The relationship between innate/adaptive immunity and gastrointestinal cancer : a multi-omics Mendelian randomization study.

BACKGROUND: Innate/adaptive immunity is the key to anti-tumor therapy. However, its causal relationship to Gastrointestinal (GI) cancer remains unclear. METHODS: Immunity genes were extracted from the MSigDB database. The Genome-wide association studies (GWAS) summary data of GI cancer were integrated with expression quantitative trait loci (eQTL) and DNA methylation quantitative trait loci (mQTL) associated with genes. Summary-data-based Mendelian randomization (SMR) and co-localization analysis were used to reveal causal relationships between genes and GI cancer. Two-sample MR analysis was used for sensitivity analysis. Single cell analysis clarified the enrichment of genes. RESULTS: Three-step SMR analysis showed that a putative mechanism, cg17294865 CpG site regulating HLA-DRA expression was negatively associated with gastric cancer risk. HLA-DRA was significantly differentially expressed in monocyte/macrophage and myeloid cells in gastric cancer. CONCLUSION: This study provides evidence that upregulating the expression level of HLA-DRA can reduce the risk of gastric cancer.

Targeting OXCT1-mediated ketone metabolism reprograms macrophages to promote antitumor immunity via CD8+ T cells in hepatocellular carcinoma.

BACKGROUND & AIMS: The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme 3-oxoacid CoA-transferase 1 (OXCT1). We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear. METHODS: To investigate the expression pattern of OXCT1 in HCC in vivo, we conducted multiplex immunohistochemistry experiments on human HCC specimens. To explore the role of OXCT1 in mouse HCC tumor-associated macrophages (TAMs), we generated LysMcreOXCT1f/f (OXCT1 conditional knockout in macrophages) mice. RESULTS: Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8+ T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8+ T-cell exhaustion and increasing CD8+ T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4me3 level in the Arg1 promoter. In addition, pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreased CD8+ T-cell exhaustion and slower tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in patients with HCC. CONCLUSIONS: In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer. IMPACT AND IMPLICATIONS: The intricate metabolism of liver macrophages plays a critical role in shaping hepatocellular carcinoma progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for hepatocellular carcinoma treatment. Herein, we found that the ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages (TAMs) and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. Pharmacological targeting or genetic downregulation of OXCT1 in TAMs enhances antitumor immunity and slows tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer.

Carnosine regulation of intracellular pH homeostasis promotes lysosome-dependent tumor immunoevasion.

Tumor cells and surrounding immune cells undergo metabolic reprogramming, leading to an acidic tumor microenvironment. However, it is unclear how tumor cells adapt to this acidic stress during tumor progression. Here we show that carnosine, a mobile buffering metabolite that accumulates under hypoxia in tumor cells, regulates intracellular pH homeostasis and drives lysosome-dependent tumor immune evasion. A previously unrecognized isoform of carnosine synthase, CARNS2, promotes carnosine synthesis under hypoxia. Carnosine maintains intracellular pH (pHi) homeostasis by functioning as a mobile proton carrier to accelerate cytosolic H+ mobility and release, which in turn controls lysosomal subcellular distribution, acidification and activity. Furthermore, by maintaining lysosomal activity, carnosine facilitates nuclear transcription factor X-box binding 1 (NFX1) degradation, triggering galectin-9 and T-cell-mediated immune escape and tumorigenesis. These findings indicate an unconventional mechanism for pHi regulation in cancer cells and demonstrate how lysosome contributes to immune evasion, thus providing a basis for development of combined therapeutic strategies against hepatocellular carcinoma that exploit disrupted pHi homeostasis with immune checkpoint blockade.

Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion.

