The upregulation of VGF enhances the progression of oral squamous carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a prevalent neoplasm worldwide, necessitating a deeper understanding of its pathogenesis. VGF nerve growth factor inducible (VGF), a neuropeptide, plays critical roles in nerve and endocrine cell regulation. METHODS: In this study, the TCGA datasets were initially screened, identifying the upregulation of VGF in various malignancies. We focused on OSCC cell lines, identifying the suppressor mRNA miR-432-5p as a negative regulator of VGF. Additionally, we examined the prognostic value of VGF expression in OSCC tumors and its impact on cellular functions. RESULTS: VGF expression was found to be an independent prognostic predictor in OSCC tumors. Cells expressing VGF exhibited increased oncogenicity, influencing the proliferation and migration of oral mucosal fibroblast. Transcriptome analysis revealed associations between VGF and various pathological processes, including malignancies, exosome release, fibrosis, cell cycle disruption, and tumor immune suppression. Moreover, IL23R expression, a favorable OSCC prognostic factor, was inversely correlated with VGF expression. Exogenous IL23R expression was found to suppress VGF-associated mobility phenotypes. CONCLUSIONS: This study highlights the multifaceted role of VGF in OSCC pathogenesis and introduces the miR-432-5p-VGF-IL23R regulatory axis as a critical mediator. The combined expression of VGF and IL23R emerges as a potent predictor of survival in oral carcinoma cases, suggesting potential implications for future therapeutic strategies.

Cold Atmospheric Plasma Jet Irradiation Decreases the Survival and the Expression of Oncogenic miRNAs of Oral Carcinoma Cells.

Despite recent advancements, therapies against advanced oral squamous cell carcinoma (OSCC) remain ineffective, resulting in unsatisfactory therapeutic outcomes. Cold atmospheric plasma (CAP) offers a promising approach in the treatment of malignant neoplasms. Although the effects of CAP in abrogating OSCC have been explored, the exact mechanisms driving CAP-induced cancer cell death and the changes in microRNA (miRNA) expression are not fully understood. We fabricated and calibrated an argon-CAP device to explore the effects of CAP irradiation on the growth and expression of oncogenic miRNAs in OSCC. The analysis revealed that, in OSCC cell lines following CAP irradiation, there was a significant reduction in viability; a downregulation of miR-21, miR-31, miR-134, miR-146a, and miR-211 expression; and an inactivation of the v-akt murine thymoma viral oncogene homolog (AKT) and extracellular signal-regulated kinase (ERK) signals. Pretreatment with blockers of apoptosis, autophagy, and ferroptosis synergistically reduced CAP-induced cell death, indicating a combined induction of variable death pathways via CAP. Combined treatments using death inhibitors and miRNA mimics, alongside the activation of AKT and ERK following the exogenous expression, counteracted the cell mortality associated with CAP. The CAP-induced downregulation of miR-21, miR-31, miR-187, and miR-211 expression was rescued through survival signaling. Additionally, CAP irradiation notably inhibited the growth of SAS OSCC cell xenografts on nude mice. The reduced expression of oncogenic miRNAs in vivo aligned with in vitro findings. In conclusion, our study provides new lines of evidence demonstrating that CAP irradiation diminishes OSCC cell viability by abrogating survival signals and oncogenic miRNA expression.

The Concordant Disruption of B7/CD28 Immune Regulators Predicts the Prognosis of Oral Carcinomas.

Immune modulation is a critical factor in determining the survival of patients with malignancies, including those with oral squamous cell carcinoma (OSCC) and head and neck SCC (HNSCC). Immune escape or stimulation may be driven by the B7/CD28 family and other checkpoint molecules, forming ligand-receptor complexes with immune cells in the tumor microenvironment. Since the members of B7/CD28 can functionally compensate for or counteract each other, the concomitant disruption of multiple members of B7/CD28 in OSCC or HNSCC pathogenesis remains elusive. Transcriptome analysis was performed on 54 OSCC tumors and 28 paired normal oral tissue samples. Upregulation of CD80, CD86, PD-L1, PD-L2, CD276, VTCN1, and CTLA4 and downregulation of L-ICOS in OSCC relative to the control were noted. Concordance in the expression of CD80, CD86, PD-L1, PD-L2, and L-ICOS with CD28 members was observed across tumors. Lower ICOS expression indicated a worse prognosis in late-stage tumors. Moreover, tumors harboring higher PD-L1/ICOS, PD-L2/ICOS, or CD276/ICOS expression ratios had a worse prognosis. The survival of node-positive patients was further worsened in tumors exhibiting higher ratios between PD-L1, PD-L2, or CD276 and ICOS. Alterations in T cell, macrophage, myeloid dendritic cell, and mast cell populations in tumors relative to controls were found. Decreased memory B cells, CD8+ T cells, and Tregs, together with increased resting NK cells and M0 macrophages, occurred in tumors with a worse prognosis. This study confirmed frequent upregulation and eminent co-disruption of B7/CD28 members in OSCC tumors. The ratio between PD-L2 and ICOS is a promising survival predictor in node-positive HNSCC patients.

