The FBXW7-binding sites on FAM83D are potential targets for cancer therapy.

Increasing evidence shows the oncogenic function of FAM83D in human cancer, but how FAM83D exerts its oncogenic function remains largely unclear. Here, we investigated the importance of FAM83D/FBXW7 interaction in breast cancer (BC). We systematically mapped the FBXW7-binding sites on FAM83D through a comprehensive mutational analysis together with co-immunoprecipitation assay. Mutations at the FBXW7-binding sites on FAM83D led to that FAM83D lost its capability to promote the ubiquitination and proteasomal degradation of FBXW7; cell proliferation, migration, and invasion in vitro; and tumor growth and metastasis in vivo, indicating that the FBXW7-binding sites on FAM83D are essential for its oncogenic functions. A meta-evaluation of FAM83D revealed that the prognostic impact of FAM83D was independent on molecular subtypes. The higher expression of FAM83D has poorer prognosis. Moreover, high expression of FAM83D confers resistance to chemotherapy in BCs, which is experimentally validated in vitro. We conclude that identification of FBXW7-binding sites on FAM83D not only reveals the importance for FAM83D oncogenic function, but also provides valuable insights for drug target.

KAT8-catalyzed lactylation promotes eEF1A2-mediated protein synthesis and colorectal carcinogenesis.

Aberrant lysine lactylation (Kla) is associated with various diseases which are caused by excessive glycolysis metabolism. However, the regulatory molecules and downstream protein targets of Kla remain largely unclear. Here, we observed a global Kla abundance profile in colorectal cancer (CRC) that negatively correlates with prognosis. Among lactylated proteins detected in CRC, lactylation of eEF1A2K408 resulted in boosted translation elongation and enhanced protein synthesis which contributed to tumorigenesis. By screening eEF1A2 interacting proteins, we identified that KAT8, a lysine acetyltransferase that acted as a pan-Kla writer, was responsible for installing Kla on many protein substrates involving in diverse biological processes. Deletion of KAT8 inhibited CRC tumor growth, especially in a high-lactic tumor microenvironment. Therefore, the KAT8-eEF1A2 Kla axis is utilized to meet increased translational requirements for oncogenic adaptation. As a lactyltransferase, KAT8 may represent a potential therapeutic target for CRC.

Oncogenic ß-catenin-driven liver cancer is susceptible to methotrexate-mediated disruption of nucleotide synthesis.

BACKGROUND: Liver cancer is largely resistant to chemotherapy. This study aimed to identify the effective chemotherapeutics for ß-catenin-activated liver cancer which is caused by gain-of-function mutation of catenin beta 1 ( CTNNB1 ), the most frequently altered proto-oncogene in hepatic neoplasms. METHODS: Constitutive ß-catenin-activated mouse embryonic fibroblasts (MEFs) were established by deleting exon 3 ( ß-catenin Δ(ex3)/+ ), the most common mutation site in CTNNB1 gene. A screening of 12 widely used chemotherapy drugs was conducted for the ones that selectively inhibited ß-catenin Δ(ex3)/+ but not for wild-type MEFs. Untargeted metabolomics was carried out to examine the alterations of metabolites in nucleotide synthesis. The efficacy and selectivity of methotrexate (MTX) on ß-catenin-activated human liver cancer cells were determined in vitro . Immuno-deficient nude mice subcutaneously inoculated with ß-catenin wild-type or mutant liver cancer cells and hepatitis B virus ( HBV ); ß-catenin lox(ex3)/+ mice were used, respectively, to evaluate the efficacy of MTX in the treatment of ß-catenin mutant liver cancer. RESULTS: MTX was identified and validated as a preferential agent against the proliferation and tumor formation of ß-catenin-activated cells. Boosted nucleotide synthesis was the major metabolic aberration in ß-catenin-active cells, and this alteration was also the target of MTX. Moreover, MTX abrogated hepatocarcinogenesis of HBV ; ß-catenin lox(ex3)/+ mice, which stimulated concurrent Ctnnb1- activated mutation and HBV infection in liver cancer. CONCLUSION: MTX is a promising chemotherapeutic agent for ß-catenin hyperactive liver cancer. Since repurposing MTX has the advantages of lower risk, shorter timelines, and less investment in drug discovery and development, a clinical trial is warranted to test its efficacy in the treatment of ß-catenin mutant liver cancer.