Itaconate is a well-known immunomodulatory metabolite; however, its role in hepatocellular carcinoma (HCC) remains unclear. Here, we find that macrophage-derived itaconate promotes HCC by epigenetic induction of Eomesodermin (EOMES)-mediated CD8+ T-cell exhaustion. Our results show that the knockout of immune-responsive gene 1 (IRG1), responsible for itaconate production, suppresses HCC progression. Irg1 knockout leads to a decreased proportion of PD-1+ and TIM-3+ CD8+ T cells. Deletion or adoptive transfer of CD8+ T cells shows that IRG1-promoted tumorigenesis depends on CD8+ T-cell exhaustion. Mechanistically, itaconate upregulates PD-1 and TIM-3 expression levels by promoting succinate-dependent H3K4me3 of the Eomes promoter. Finally, ibuprofen is found to inhibit HCC progression by targeting IRG1/itaconate-dependent tumor immunoevasion, and high IRG1 expression in macrophages predicts poor prognosis in HCC patients. Taken together, our results uncover an epigenetic link between itaconate and HCC and suggest that targeting IRG1 or itaconate might be a promising strategy for HCC treatment.

ENO1 promotes liver carcinogenesis through YAP1-dependent arachidonic acid metabolism.

Enolase 1 (ENO1) is a glycolytic enzyme that plays essential roles in various pathological activities including cancer development. However, the mechanisms underlying ENO1-contributed tumorigenesis are not well explained. Here, we uncover that ENO1, as an RNA-binding protein, binds to the cytosine-uracil-guanine-rich elements of YAP1 messenger RNA to promote its translation. ENO1 and YAP1 positively regulate alternative arachidonic acid (AA) metabolism by inverse regulation of PLCB1 and HPGD (15-hydroxyprostaglandin dehydrogenase). The YAP1/PLCB1/HPGD axis-mediated activation of AA metabolism and subsequent accumulation of prostaglandin E2 (PGE2) are responsible for ENO1-mediated cancer progression, which can be retarded by aspirin. Finally, aberrant activation of ENO1/YAP1/PLCB1 and decreased HPGD expression in clinical hepatocellular carcinoma samples indicate a potential correlation between ENO1-regulated AA metabolism and cancer development. These findings underline a new function of ENO1 in regulating AA metabolism and tumorigenesis, suggesting a therapeutic potential for aspirin in patients with liver cancer with aberrant expression of ENO1 or YAP1.

Pretreatment synthetic magnetic resonance imaging predicts disease progression in nonmetastatic nasopharyngeal carcinoma after intensity modulation radiation therapy.

BACKGROUND: To investigate the potential of synthetic MRI (SyMRI) in the prognostic assessment of patients with nonmetastatic nasopharyngeal carcinoma (NPC), and the predictive value when combined with diffusion-weighted imaging (DWI) as well as clinical factors. METHODS: Fifty-three NPC patients who underwent SyMRI were prospectively included. 10th Percentile, Mean, Kurtosis, and Skewness of T1, T2, and PD maps and ADC value were obtained from the primary tumor. Cox regression analysis was used for analyzing the association between SyMRI and DWI parameters and progression-free survival (PFS), and then age, sex, staging, and treatment as confounding factors were also included. C-index was obtained by bootstrap. Moreover, significant parameters were used to construct models in predicting 3-year disease progression. ROC curves and leave-one-out cross-validation were used to evaluate the performance and stability. RESULTS: Disease progression occurred in 16 (30.2%) patients at a follow-up of 39.6 (3.5, 48.2) months. T1_Kurtosis, T1_Skewness, T2_10th, PD_Mean, and ADC were correlated with PFS, and T1_Kurtosis (HR: 1.093) and ADC (HR: 1.009) were independent predictors of PFS. The C-index of SyMRI and SyMRI + DWI + Clinic models was 0.687 and 0.779. Moreover, the SyMRI + DWI + Clinic model predicted 3-year disease progression better than DWI or Clinic model (p ≤ 0.008). Interestingly, there was no significant difference between the SyMRI model (AUC: 0.748) and SyMRI + DWI + Clinic model (AUC: 0.846, p = 0.092). CONCLUSION: SyMRI combined with histogram analysis could predict disease progression in NPC patients, and SyMRI + DWI + Clinic model further improved the predictive performance.

Histogram analysis of synthetic magnetic resonance imaging: Correlations with histopathological factors in head and neck squamous cell carcinoma.

