0.74; P = .06) and rBF (r = 0.85; P = .02) correlated with ex vivo percent area of blood vessels, although the statistical significance of rBV was not reached, likely because of small sample size. Overall, 2D DCE-US overestimated and underestimated treatment effects from up to 125-fold to170-fold compared with 3D DCE US imaging. If the central tumor plane was assessed, treatment response was underestimated up to threefold or overestimated up to 57-fold on 2D versus 3D DCE US images. CONCLUSION: Three-dimensional DCE US imaging with a clinical matrix array transducer is feasible and reproducible to assess tumor perfusion in human colon cancer xenografts in mice and allows for assessment of early treatment response after antiangiogenic therapy.

Methotrexate management for placenta accreta: a prospective study.

OBJECTIVE: To observe efficacy following methotrexate (MTX) management in women with placenta accreta. METHODS: Twenty-four stable patients with placenta accreta were treated with MTX. Beta-hCG values, vascular indices of the residual placenta, and other clinical characteristics were collected prospectively and were compared between the success and failure groups. RESULTS: After MTX management, the residual placentas were expulsed spontaneously in 33.3% of the patients. This was done through dilatation and curettage (D & C) in 45.8% of the patients. The residuals in the uterine wall were completely absorbed within 5.7 months. In the patients who were successfully treated with MTX, their beta-hCG values and vascular indices of the placentas decreased faster than those of failure patients (P < 0.05). Those (20.8%) failing MTX management and subsequent D & C showed that their vascular indices persisted high levels and some even experienced elevations despite significantly decreased hCG values. CONCLUSIONS: MTX management, when the beta-hCG value and vascular indices of placenta decreased significantly, is a conservative option for a stable patient with placenta accreta in China. 3D power Doppler ultrasound should be utilized for the follow-up of this condition.

FXN targeting induces cell death in ovarian cancer stem-like cells through PRDX3-Mediated oxidative stress.

Ovarian cancer stem cells (OCSCs) significantly impact the prognosis, chemoresistance, and treatment outcomes in OC. While ferroptosis has been proven effective against OCSCs, the intricate relationship between ferroptosis and OCSCs remains incompletely understood. Here, we enriched ovarian cancer stem-like cells (OCSLCs) through mammosphere culture, as an OCSC model. OCSLCs displayed heightened ferroptosis susceptibility, correlating with elevated FXN levels compared to non-stem OC cells. FXN has recently emerged as a potential regulator in ferroptosis. FXN knockdown diminished stemness marker nanog, sphere-forming ability, increased reactive oxygen species (ROS) generation, and attenuated OCSLCs viability. FXN overexpression exacerbated ferroptosis resistance and reduced RSL3-induced cell death. FXN knockdown impeded OCSLC xenograft tumor growth and exacerbated the degeneration of peroxiredoxin 3 (PRDX3), a mitochondrial antioxidant protein participates in oxidative stress. Thus, elevated FXN in OCSLCs suppresses ROS accumulation, fostering ferroptosis resistance, and regulates the antioxidant protein PRDX3. FXN emerges as a potential therapeutic target for OC.

Metabolism-regulated ferroptosis in cancer progression and therapy.

Cancer metabolism mainly includes carbohydrate, amino acid and lipid metabolism, each of which can be reprogrammed. These processes interact with each other to adapt to the complicated microenvironment. Ferroptosis is a regulated cell death induced by iron-dependent lipid peroxidation, which is morphologically different from apoptosis, necrosis, necroptosis, pyroptosis, autophagy-dependent cell death and cuprotosis. Cancer metabolism plays opposite roles in ferroptosis. On the one hand, carbohydrate metabolism can produce NADPH to maintain GPX4 and FSP1 function, and amino acid metabolism can provide substrates for synthesizing GPX4; on the other hand, lipid metabolism might synthesize PUFAs to trigger ferroptosis. The mechanisms through which cancer metabolism affects ferroptosis have been investigated extensively for a long time; however, some mechanisms have not yet been elucidated. In this review, we summarize the interaction between cancer metabolism and ferroptosis. Importantly, we were most concerned with how these targets can be utilized in cancer therapy.

MEK-mediated CHPF2 phosphorylation promotes colorectal cancer cell proliferation and metastasis by activating NF-κB signaling.

The cytokine tumor necrosis factor (TNF) plays a crucial role in the proliferation and metastasis of colorectal cancer (CRC) cells, but the underlying mechanisms remain poorly understood. Here, we report that chondroitin polymerizing factor 2 (CHPF2) promotes CRC cell proliferation and metastasis mediated by TNF, independently of its enzymatic activity. CHPF2 is highly expressed in CRC, and its elevated expression is associated with poor prognosis of CRC patients. Mechanistically, upon TNF stimulation, CHPF2 is phosphorylated at the T588 residue by MEK, enabling CHPF2 to interact with both TAK1 and IKKα. This interaction enhances the binding of TAK1 and IKKα, leading to increased phosphorylation of the IKK complex and activation of NF-κB signaling. As a result, the expression of early growth factors (EGR1) is upregulated to promote CRC cell proliferation and metastasis. In contrast, introduction of a phospho-deficient T588A mutation in CHPF2 weakened the interaction between CHPF2 and TAK1, thus impairing NF-κB signaling. CHPF2 T588A mutation reduced the ability of CHPF2 to promote the proliferation and metastasis of CRC in vitro and in vivo. Furthermore, the NF-κB RELA subunit promotes CHPF2 expression, further amplifying TNF-induced NF-κB signaling activation. These findings identify a moonlighting function of CHPF2 in promoting tumor cell proliferation and metastasis and provide insights into the mechanism by which CHPF2 amplifies TNF-mediated NF-κB signaling activation. Our study provides a molecular basic for the development of therapeutic strategies for CRC treatment.