DEHP and DBP, common phthalates, induce glucose metabolism disorders in rats via oxidative damage of PI3K/Akt/GLUT4 signaling.

Phthalic acid esters (PAEs) are environmental endocrine disruptors thought to interfere with glucose metabolism in humans. Most of the related research has focused on population epidemiological studies, with the underlying mechanisms remaining unresolved. Using an in vivo animal model, we examined the effects of oral administration of two commonly used PAEs [di(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP)] on glucose homeostasis and insulin secretion. DEHP (750 mg/kg, 1/40 LD50), DBP (500 mg/kg, 1/40 LD50), and DEHP (750 mg/kg) + DBP (500 mg/kg) exert an influence on glucose metabolism and elicit a reduction in insulin sensitivity in rats. Furthermore, these substances induce detrimental effects on the structure and functionality of pancreatic ß-cells. DEHP and/or DBP triggered an increase in plasma malondialdehyde (MDA) and reduction in superoxide dismutase (SOD) activity; a reduction in the phosphorylation of phosphatidyl inositol 3 kinase (PI3K) and phospho-protein kinase B (p-Akt473) proteins; an increase in the relative expression of Bax, Caspase-8, cleaved-Caspase-9, and cleaved-Caspase-3; and a reduction in the relative expression of Bcl-2-related Bax in pancreatic tissue and of gastrocnemius glucose transporter 4 (GLUT4) in the gastrocnemius muscle. Based on these findings, these PAEs can disrupt glucose metabolism, possibly via oxidative damage of the PI3K/Akt/GLUT4 pathway; this damage induces pancreatic ß-cell apoptosis, affects pancreatic ß-cell function, and affects glucose metabolism and insulin resistance in rats. To the best of our knowledge, this study was the first to show that the combined effect of the two PAEs affects glucose metabolism and insulin resistance in rats that is significantly higher than the effects of each PAE. Thus, safety standards and studies do not consider this effect as a significant oversight when blending PAEs. We assert that this must be addressed and corrected for establishing more impactful and safer standards.

A risk model based on ferroptosis- and cuproptosis-related lncRNAs predicts prognosis and immune microenvironment in lung adenocarcinoma by bioinformatics analysis and experimental verification.

Ferroptosis and cuproptosis are both novel types of cell death. Long noncoding RNAs (lncRNAs) are associated with multiple cancers. Notably, bioinformatics study of ferroptosis- and cuproptosis-related lncRNAs (FCLs) in lung adenocarcinoma (LUAD) has not been elucidated. In this study, we used univariate Cox, multivariate Cox, and least absolute shrinkage and selection operator Cox (LASSO-Cox) analyses to screen three FCLs, namely AC079193.2, AC090559.1, and AL512363.1. We then showed that these three FCLs were tumor-specific and correlated with ferroptosis and cuproptosis using qRT-PCR. Next, a prognostic risk model consisting of high- and low-risk cohorts was successfully constructed based on The Cancer Genome Atlas-LUAD data. The high-risk group consistently demonstrated poor prognosis. The accuracy of the model was evaluated using AUC, C-index curves, and nomograms. Furthermore, KEGG and GO analysis with R software showed significant enrichment in immune functions and metabolic pathways. Hereto, the immune function and immune cell expression results were more pronounced in the low-risk versus high-risk group. In conclusion, the prognostic risk model comprised of three FCLs effectively predicted patient outcomes and is associated with the immune microenvironment in LUAD.