PURPOSE: To analyse the association between histogram parameters derived from synthetic MRI (SyMRI) and different histopathological factors in head and neck squamous cell carcinoma (HNSCC). METHOD: Sixty-one patients with histologically proven primary HNSCC were prospectively enrolled. The correlations between histogram parameters of SyMRI (T1, T2 and proton density (PD) maps) and histopathological factors were analysed using Spearman analysis. The Mann-Whitney U test or Student's t test was utilized to differentiate histological grades and human papillomavirus (HPV) status. The ROC curves and leave-one-out cross-validation (LOOCV) were used to evaluate the differentiation performance. Bootstrapping was applied to avoid overfitting. RESULTS: Several histogram parameters were associated with histological grade: T1 map (r = 0.291) and PD map (r = 0.294 - 0.382/-0.343), and PD_75th Percentile showed the highest differentiation performance (AUC: 0.721 (ROC) and 0.719 (LOOCV)). Moderately negative correlations were found between p16 status and the histogram parameters: T1 map (r = -0.587 - -0.390), T2 map (r = -0.649 - -0.357) and PD map (r = -0.537 - -0.338). In differentiating HPV infection, Entropy was the most discriminative parameter in each map and T2_Entropy showed the highest diagnostic performance (AUC: 0.851 [ROC] and 0.851 [LOOCV]). Additionally, several histogram parameters were correlated with Ki-67 (r = -0.379/-0.397), epidermal growth factor receptor (EGFR) (r = 0.318/0.322) status and p53 (r = 0.452 - 0.665/-0.607) status. CONCLUSIONS: Histogram parameters derived from SyMRI may serve as a potential biomarker for discriminating relevant histopathological features, including histological differentiation grade, HPV infection, Ki-67, EGFR and p53 statuses.

Non-canonical phosphoglycerate dehydrogenase activity promotes liver cancer growth via mitochondrial translation and respiratory metabolism.

Phosphoglycerate dehydrogenase (PHGDH) is a key serine biosynthesis enzyme whose aberrant expression promotes various types of tumors. Recently, PHGDH has been found to have some non-canonical functions beyond serine biosynthesis, but its specific mechanisms in tumorigenesis remain unclear. Here, we show that PHGDH localizes to the inner mitochondrial membrane and promotes the translation of mitochondrial DNA (mtDNA)-encoded proteins in liver cancer cells. Mechanistically, we demonstrate that mitochondrial PHGDH directly interacts with adenine nucleotide translocase 2 (ANT2) and then recruits mitochondrial elongation factor G2 (mtEFG2) to promote mitochondrial ribosome recycling efficiency, thereby promoting mtDNA-encoded protein expression and subsequent mitochondrial respiration. Moreover, we show that treatment with a mitochondrial translation inhibitor or depletion of mtEFG2 diminishes PHGDH-mediated tumor growth. Collectively, our findings uncover a previously unappreciated function of PHGDH in tumorigenesis acting via promotion of mitochondrial translation and bioenergetics.

Mitochondrion-Localized SND1 Promotes Mitophagy and Liver Cancer Progression Through PGAM5.

Staphylococcal nuclease domain-containing protein 1 (SND1) is an evolutionarily conserved multifunctional protein that functions mainly in the nucleus and cytoplasm. However, whether SND1 regulates cellular activity through mitochondrial-related functions remains unclear. Herein, we demonstrate that SND1 is localized to mitochondria to promote phosphoglycerate mutase 5 (PGAM5)-mediated mitophagy. We find that SND1 is present in mitochondria based on mass spectrometry data and verified this phenomenon in different liver cancer cell types by performing organelle subcellular isolation. Specifically, The N-terminal amino acids 1-63 of SND1 serve as a mitochondrial targeting sequence (MTS), and the translocase of outer membrane 70 (TOM 70) promotes the import of SND1 into mitochondria. By immunoprecipitation-mass spectrometry (IP-MS), we find that SND1 interacts with PGAM5 in mitochondria and is crucial for the binding of PGAM5 to dynamin-related protein 1 (DRP1). Importantly, we demonstrate that PGAM5 and SND1-MTS are required for SND1-mediated mitophagy under FCCP and glucose deprivation treatment as well as for SND1-mediated cell proliferation and tumor growth both in vitro and in vivo. Aberrant expression of SND1 and PGAM5 predicts poor outcomes in hepatocellular carcinoma (HCC) patients. Taken together, these findings establish a previously unappreciated role of SND1 and the association of mitochondrion-localized SND1 with PGAM5 in mitophagy and tumor progression.

