Glutamine Synthetase as a Therapeutic Target for Cancer Treatment.

The significance of glutamine in cancer metabolism has been extensively studied. Cancer cells consume an excessive amount of glutamine to facilitate rapid proliferation. Thus, glutamine depletion occurs in various cancer types, especially in poorly vascularized cancers. This makes glutamine synthetase (GS), the only enzyme responsible for de novo synthesizing glutamine, essential in cancer metabolism. In cancer, GS exhibits pro-tumoral features by synthesizing glutamine, supporting nucleotide synthesis. Furthermore, GS is highly expressed in the tumor microenvironment (TME) and provides glutamine to cancer cells, allowing cancer cells to maintain sufficient glutamine level for glutamine catabolism. Glutamine catabolism, the opposite reaction of glutamine synthesis by GS, is well known for supporting cancer cell proliferation via contributing biosynthesis of various essential molecules and energy production. Either glutamine anabolism or catabolism has a critical function in cancer metabolism depending on the complex nature and microenvironment of cancers. In this review, we focus on the role of GS in a variety of cancer types and microenvironments and highlight the mechanism of GS at the transcriptional and post-translational levels. Lastly, we discuss the therapeutic implications of targeting GS in cancer.

Combination of ACY-241 and JQ1 Synergistically Suppresses Metastasis of HNSCC via Regulation of MMP-2 and MMP-9.

Overexpression of histone deacetylase 6 (HDAC6) and bromodomain-containing protein 4 (BRD4) is related to aggressiveness of head and neck squamous carcinoma (HNSCC). Based on studies that HDAC6 and BRD4 are potential therapeutic targets of HNSCC, we hypothesized that the combination treatment of BET inhibitor JQ1 and HDAC6-selective inhibitor ACY-241 could exhibit synergistic anticancer effects in human papillomavirus (HPV)-positive and HPV-negative HNSCC cells. In this study, HNSCC cell growth and viability were measured by CCK-8 assay, apoptosis was analyzed by flow cytometry, and metastasis was studied by wound healing and transwell assays. Furthermore, immunoblotting is conducted to investigate proteins that modulate apoptosis or metastasis. Here, we report that the combination of ACY-241 and JQ1 shows synergistic cell growth inhibition, viability reduction, and apoptosis induction in HNSCC cells through inactivation of AKT and NF-κB signaling. Importantly, we demonstrate that combined treatment of ACY-241 and JQ1 synergistically suppresses TNF-α-induced migration and invasion via dysregulating matrix metalloproteinase (MMP)-2, MMP-9, and MT1-MMP. Overall, the combination of ACY-241 and JQ1 significantly suppresses proliferation and metastasis in HPV-positive and HPV-negative HNSCC. Collectively, these findings suggest that the co-inhibition of BET and HDAC6 can be a new therapeutic strategy in HNSCC.

Pulveribacter suum gen. nov., sp. nov., isolated from a pig farm dust collector.

An aerobic, Gram-stain-negative, polar-flagellated, rod-shaped bacterium, designated as SC2-7T, was isolated from the dust collector at a pig farm located in Wanju-gun, Jeollabuk-do, Republic of Korea. Growth occurred at 10-37 °C (optimum, 28-30 °C), pH 6.0-10.0 (optimum, 7.0-8.0) and in the presence of 0-3 % (w/v) NaCl (optimum, 0 %) on Reasoner's 2A medium. The phylogenetic tree based on the 16S rRNA gene sequences revealed that strain SC2-7T was a member of the family Comamonadaceae, forming a robust cluster with the genera Alicycliphilus, Oryzisolibacter and Melaminivora. The 16S rRNA gene sequences of strain SC2-7T showed the highest sequence similarities to Alicycliphilus denitrificans K601T (97.2 %), Oryzisolibacter propanilivorax EPL6T (97.0 %), Melaminivora alkalimesophila CY1T (96.9 %), Diaphorobacter polyhydroxybutyrativorans SL-205T (96.6 %), Diaphorobacter nitroreducens NA10BT (96.6 %) and Melaminivora jejuensis KBB12T (96.5 %). The tree based on the gyrA gene sequences also showed that strain SC2-7T fell into a phylogenetic position similar to that based on the 16S rRNA gene sequences. The polar lipids present were phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol, an unidentified aminolipid and an unidentified phospholipid. The predominant quinone was ubiquione-8. The major fatty acids were summed feature 3 (including C16 : 1ω6c and/or C16 : 1ω7c), C16 : 0 and summed feature 8 (including C18 : 1ω6c and/or C18 : 1ω7c). The genomic DNA G+C content was 69.1 mol%. On the basis of the phenotypic, phylogenetic and chemotaxonomic data presented here, strain SC2-7T represents a novel species of a new genus, for which the name Pulveribacter suum gen. nov., sp. nov., is proposed. The type strain of Pulveribacter suum is SC2-7T (=KACC 19309T=NBRC 113102T).

Paracoccus suum sp. nov., isolated from a pig farm dust collector.