Molecular subtypes of lung adenocarcinoma patients for prognosis and therapeutic response prediction with machine learning on 13 programmed cell death patterns.

BACKGROUND: Lung adenocarcinoma (LUAD) seriously threatens people's health worldwide. Programmed cell death (PCD) plays a critical role in regulating LUAD growth and metastasis as well as in therapeutic response. However, currently, there is a lack of integrative analysis of PCD-related signatures of LUAD for accurate prediction of prognosis and therapeutic response. METHODS: The bulk transcriptome and clinical information of LUAD were obtained from TCGA and GEO databases. A total of 1382 genes involved in regulating 13 various PCD patterns (apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, netotic cell death, entotic cell death, lysosome-dependent cell death, parthanatos, autophagy-dependent cell death, oxeiptosis, alkaliptosis and disulfidptosis) were included in the study. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis were performed to identify PCD-associated differential expression genes (DEGs). An unsupervised consensus clustering algorithm was used to explore the potential subtypes of LUAD based on the expression profiles of PCD-associated DEGs. Univariate Cox regression analysis, Least Absolute Shrinkage and Selection Operator (LASSO) regression, Random Forest (RF) analysis and stepwise multivariate Cox analysis were performed to construct a prognostic gene signature. The "oncoPredict" algorithm was utilized for drug-sensitive analysis. GSVA and GSEA were utilized to perform function enrichment analysis. MCPcounter, quanTIseq, Xcell and ssGSEA algorithms were used for tumor immune microenvironment analysis. A nomogram incorporating PCDI and clinicopathological characteristics was established to predict the prognosis of LUAD patients. RESULTS: Forty PCD-associated DEGs related to LUAD were obtained by WGCNA analysis and differential expression analysis, followed by unsupervised clustering to identify two LUAD molecular subtypes. A programmed cell death index (PCDI) with a five-gene signature was established by machine learning algorithms. LUAD patients were then divided into a high PCDI group and a low PCDI group using the median PCDI as a cutoff. Survival and therapeutic analysis revealed that the high PCDI group had a poor prognosis and was more sensitive to targeted drugs but less sensitive to immunotherapy compared to the low PCDI group. Further enrichment analysis showed that B cell-related pathways were significantly downregulated in the high PCDI group. Accordingly, the decreased tumor immune cell infiltration and the lower tumor tertiary lymphoid structure (TLS) scores were also found in the high PCDI group. Finally, a nomogram with reliable predictive performance PCDI was constructed by incorporating PCDI and clinicopathological characteristics, and a user-friendly online website was established for clinical reference ( https://nomogramiv.shinyapps.io/NomogramPCDI/ ). CONCLUSION: We performed the first comprehensive analysis of the clinical relevance of genes regulating 13 PCD patterns in LUAD and identified two LUAD molecular subtypes with distinct PCD-related gene signature which indicated differential prognosis and treatment sensitivity. Our study provided a new index to predict the efficacy of therapeutic interventions and the prognosis of LUAD patients for guiding personalized treatments.

USP35 promotes cell proliferation and chemotherapeutic resistance through stabilizing FUCA1 in colorectal cancer.

Ubiquitin-specific-processing proteases 35 (USP35) is an under-characterized deubiquitinase and its role in colorectal cancer (CRC) remains unclear. Here, we focus on delineating the impact of USP35 on CRC cell proliferation and chemo-resistance, as well as the possible regulatory mechanism. By examining the genomic database and clinical samples, we found that USP35 was overexpressed in CRC. Further functional studies showed that enhanced USP35 expression promoted CRC cell proliferation and resistance to oxaliplatin (OXA) and 5-fluorouracil (5-FU), whereas USP35 depletion impeded cell proliferation and sensitized cells to OXA and 5-FU treatments. Then, to explore the possible mechanism underlying USP35-triggered cellular responses, we performed co-immunoprecipitation (co-IP) followed by mass spectrometry (MS) analysis and identified α-L-fucosidase 1 (FUCA1) as a direct deubiquitiation target of USP35. Importantly, we demonstrated that FUCA1 was an essential mediator for USP35-induced cell proliferation and chemo-resistance in vitro and in vivo. Finally, we observed that nucleotide excision repair (NER) components (e.g., XPC, XPA, ERCC1) were up-regulated by USP35-FUCA1 axis, indicating a potential mechanism for USP35-FUCA1-mediated platinum resistance in CRC. Together, our results for the first time explored the role and important mechanism of USP35 in CRC cell proliferation and chemotherapeutic response, providing a rationale for USP35-FUCA1-targeted therapy in CRC.