ENO1 suppresses cancer cell ferroptosis by degrading the mRNA of iron regulatory protein 1.

α-Enolase 1 (ENO1) is a critical glycolytic enzyme whose aberrant expression drives the pathogenesis of various cancers. ENO1 has been indicated as having additional roles beyond its conventional metabolic activity, but the underlying mechanisms and biological consequences remain elusive. Here, we show that ENO1 suppresses iron regulatory protein 1 (IRP1) expression to regulate iron homeostasis and survival of hepatocellular carcinoma (HCC) cells. Mechanistically, we demonstrate that ENO1, as an RNA-binding protein, recruits CNOT6 to accelerate the messenger RNA decay of IRP1 in cancer cells, leading to inhibition of mitoferrin-1 (Mfrn1) expression and subsequent repression of mitochondrial iron-induced ferroptosis. Moreover, through in vitro and in vivo experiments and clinical sample analysis, we identified IRP1 and Mfrn1 as tumor suppressors by inducing ferroptosis in HCC cells. Taken together, this study establishes an important role for the ENO1-IRP1-Mfrn1 pathway in the pathogenesis of HCC and reveals a previously unknown connection between this pathway and ferroptosis, suggesting a potential innovative cancer therapy.

Metformin sensitises hepatocarcinoma cells to methotrexate by targeting dihydrofolate reductase.

Metformin, the first-line drug for type II diabetes, has recently been considered an anticancer agent. However, the molecular target and underlying mechanism of metformin's anti-cancer effects remain largely unclear. Herein, we report that metformin treatment increases the sensitivity of hepatocarcinoma cells to methotrexate (MTX) by suppressing the expression of the one-carbon metabolism enzyme DHFR. We show that the combination of metformin and MTX blocks nucleotide metabolism and thus effectively inhibits cell cycle progression and tumorigenesis. Mechanistically, metformin not only transcriptionally represses DHFR via E2F4 but also promotes lysosomal degradation of the DHFR protein. Notably, metformin dramatically increases the response of patient-derived hepatocarcinoma organoids to MTX without obvious toxicity to organoids derived from normal liver tissue. Taken together, our findings identify an important role for DHFR in the suppressive effects of metformin on therapeutic resistance, thus revealing a therapeutically targetable potential vulnerability in hepatocarcinoma.

RBM20 Is a Candidate Gene for Hypertrophic Cardiomyopathy.

BACKGROUND: The genetic basis of a considerable fraction of hypertrophic cardiomyopathy (HCM) cases remains unknown. Whether the gene encoding RNA binding motif protein 20 (RBM20) is implicated in HCM and the correlation of clinical characteristics of RBM20 heterozygotes with HCM remain unresolved. We aimed to investigate the association between RBM20 variants and HCM. METHODS: We compared rare variants in the RBM20 gene by exome sequencing in 793 patients with HCM and 414 healthy controls. Based on a case-control approach, we used optimal sequence kernel association test (SKAT-O) to explore whether RBM20 is associated with HCM. The genetic distribution of RBM20 rare variants was then compared between HCM heterozygotes and dilated cardiomyopathy (DCM) heterozygotes. Clinical features and prognosis of RBM20 heterozygotes were compared with nonheterozygotes. RESULTS: Gene-based association analysis implicated RBM20 as a susceptibility gene for developing HCM. Patients with RBM20 variants displayed a higher prevalence of sudden cardiac arrest (SCA) (6.7% vs 0.9%, P = 0.001), increased sudden cardiac death (SCD) risk factor counts and impaired left ventricle systolic function. Further survival analysis revealed that RBM20 heterozygotes had higher incidences of resuscitated cardiac arrest, recurrent nonsustained ventricular tachycardia, and malignant arrhythmias. Mendelian randomization suggested that RBM20 expression in the left ventricle was causally associated with HCM and DCM with opposite effects. CONCLUSIONS: This study identified RBM20 as a potential causal gene of HCM. RBM20 variants are associated with increased risk for SCA in HCM.