A Gram-stain-negative, strictly aerobic, non-motile, non-spore-forming, coccoid- or short rod-shaped bacterial strain, designated SC2-6T, was isolated from a dust collector of a pig farm located in Wanju-gun, Jeollabuk-do, Republic of Korea. Strain SC2-6T grew within the ranges of 10-37 °C (28-30 °C, optimally), pH 6.0-10.0 (pH 7.0-8.0, optimally) and 0-3% NaCl (w/v). The 16S rRNA gene sequence similarity of strain SC2-6T showed the highest values to Paracoccus kondratievae GBT (96.3%), Paracoccus denitrificans DSM 413T (96.3%) and Paracoccus sanguinis 5503T (96.1%). The phylogenetic tree based on the 16S rRNA gene sequences revealed that strain SC2-6T belonged to the genus Paracoccus and clustered with Paracoccus pacificus F14T. The phylogenetic tree based on the rpoD gene sequences also demonstrated that strain SC2-6T fell into the clade of the genus Paracoccus. The DNA G+C content was 66.9 mol%. The major respiratory quinone was ubiquinone-10 and the major fatty acids (> 10% of the total fatty acids) were summed feature 8 (comprising C18 : 1 ω6c and/or C18 : 1 ω7c). The polar lipids were composed of diphosphatidylglycerol, phosphatidylcholine, an unidentified glycolipid, two unidentified aminolipids and two unidentified lipids. On the basis of phenotypic, phylogenetic and genomic data, strain SC2-6T was classified in the genus Paracoccus as a member of a novel species, for which the name Paracoccus suum sp. nov. is proposed. The type strain is SC2-6T (=KACC 19328T=NBRC 113110T).

Simplicispira suum sp. nov., isolated from a dust collector at a pig farm.

A novel Gram-stain-negative, strictly aerobic, polar-flagellated and rod-shaped bacterium, designated SC1-8T, was isolated from a dust collector at a pig farm located in Wanju-gun, Jeollabuk-do, Republic of Korea. The strain grew within a temperature range of 4-37 °C (optimum, 28-30 °C), at pH 7.0-9.0 (pH 7.0-8.0) and with 0-2 % (w/v) NaCl (0 %). Colonies were white-beige, circular and convex after 4 days of incubation on Reasoner's 2A agar. Based on the 16S rRNA gene sequence analysis, strain SC1-8T was a member of the genus Simplicispira, revealing the highest sequence similarities to Simplicispira limi EMB325T (97.9 %), Simplicispira psychrophila DSM 11588T (97.4 %), Acidovorax defluvii BSB411T (97.3 %), Simplicispira piscis RSG39T (97.1 %) and Simplicispira metamorpha DSM 1837T (97.0 %). The predominant respiratory quinone was Q-8. The polar lipids were phosphatidylethanolamone, diphosphatidylglycerol and phosphatidylglycerol. The major fatty acids (>10 % of the total fatty acids) were composed of C16 : 0 and summed feature 3 (C16 : 1ω6c and/or C16 : 1ω7c). The DNA G+C content was 63.3 mol%. On the basis of phenotypic, genotypic and phylogenetic evidence, strain SC1-8T is presented as a novel species, for which the name Simplicispira suum sp. nov. is proposed. The type strain is SC1-8T (=KACC 19329T=NBRC 113111T).

Evolutionarily informed machine learning enhances the power of predictive gene-to-phenotype relationships.

Inferring phenotypic outcomes from genomic features is both a promise and challenge for systems biology. Using gene expression data to predict phenotypic outcomes, and functionally validating the genes with predictive powers are two challenges we address in this study. We applied an evolutionarily informed machine learning approach to predict phenotypes based on transcriptome responses shared both within and across species. Specifically, we exploited the phenotypic diversity in nitrogen use efficiency and evolutionarily conserved transcriptome responses to nitrogen treatments across Arabidopsis accessions and maize varieties. We demonstrate that using evolutionarily conserved nitrogen responsive genes is a biologically principled approach to reduce the feature dimensionality in machine learning that ultimately improved the predictive power of our gene-to-trait models. Further, we functionally validated seven candidate transcription factors with predictive power for NUE outcomes in Arabidopsis and one in maize. Moreover, application of our evolutionarily informed pipeline to other species including rice and mice models underscores its potential to uncover genes affecting any physiological or clinical traits of interest across biology, agriculture, or medicine.

Neighboring base sequence effect on DNA damage.