Analysis of immunotherapeutic response-related signatures in esophageal squamous-cell carcinoma.

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common and lethal malignant diseases. Immunotherapy has been widely studied and has exhibited potential in ESCC treatment. However, there are only a portion of ESCC patients have benefited from immunotherapy. We herein identified immunotherapeutic response-related signatures (IRRS) and evaluated their performance in ESCC prognosis and immunotherapeutic responsiveness. Methods: We constructed an IRRS using the gene expression data of 274 ESCC patients based on y -30significantly differentially expressed genes, which were compared responders and non-responders from various patient cohorts treated with immunotherapy. Survival analysis was performed in both the GSE53625 and TCGA-ESCC cohorts. We also explored the differences in the tumor microenvironment between the high-IRRS and low-IRRS score groups using single-cell data as a reference. Three immunotherapy cohorts were used to verify the value of the IRRS in predicting immunotherapy response. Results: Twelve immunotherapy-related genes were selected to construct a signature score and were validated as independent prognostic predictors for patients with ESCC. Patients with high IRRS scores exhibited an immunosuppressive phenotype. Therefore, patients with low IRRS scores may benefit from immunotherapy. Conclusions: IRRS score is a biomarker for immunotherapy response and prognosis of ESCC.

Mechanism of 2,4-Dichlorophenoxyacetic acid-induced damage to rat testis via Fas/FasL pathway and the protective effect of Lycium barbarum polysaccharides.

The herbicide 2,4-Dichlorophenoxyacetic acid (2,4-D) is widely used to control broadleaved weeds and has been associated with male infertility. We studied the molecular mechanisms of 2,4-D induced male reproductive system damage and the protective effects of Lycium barbarum polysaccharides (LBP) using Sprague Dawley rats and TM4 cells. Treatment with 2,4-D caused architectural and functional changes in the testis, including collapsed and atrophied seminiferous tubules with reduced number of spermatozoa, scarce sperm in the epididymal duct, low levels of serum testosterone, decreased superoxide dismutase and glutathione peroxidase activity, high malondialdehyde content, and increased apoptosis in the testis and epididymis. The expression of Fas, FasL, FADD, Pro-caspase-8, Cleaved-Caspase-8, Pro-Caspase-3, and Cleaved-Caspase-3 were significantly increased in the testicular tissue of 2,4-D-treated rats. The proliferative activity of TM4 cells decreased with an increase in dose and time of 2,4-D exposure, along with enhanced Fas/Fas ligand expression and a decreased concentration of inhibin B in TM4 cell culture medium. Depletion of Fas by specific shRNA transfection reversed the effects of 2,4-D in TM4 cells, further confirming the involvement of death receptor pathway in 2,4-D-mediated apoptosis of sertoli cells. Treatment with LBP also reversed the effects of 2,4-D in testicular cells, resulting in improved cell architecture along with enhanced proliferative capacity. Moreover, in response to LBP treatment of Sertoli cells, the content of inhibin B increased, the level of reactive oxygen species and malondialdehyde decreased, the activities of superoxide dismutase and glutathione peroxidase increased, and the rate of apoptosis as well as the expression of Fas/Fas ligand signaling pathway proteins decreased.