KDELR2 promotes breast cancer proliferation via HDAC3-mediated cell cycle progression.

BACKGROUND: Histone deacetylases (HDACs) engage in the regulation of various cellular processes by controlling global gene expression. The dysregulation of HDACs leads to carcinogenesis, making HDACs ideal targets for cancer therapy. However, the use of HDAC inhibitors (HDACi) as single agents has been shown to have limited success in treating solid tumors in clinical studies. This study aimed to identify a novel downstream effector of HDACs to provide a potential target for combination therapy. METHODS: Transcriptome sequencing and bioinformatics analysis were performed to screen for genes responsive to HDACi in breast cancer cells. The effects of HDACi on cell viability were detected using the MTT assay. The mRNA and protein levels of genes were determined by quantitative reverse transcription-PCR (qRT-PCR) and Western blotting. Cell cycle distribution and apoptosis were analyzed by flow cytometry. The binding of CREB1 (cAMP-response element binding protein 1) to the promoter of the KDELR (The KDEL (Lys-Asp-Glu-Leu) receptor) gene was validated by the ChIP (chromatin immunoprecipitation assay). The association between KDELR2 and protein of centriole 5 (POC5) was detected by immunoprecipitation. A breast cancer-bearing mouse model was employed to analyze the effect of the HDAC3-KDELR2 axis on tumor growth. RESULTS: KDELR2 was identified as a novel target of HDAC3, and its aberrant expression indicated the poor prognosis of breast cancer patients. We found a strong correlation between the protein expression patterns of HADC3 and KDELR2 in tumor tissues from breast cancer patients. The results of the ChIP assay and qRT-PCR analysis validated that HDAC3 transactivated KDELR2 via CREB1. The HDAC3-KDELR2 axis accelerated the cell cycle progression of cancer cells by protecting the centrosomal protein POC5 from proteasomal degradation. Moreover, the HDAC3-KDELR2 axis promoted breast cancer cell proliferation and tumorigenesis in vitro and in vivo. CONCLUSION: Our results uncovered a previously unappreciated function of KDELR2 in tumorigenesis, linking a critical Golgi-the endoplasmic reticulum traffic transport protein to HDAC-controlled cell cycle progression on the path of cancer development and thus revealing a potential therapeutical target for breast cancer.

GSTP1 and cancer: Expression, methylation, polymorphisms and signaling (Review).

Glutathione S­transferase Pi (GSTP1) is an isozyme encoded by the GST pi gene that plays an important regulatory role in detoxification, anti­oxidative damage, and the occurrence of various diseases. The aim of the present study was to review the association between the expression of GSTP1 and the development and treatment of various cancers, and discuss GSTP1 methylation in several malignant tumors, such as prostate, breast and lung cancer, as well as hepatocellular carcinoma; to review the association between polymorphism of the GSTP1 gene and various diseases; and to review the effects of GSTP1 on electrophilic oxidative stress, cell signal transduction, and the regulation of carcinogenic factors. Collectively, GSTP1 plays a major role in the development of various diseases.

Bromide ion-functionalized nanoprobes for sensitive and reliable pH measurement by surface-enhanced Raman spectroscopy.