Prediction of ovarian cancer prognosis using statistical radiomic features of ultrasound images.

Objective. Ovarian cancer is the deadliest gynecologic malignancy worldwide. Ultrasound is the most useful non-invasive test for preoperative diagnosis of ovarian cancer. In this study, by leveraging multiple ultrasound images from the same patient to generate personalized, informative statistical radiomic features, we aimed to develop improved ultrasound image-based prognostic models for ovarian cancer.Approach. A total of 2057 ultrasound images from 514 ovarian cancer patients, including 355 patients with epithelial ovarian cancer, from two hospitals in China were collected for this study. The models were constructed using our recently developed Frequency Appearance in Multiple Univariate pre-Screening feature selection algorithm and Cox proportional hazards model.Main results. The models showed high predictive performance for overall survival (OS) and recurrence-free survival (RFS) in both epithelial and nonepithelial ovarian cancer, with concordance indices ranging from 0.773 to 0.794. Radiomic scores predicted 2 year OS and RFS risk groups with significant survival differences (log-rank test,P< 1.0 × 10-4for both validation cohorts). OS and RFS hazard ratios between low- and high-risk groups were 15.994 and 30.692 (internal cohort) and 19.339 and 19.760 (external cohort), respectively. The improved performance of these newly developed prognostic models was mainly attributed to the use of multiple preoperative ultrasound images from the same patient to generate statistical radiomic features, rather than simply using the largest tumor region of interest among them. The models also revealed that the roundness of tumor lesion shape was positively correlated with prognosis for ovarian cancer.Significance.The newly developed prognostic models based on statistical radiomic features from ultrasound images were highly predictive of the risk of cancer-related death and possible recurrence not only for patients with epithelial ovarian cancer but also for those with nonepithelial ovarian cancer. They thereby provide reliable, non-invasive markers for individualized prognosis evaluation and clinical decision-making for patients with ovarian cancer.

MAPK Signaling-Mediated RFNG Phosphorylation and Nuclear Translocation Restrain Oxaliplatin-Induced Apoptosis and Ferroptosis.

Chemotherapy resistance remains a major challenge in the treatment of colorectal cancer (CRC). Therefore, it is crucial to develop novel strategies to sensitize cancer cells to chemotherapy. Here, the fringe family is screened to determine their contribution to chemotherapy resistance in CRC. It is found that RFNG depletion significantly sensitizes cancer cells to oxaliplatin treatment. Mechanistically, chemotherapy-activated MAPK signaling induces ERK to phosphorylate RFNG Ser255 residue. Phosphorylated RFNG S255 (pS255) interacts with the nuclear importin proteins KPNA1/importin-α1 and KPNB1/importin-ß1, leading to its translocation into the nucleus where it targets p53 and inhibits its phosphorylation by competitively inhibiting the binding of CHK2 to p53. Consequently, the expression of CDKN1A is decreased and that of SLC7A11 is increased, leading to the inhibition of apoptosis and ferroptosis. In contrast, phosphor-deficient RFNG S225A mutant showed increased apoptosis and ferroptosis, and exhibited a notable response to oxaliplatin chemotherapy both in vitro and in vivo. It is further revealed that patients with low RFNG pS255 exhibited significant sensitivity to oxaliplatin in a patient-derived xenograft (PDX) model. These findings highlight the crosstalk between the MAPK and p53 signaling pathways through RFNG, which mediates oxaliplatin resistance in CRC. Additionally, this study provides guidance for oxaliplatin treatment of CRC patients.

ACSL6-activated IL-18R1-NF-κB promotes IL-18-mediated tumor immune evasion and tumor progression.

Aberrant activation of IL-18 signaling regulates tumor immune evasion and progression. However, the underlying mechanism remains unclear. Here, we report that long-chain acyl-CoA synthase 6 (ACSL6) is highly expressed in liver cancer and correlated with poor prognosis. ACSL6 promotes tumor growth, metastasis, and immune evasion mediated by IL-18, independent of its metabolic enzyme activity. Mechanistically, upon IL-18 stimulation, ACSL6 is phosphorylated by ERK2 at S674 and recruits IL-18RAP to interact with IL-18R1, thereby reinforcing the IL-18R1-IL-18RAP heterodimer and triggering NF-κB-dependent gene expression to facilitate tumor development. Furthermore, the up-regulation of CXCL1 and CXCL5 by ACSL6 promotes tumor-associated neutrophil and tumor-associated macrophage recruitment, thereby inhibiting cytotoxic CD8+ T cell infiltration. Ablation or S674A mutation of ACSL6 potentiated anti-PD-1 therapeutic efficacy by increasing the effector activity of intertumoral CD8+ T cells. We revealed that ACSL6 is a potential adaptor that activates IL-18-NF-κB axis-mediated tumor immune evasion and provides valuable insights for developing effective immunotherapy strategies for cancer.