Comprehensive analysis to identify GNG7 as a prognostic biomarker in lung adenocarcinoma correlating with immune infiltrates.

Background: G Protein Subunit Gamma 7 (GNG7), an important regulator of cell proliferation and cell apoptosis, has been reported to be downregulated in a variety of tumors including lung adenocarcinoma (LUAD). However, the correlation between low expression of GNG7 and prognosis of LUAD as well as the immune infiltrates of LUAD remains unclear. Methods: The samples were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). R software was performed for statistical analysis. GNG7 expression and its prognostic value in LUAD were assessed through statistically analyzing the data from different databases. A nomogram was constructed to predict the impact of GNG7 on prognosis. Gene set enrichment analysis (GSEA) and single-sample gene set enrichment analyses GSEA (ssGSEA) were employed to determine the potential signal pathways and evaluated the immune cell infiltration regulated by GNG7. The prognostic significance of GNG7 expression associated with immune cell infiltration was investigated using the Tumor Immune Estimation Resource 2.0 (TIMER2.0) and the Kaplan-Meier plotter database. The UALCAN, cBio Cancer Genomics Portal (cBioPortal) and MethSurv database were used to analyze the correlation between the methylation of GNG7 and its mRNA expression as well as prognostic significance. Results: GNG7 was demonstrated to be down-regulated in LUAD and its low expression was associated with poor prognosis. A clinical reliable prognostic-predictive model was constructed. Pathway enrichment showed that GNG7 was highly related to the B cell receptor signaling pathway. Further analysis showed that GNG7 was positively associated with B cell infiltration and low levels of B cell infiltration tended to associate with worse prognosis in patients with low GNG7 expression. Moreover, methylation analysis suggested hypermethylation may contribute to the low expression of GNG7 in LUAD. Conclusion: Decreased expression of GNG7 at least partly caused by hypermethylation of the GNG7 promoter is closely associated with poor prognosis and tumor immune cell infiltration (especially B cells) in LUAD. These results suggest that GNG7 may be a promising prognostic biomarker and a potential immunotherapeutic target for LUAD, which provides new insights into immunotherapy for LUAD.

Different timescales during ultrafast stilbene isomerization in the gas and liquid phases revealed using time-resolved photoelectron spectroscopy.

Directly contrasting ultrafast excited-state dynamics in the gas and liquid phases is crucial to understanding the influence of complex environments. Previous studies have often relied on different spectroscopic observables, rendering direct comparisons challenging. Here, we apply extreme-ultraviolet time-resolved photoelectron spectroscopy to both gaseous and liquid cis-stilbene, revealing the coupled electronic and nuclear dynamics that underlie its isomerization. Our measurements track the excited-state wave packets from excitation along the complete reaction path to the final products. We observe coherent excited-state vibrational dynamics in both phases of matter that persist to the final products, enabling the characterization of the branching space of the S1-S0 conical intersection. We observe a systematic lengthening of the relaxation timescales in the liquid phase and a red shift of the measured excited-state frequencies that is most pronounced for the complex reaction coordinate. These results characterize in detail the influence of the liquid environment on both electronic and structural dynamics during a complete photochemical transformation.

Retraction: MicroRNA-497 inhibits thyroid cancer tumor growth and invasion by suppressing BDNF.

[This retracts the article DOI: 10.18632/oncotarget.13747.].

Structural basis and molecular mechanism of biased GPBAR signaling in regulating NSCLC cell growth via YAP activity.