4-Mercaptopyridine (4-Mpy) is a pH reporter molecule commonly used to functionalize nanoprobes for surface-enhanced Raman spectroscopy (SERS) based pH measurements. However, nanoprobes functionalized by 4-Mpy alone have low pH sensitivity and are subject to interference by halide ions in sample media. To improve nanoprobe pH sensitivity and reliability, we functionalized gold nanoparticles (AuNPs) with both 4-Mpy and bromide ion (Br-). Br- electrostatically stabilizes protonated 4-Mpy, thus enabling sensitive SERS detection of the protonation state of 4-Mpy as a function of pH while also reducing variability caused by external halide ions. Through optimization of the functionalization parameters, including suspension pH, [4-Mpy], and [Br-], the developed nanoprobes enable monitoring of pH from 2.1 to 10 with high SERS activity and minimal interference from halide ions within the sample matrix. As a proof of concept, we were able to track nanoprobe location and image the pH distribution inside individual cancer cells. This study provides a novel way to engineer reliable 4-Mpy-functionalized SERS nanoprobes for the sensitive analysis of spatially localized pH features in halide ion-containing microenvironments.

DIS3L2 Promotes Progression of Hepatocellular Carcinoma via hnRNP U-Mediated Alternative Splicing.

DIS3-like 3'-5' exoribonuclease 2 (DIS3L2) degrades aberrant RNAs, however, its function in tumorigenesis remains largely unexplored. Here, aberrant DIS3L2 expression promoted human hepatocellular carcinoma (HCC) progression via heterogeneous nuclear ribonucleoproteins (hnRNP) U-mediated alternative splicing. DIS3L2 directly interacted with hnRNP U through its cold-shock domains and promoted inclusion of exon 3b during splicing of pre-Rac1 independent of its exonuclease activity, yielding an oncogenic splicing variant, Rac1b, which is known to stimulate cellular transformation and tumorigenesis. DIS3L2 regulated alternative splicing by recruiting hnRNP U to pre-Rac1. Rac1b was critical for DIS3L2 promotion of liver cancer development both in vitro and in vivo. Importantly, DIS3L2 and Rac1b expression highly correlated with HCC progression and patient survival. Taken together, our findings uncover an oncogenic role of DIS3L2, in which it promotes liver cancer progression through a previously unappreciated mechanism of regulating hnRNP U-mediated alterative splicing. SIGNIFICANCE: These findings establish the role and mechanism of the 3'-5' exoribonuclease DIS3L2 in hepatocellular carcinoma carcinogenesis.

Amlodipine induces vasodilation via Akt2/Sp1-activated miR-21 in smooth muscle cells.

BACKGROUND AND PURPOSE: The calcium antagonist amlodipine exerts important cardioprotective effects by modulating smooth muscle and endothelial functions. However, the mechanisms underlying these effects are incompletely understood. EXPERIMENTAL APPROACH: Western blotting was used to compare the expression of key genes involved in vascular smooth muscle cell (VSMC) phenotype conversion. Recombinant adeno-associated virus system was used to regulate miRNA expression in rats via tail vein. Bioinformatics was used to predict the transcriptional regulation of miR-21 upstream followed by biochemical validation using quantitative real-time polymerase chain reaction, ChIP-qPCR and EMSA assays. KEY RESULTS: Only the calcium antagonist amlodipine, and no other type of anti-hypertensive drug, induced miR-21 overexpression in plasma and aortic vessels in the animal model. Real-time PCR and luciferase assays showed that amlodipine induced miR-21 overexpression in vascular smooth muscle cells. Western blot and immunofluorescence assays demonstrated that amlodipine activated Akt2, rather than Akt1, followed by activation of transcription factor Sp1, which regulated VSMC phenotype conversion via binding to the miR-21 promoter. Furthermore, bioinformatic analyses and luciferase assays demonstrated that amlodipine activated miR-21 transcription at the -2034/-2027 Sp1-binding site, which was further demonstrated by ChIP-qPCR and EMSA assays. Consistently, small-interfering RNA-mediated knockdown of Akt2 and Sp1 significantly attenuated the effects of amlodipine on miR-21 expression in smooth muscle cells. CONCLUSION AND IMPLICATIONS: These results indicate that amlodipine induces smooth muscle cell differentiation via miR-21, which is regulated by p-Akt2 and Sp1 nuclear translocation, thereby providing a novel target for cardiovascular diseases.

Polo-like kinase 1 coordinates biosynthesis during cell cycle progression by directly activating pentose phosphate pathway.