Guanine is the most strongly oxidized base in DNA; generation of a guanine radical cation as an intermediate in an oxidation reaction leads to migration through a resulting cationic hole in the DNA π-stack until it is trapped by irreversible reaction with water or other free radicals. In the case of normal sequences, the primary position of Guanine oxidations by one-electron oxidants such as carbonate radical anions, BPT(7,8,9,10-tetrahydroxytetrahydrobenzo[a]pyrene), and riboflavin are 5'-G in GG doublets and the central G in a GGG triplet. According to results, the properties of guanine oxidation on abasic site containing sequences are independent from the position of AP(apurinic/apyrimidinic) site in the presence of carbonate radical anions under a short irradiation time, although this radical is exposed to solvent by the existence of an abasic site. The lack of abasic site effect on guanine oxidative damage by the carbonate radical may be due to a sequence-independent property of the initial electron transfer rate in the hole injection step, or may relate to an electron transfer mechanism with large reorganization energy dependency. Consequently, the carbonate radical anions may easily migrate to another single G in the charge re-distribution step. Meanwhile, there is a strong dependency on the presence of an AP(apurinic/apyrimidinic) site in the cleavage patterns of guanine oxidations by physically large oxidizing agents, such as BPT(7,8,9,10-tetrahydroxytetrahydrobenzo[a]pyrene) and riboflavin. These radicals show strong AP(apurinic/apyrimidinic) site dependency and clear G-site selectivity.Communicated by Ramaswamy H. Sarma.

Advances in Histone Demethylase KDM3A as a Cancer Therapeutic Target.

Lysine-specific histone demethylase 3 (KDM3) subfamily proteins are H3K9me2/me1 histone demethylases that promote gene expression. The KDM3 subfamily primarily consists of four proteins (KDM3A-D). All four proteins contain the catalytic Jumonji C domain (JmjC) at their C-termini, but whether KDM3C has demethylase activity is under debate. In addition, KDM3 proteins contain a zinc-finger domain for DNA binding and an LXXLL motif for interacting with nuclear receptors. Of the KDM3 proteins, KDM3A is especially deregulated or overexpressed in multiple cancers, making it a potential cancer therapeutic target. However, no KDM3A-selective inhibitors have been identified to date because of the lack of structural information. Uncovering the distinct physiological and pathological functions of KDM3A and their structure will give insight into the development of novel selective inhibitors. In this review, we focus on recent studies highlighting the oncogenic functions of KDM3A in cancer. We also discuss existing KDM3A-related inhibitors and review their potential as therapeutic agents for overcoming cancer.

Binding mode of a cationic porphyrin to parallel and antiparallel thrombin binding aptamer G-quadruplex.

The spectral properties of meso-tetrakis (N-methylpyridinium-4-yl)porphyrin (TMPyP) in the presence of parallel and antiparallel G-quadruplexes formed from a thrombin-binding aptamer G-quadruplex (5'-G3T2G3TGTG3T2G3) were investigated in this study. Red shift and hypochromism in the Soret absorption band of TMPyP were observed after binding to both parallel and antiparallel G-quadruplexes. The extent of changes in the absorption spectra were similar for both conformers. No circular dichroism spectrum was induced in the Soret region for both parallel and antiparallel G-quadruplexes. This is suggest that there is no or very weak interaction between electric transitions of nucleobases and porphyrin molecule. The accessibility of the neutral quencher I2 to the G-quadruplex-bound TMPyP was similar for both parallel and antiparallel G-quadruplexes. All these observations suggest that TMPyP was bound at the outside of the quadruplexes, and conceivably interacted with the phosphate group via a weak electrostatic interaction.Communicated by Ramaswamy H. Sarma.

Automatic delirium prediction system and nursing-sensitive outcomes in the medical intensive care unit.

In Korea, delirium risk screening has not been routinely implemented in intensive care units (ICUs). The purpose of this study was to implement an Automatic Prediction of Delirium in Intensive Care Units (APREDEL-ICU) system to investigate its impact on nursing-sensitive outcomes and to assess nurse satisfaction with the system. A pre-post research design was used. A total of 145 patients were involved prior to the system implementation and 172 were involved after implementation. Forty medical ICU nurses evaluated the system. The APREDEL-ICU system did not result in a reduction in the incidence of delirium. However, the nurses reported that their knowledge regarding delirium care increased after the system was introduced. The proposed system was successfully implemented without increasing the burden of nurses in their assessment of delirium risk. Long-term use of APREDEL-ICU could enhance preventive care and consequently result in positive patient outcomes.

Promoter decommissioning by the NuRD chromatin remodeling complex triggers synaptic connectivity in the mammalian brain.

Precise control of gene expression plays fundamental roles in brain development, but the roles of chromatin regulators in neuronal connectivity have remained poorly understood. We report that depletion of the NuRD complex by in vivo RNAi and conditional knockout of the core NuRD subunit Chd4 profoundly impairs the establishment of granule neuron parallel fiber/Purkinje cell synapses in the rodent cerebellar cortex in vivo. By interfacing genome-wide sequencing of transcripts and ChIP-seq analyses, we uncover a network of repressed genes and distinct histone modifications at target gene promoters that are developmentally regulated by the NuRD complex in the cerebellum in vivo. Finally, in a targeted in vivo RNAi screen of NuRD target genes, we identify a program of NuRD-repressed genes that operate as critical regulators of presynaptic differentiation in the cerebellar cortex. Our findings define NuRD-dependent promoter decommissioning as a developmentally regulated programming mechanism that drives synaptic connectivity in the mammalian brain.