The G protein-coupled bile acid receptor (GPBAR) is the membrane receptor for bile acids and a driving force of the liver-bile acid-microbiota-organ axis to regulate metabolism and other pathophysiological processes. Although GPBAR is an important therapeutic target for a spectrum of metabolic and neurodegenerative diseases, its activation has also been found to be linked to carcinogenesis, leading to potential side effects. Here, via functional screening, we found that two specific GPBAR agonists, R399 and INT-777, demonstrated strikingly different regulatory effects on the growth and apoptosis of non-small cell lung cancer (NSCLC) cells both in vitro and in vivo. Further mechanistic investigation showed that R399-induced GPBAR activation displayed an obvious bias for ß-arrestin 1 signaling, thus promoting YAP signaling activation to stimulate cell proliferation. Conversely, INT-777 preferentially activated GPBAR-Gs signaling, thus inactivating YAP to inhibit cell proliferation and induce apoptosis. Phosphorylation of GPBAR by GRK2 at S310/S321/S323/S324 sites contributed to R399-induced GPBAR-ß-arrestin 1 association. The cryoelectron microscopy (cryo-EM) structure of the R399-bound GPBAR-Gs complex enabled us to identify key interaction residues and pivotal conformational changes in GPBAR responsible for the arrestin signaling bias and cancer cell proliferation. In summary, we demonstrate that different agonists can regulate distinct functions of cell growth and apoptosis through biased GPBAR signaling and control of YAP activity in a NSCLC cell model. The delineated mechanism and structural basis may facilitate the rational design of GPBAR-targeting drugs with both metabolic and anticancer benefits.

Progesterone activates GPR126 to promote breast cancer development via the Gi pathway.

GPR126 is a member of the adhesion G protein-coupled receptors (aGPCRs) that is essential for the normal development of diverse tissues, and its mutations are implicated in various pathological processes. Here, through screening 34 steroid hormones and their derivatives for cAMP production, we found that progesterone (P4) and 17-hydroxyprogesterone (17OHP) could specifically activate GPR126 and trigger its downstream Gi signaling by binding to the ligand pocket in the seven-transmembrane domain of the C-terminal fragment of GPR126. A detailed mutagenesis screening according to a computational simulated structure model indicated that K1001ECL2 and F1012ECL2 are key residues that specifically recognize 17OHP but not progesterone. Finally, functional analysis revealed that progesterone-triggered GPR126 activation promoted cell growth in vitro and tumorigenesis in vivo, which involved Gi-SRC pathways in a triple-negative breast cancer model. Collectively, our work identified a membrane receptor for progesterone/17OHP and delineated the mechanisms by which GPR126 participated in potential tumor progression in triple-negative breast cancer, which will enrich our understanding of the functions and working mechanisms of both the aGPCR member GPR126 and the steroid hormone progesterone.

2,4-dichlorophenoxyacetic acid induces ROS activation in NLRP3 inflammatory body-induced autophagy disorder in microglia and the protective effect of Lycium barbarum polysaccharide.

The pesticide 2,4-dichlorophenoxyacetic acid (2,4-D) exerts neurotoxic effects; however, its action mechanism remains unclear. Here, we used BV2 cells as a model and divided them into six groups: control group (serum-free medium), lipopolysaccharide (LPS) (1 µg/mL), 2,4-D (1.2 µmol/mL), Lycium barbarum polysaccharide (LBP; 300 µg/mL LBP), LPS (1 µg/mL) + LBP (300 µg/mL), and 2,4-D (1.2 µmol/mL) + LBP (300 µg/mL) with dimethyl sulfoxide as the solvent. Our results showed that 2,4-D treatment decreased superoxide dismutase and glutathione peroxidase activities and increased malondialdehyde content. The percentage of microglial activation (co-expression of ionized calcium-binding adaptor protein-1 + CD68) in the LPS and 2,4-D groups and the levels of tumor necrosis factor alpha, interleukin (IL) 1 beta, IL-6, and IL-18 in the cell supernatant were increased. The protein and mRNA levels of Nod-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein, caspase-1, IL-1ß, IL-18, and p62 increased, whereas those of LC3II/I and Beclin-1 decreased in the 2,4-D group. The protein expression and mRNA levels of NLRP3, cleaved caspase-1, IL-1ß, IL-18, and p62 decreased significantly, whereas the protein expression and mRNA levels of LC3II/I and Beclin-1 increased in small interfering RNA of NLRP3-treated BV2 cells stimulated with 2,4-D and LPS. In conclusion, 2,4-D enhanced cell migration, promoted oxidative stress, induced excessive release of mitochondrial reactive oxygen species, promoted microglial cell activation, released inflammatory factors, activated NLRP3 inflammasomes, and inhibited autophagy. Meanwhile, LBP reduced inflammation and the release of mitochondrial reactive oxygen species, inhibited NLRP3 inflammasome activation, and regulated autophagy, thereby playing a neuroprotective role.