Two hallmarks for cancer cells are the accelerated cell cycle progression as well as the altered metabolism, however, how these changes are coordinated to optimize the growth advantage for cancer cells are still poorly understood. Here we identify that Polo-like kinase 1 (Plk1), a key regulator for cell mitosis, plays a critical role for biosynthesis in cancer cells through activating pentose phosphate pathway (PPP). We find that Plk1 interacts with and directly phosphorylates glucose-6-phosphate dehydrogenase (G6PD). By activating G6PD through promoting the formation of its active dimer, Plk1 increases PPP flux and directs glucose to the synthesis of macromolecules. Importantly, we further demonstrate that Plk1-mediated activation of G6PD is critical for its role to promote cell cycle progression and cancer cell growth. Collectively, these findings establish a critical role for Plk1 in regulating biosynthesis in cancer cells, exemplifying how cell cycle progression and metabolic reprogramming are coordinated for cancer progression.

Highly stable SERS pH nanoprobes produced by co-solvent controlled AuNP aggregation.

Production of gold nanoparticle (AuNP) surface-enhanced Raman spectroscopy (SERS) nanoprobes requires replicable aggregation to produce multimers with high signal intensity. Herein, we illustrate a novel, yet simple, approach to produce SERS nanoprobes through control of co-solvent composition. AuNP multimers were produced by mixing AuNP monomers in water : ethanol co-solvent for variable periods of time. By varying the water : ethanol ratio and the amount of 4-mercaptobenzoic acid (4-MBA) present, the aggregation rate can be systematically controlled. Thiolated poly(ethylene glycol) was then added to halt the aggregation process and provide steric stability. This approach was used to produce pH nanoprobes with excellent colloidal stability in high ionic strength environments and in complex samples. The pH probe exhibits broad pH sensitivity over the range 6-11 and we calculate that a single AuNP dimer in a 35 fL volume is sufficient to generate a detectable SERS signal. As a proof-of-concept, the probes were used to detect the intracellular pH of human prostate cancer cells (PC-3). The internalized probes exhibit a strong 4-MBA signal without any interfering bands from either the cells or the culture media and produce exceptionally detailed pH maps. pH maps obtained from 19 xy surface scans and 14 yz depth scans exhibit highly consistent intracellular pH in the range of 5 to 7, thus indicating the greater reliability and reproducibility of our pH probes compared with other probes previously reported in the literature. Our water : ethanol co-solvent production process is fast, simple, and efficient. Adjustment of solvent composition may become a powerful way to produce SERS tags or nanoprobes in the future.

Polyethylenimine-impregnated resin for high CO2 adsorption: an efficient adsorbent for CO2 capture from simulated flue gas and ambient air.

Polyethylenimine (PEI)-impregnated resins with high CO2 adsorption capacity were successfully prepared in this study. The nonpolar resin HP20 was suitable for PEI loading to achieve high CO2 adsorption, and the optimal PEI loading was 50 wt %. On the basis of the pore-size distribution of the resin before and after PEI modification, it can be found that mesopores of <43 nm were mainly responsible for PEI loading and pores in the range of 43-68 nm were probably favorable for CO2 diffusion. The adsorbed amount of CO2 on HP20/PEI-50 decreased with increasing adsorption temperature because of the dominant role of exothermic reaction of CO2 adsorption. The adsorption of CO2 on the adsorbent was very fast, and sorption equilibrium was achieved within 6 min at 75 °C. HP20/PEI-50 almost kept a stable adsorption capacity for CO2 at concentrations of 15 vol % and 400 ppm in the consecutive adsorption-desorption cycles, and its adsorption capacity was 181 mg/g from pure CO2 and 99.3 mg/g from 400 ppm CO2 at 25 °C, higher than all PEI-modified materials reported. The high volume-based amount of CO2 adsorbed on HP20/PEI-50 (96.0 mg/cm(3) at 25 °C and 84.5 mg/cm(3) at 75 °C for pure CO2) is beneficial to reducing the required volume of the adsorption bed for CO2 capture. This spherical and stable HP20/PEI-50 adsorbent with high and fast CO2 adsorption exhibits a very promising application in CO2 capture from flue gas and ambient air.