USP35 mitigates endoplasmic reticulum stress-induced apoptosis by stabilizing RRBP1 in non-small cell lung cancer.

Deubiquitinating enzymes (DUBs) serve to maintain cellular homeostasis via protein ubiquitination and exert diverse regulatory functions in cancers and other diseases. Much progress has been made in characterizing biological roles of DUBs over the decades, yet the specific functions of many subclass members remain largely unexplored. It was not until recent years that the role of ubiquitin-specific-processing protease 35 (USP35) in cancers began to be understood. Here, we focus on delineating the roles and underlying mechanisms of USP35 in non-small cell lung cancer (NSCLC). The isobaric tags for relative and absolute quantitation (iTRAQ) comparative proteomic approach were employed to identify differentially expressed proteins (DEPs) in H1299 cells induced by USP35 overexpression or silencing. Among the potential interactome of USP35, ribosome-binding protein 1 (RRBP1), a membrane-bound protein in endoplasmic reticulum (ER), captured our attentions. RRBP1 expression was found to positively correlate with USP35 levels in both genetically modified cells and human NSCLC tissues. Concordantly, both RRBP1 expression and USP35 expression were found to positively correlate with poor prognoses in lung adenocarcinoma patients. At the molecular level, USP35 was verified to directly interact with RRBP1 to prevent it from proteasomal-dependent degradation. Functionally, USP35 alleviated ER stress-induced cell apoptosis by stabilizing RRBP1 in NSCLC cells. Collectively, these findings indicate that USP35 plays a critical role in resisting ER stress-induced cell death through deubiquitinating RRBP1, hence providing a rationale to target the USP35-RRBP1 axis as an alternative therapeutic option for NSCLC.

HRCT features between lepidic-predominant type and other pathological subtypes in early-stage invasive pulmonary adenocarcinoma appearing as a ground-glass nodule.

BACKGROUND: Different pathological subtypes of invasive pulmonary adenocarcinoma (IPA) have different surgical methods and heterogeneous prognosis. It is essential to clarify IPA subtypes before operation and high-resolution computed tomography (HRCT) plays a very important role in this regard. We aimed to investigate the HRCT features of lepidic-predominant type and other pathological subtypes of early-stage (T1N0M0) IPA appearing as a ground-glass nodule (GGN). METHODS: We performed a retrospective analysis on clinical data and HRCT features of 630 lesions in 589 patients with pathologically confirmed IPA (invasive foci > 5 mm) appearing as pure GGN (pGGN) and mixed GGN (mGGN) with consolidation-to-tumor ratio (CTR) ≤0.5 from January to December 2019. All GGNs were classified as lepidic-predominant adenocarcinoma (LPA) and nonlepidic-predominant adenocarcinoma (n-LPA) groups. Univariate analysis was performed to analyze the differences of clinical data and HRCT features between the LPA and n-LPA groups. Multivariate analysis was conducted to determine the variables to distinguish the LPA from n-LPA group independently. The diagnostic performance of different parameters was compared using receiver operating characteristic curves. RESULTS: In total, 367 GGNs in the LPA group and 263 GGNs in the n-LPA group were identified. In the univariate analysis, the CTR, mean CT values, and mean diameters as well as mixed GGN, deep lobulation, spiculation, vascular change, bronchial change, and tumor-lung interface were smaller in the LPA group than in the n-LPA group (P <  0.05). Logistic regression model was reconstructed including the mean CT value, CTR, deep lobulation, spiculation, vascular change, and bronchial change (P <  0.05). Area under the curve of the logistic regression model for differentiating LPA and n-LPA was 0.840 (76.4% sensitivity, 78.7% specificity), which was significantly higher than that of the mean CT value or CTR. CONCLUSIONS: Deep lobulation, spiculation, vascular change, and bronchial change, CT value > - 472.5 HU and CTR > 27.4% may indicate nonlepidic predominant invasive pulmonary adenocarcinoma in GGNs.

Candida albicans requires iron to sustain hyphal growth.

Candida albicans is an important opportunistic fungal pathogen of immunocompromised individuals. The ability to switch between yeast and hyphal growth forms is critical for its pathogenesis. Hyphal development in C. albicans requires two temporally linked regulations for initiation and maintenance. Here, we performed transcriptome sequencing (RNA-Seq) to analyze the transcriptional consequences for the two different phases of hyphal development. Genome-wide transcription profiling reveals that the sets associated with hyphal initiation were significantly enriched in genes for hyphal cell wall, biofilm matrix and actin polarization. In addition to hypha-specific genes, numerous genes involved in iron acquisition, such as FTR1 and SEF1, are highly induced specifically during sustained hyphal development even when additional free iron is supplied in the medium. Therefore, iron uptake genes are induced by signals that can support prolonged hyphal development in an iron-independent manner. The induction of iron acquisition genes during hyphal elongation was further confirmed by quantitative reverse transcription-PCR under various hypha-inducing conditions. Remarkably, preventing C. albicans from acquiring iron blocks BRG1 activation, leading to impaired hyphal maintenance, and ectopically expressed BRG1 can sustain hyphal development bypassing the requirement of iron. Our study elucidates an underlying mechanism of how multiple virulence factors are interconnected and are induced simultaneously during infection.

Photoelectron Spectroscopy of Liquid Water with Tunable Extreme-Ultraviolet Radiation: Effects of Electron Scattering.

We report the first systematic photoelectron measurements of the three outer-valence bands of liquid water as a function of the ionizing photon energy in the near-threshold region. We use extreme-ultraviolet (XUV) radiation tunable between ∼17.1 and 35.6 eV, obtained through monochromatization of a high-harmonic source. We show that the absolute values of the apparent vertical ionization energies and their respective peak widths show a decreasing trend of their magnitudes with increasing photon energy close to the ionization threshold. We find that the observed effects do not only depend on the electron kinetic energy but are also different for the various outer-valence bands. These observations are consistent with, but not fully explained by, the effects of inelastic electron scattering.

lncRNA MALAT1 Regulates Mouse Granulosa Cell Apoptosis and 17ß-Estradiol Synthesis via Regulating miR-205/CREB1 Axis.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a known long noncoding RNA, was reported to play a crucial role in follicular growth and ovarian disease. However, the physiological function of MALAT1 in mouse granulosa cells (mGCs) remains largely unclear. The aims of this study were to determine the biological function and molecular mechanism of MALAT1 in mGCs. We knocked down MALAT1 in mGCs by using siRNA against MALAT1. We found that knockdown of MALAT1 promoted apoptosis and caspase-3/9 activities in mGCs. Enzyme-linked immunosorbent assay demonstrated that knockdown of MALAT1 significantly decreased the production of estradiol (E2) and progesterone (P4) in mGCs. Mechanistically, MALAT1 serves as a competing endogenous RNA (ceRNA) to sponge microRNA-205 (miR-205), thereby facilitating its downstream target of cyclic AMP response element- (CRE-) binding protein 1 (CREB1). Furthermore, CREB1 overexpression or miR-205 downregulation partially recovered the effect of MALAT1 depletion in mGCs. In summary, these findings suggested that MALAT1 regulated apoptosis and estradiol synthesis of mGCs through the miR-205/CREB1 axis.