Precise Identification of Recurrent Somatic Mutations in Oral Cancer Through Whole-Exome Sequencing Using Multiple Mutation Calling Pipelines.

Understanding the genomic alterations in oral carcinogenesis remains crucial for the appropriate diagnosis and treatment of oral squamous cell carcinoma (OSCC). To unveil the mutational spectrum, in this study, we conducted whole-exome sequencing (WES), using six mutation calling pipelines and multiple filtering criteria applied to 50 paired OSCC samples. The tumor mutation burden extracted from the data set of somatic variations was significantly associated with age, tumor staging, and survival. Several genes (MUC16, MUC19, KMT2D, TTN, HERC2) with a high frequency of false positive mutations were identified. Moreover, known (TP53, FAT1, EPHA2, NOTCH1, CASP8, and PIK3CA) and novel (HYDIN, ALPK3, ASXL1, USP9X, SKOR2, CPLANE1, STARD9, and NSD2) genes have been found to be significantly and frequently mutated in OSCC. Further analysis of gene alteration status with clinical parameters revealed that canonical pathways, including clathrin-mediated endocytotic signaling, NFκB signaling, PEDF signaling, and calcium signaling were associated with OSCC prognosis. Defining a catalog of targetable genomic alterations showed that 58% of the tumors carried at least one aberrant event that may potentially be targeted by approved therapeutic agents. We found molecular OSCC subgroups which were correlated with etiology and prognosis while defining the landscape of major altered events in the coding regions of OSCC genomes. These findings provide information that will be helpful in the design of clinical trials on targeted therapies and in the stratification of patients with OSCC according to therapeutic efficacy.

miR-31-NUMB Cascade Modulates Monocarboxylate Transporters to Increase Oncogenicity and Lactate Production of Oral Carcinoma Cells.

Oral squamous cell carcinoma (OSCC) is among the leading causes of cancer-associated death worldwide. miR-31 is an oncogenic miRNA in OSCC. NUMB is an adaptor protein capable of suppressing malignant transformation. Disruption of the miR-31-NUMB regulatory axis has been demonstrated in malignancies. Mitochondrial dysfunction and adaptation to glycolytic respiration are frequent events in malignancies. Monocarboxylate transporters (MCTs) function to facilitate lactate flux in highly glycolytic cells. Upregulation of MCT1 and MCT4 has been shown to be a prognostic factor of OSCC. Here, we reported that miR-31-NUMB can modulate glycolysis in OSCC. Using the CRISPR/Cas9 gene editing strategy, we identified increases in oncogenic phenotypes, MCT1 and MCT4 expression, lactate production, and glycolytic respiration in NUMB-deleted OSCC subclones. Transfection of the Numb1 or Numb4 isoform reversed the oncogenic induction elicited by NUMB deletion. This study also showed, for the first time, that NUMB4 binds MCT1 and MCT4 and that this binding increases their ubiquitination, which may decrease their abundance in cell lysates. The disruptions in oncogenicity and metabolism associated with miR-31 deletion and NUMB deletion were partially rescued by MCT1/MCT4 expression or knockdown. This study demonstrated that NUMB is a novel binding partner of MCT1 and MCT4 and that the miR-31-NUMB-MCT1/MCT4 regulatory cascade is present in oral carcinoma.

LncRNA MIR31HG Drives Oncogenicity by Inhibiting the Limb-Bud and Heart Development Gene (LBH) during Oral Carcinoma.

The miR-31 host gene (MIR31HG) encodes a long non-coding RNA (LncRNA) that harbors miR-31 in its intron 2; miR-31 promotes malignant neoplastic progression. Overexpression of MIR31HG and of miR-31 occurs during oral squamous cell carcinoma (OSCC). However, the downstream effectors modulated by MIR31HG during OSCC pathogenesis remain unclear. The present study identifies up-regulation of MIR31HG expression during the potentially premalignant disorder stage of oral carcinogenesis. The potential of MIR31HG to enhance oncogenicity and to activate Wnt and FAK was identified when there was exogenous MIR31HG expression in OSCC cells. Furthermore, OSCC cell subclones with MIR31HG deleted were established using a Crispr/Cas9 strategy. RNA sequencing data obtained from cells expressing MIR31HG, cells with MIR31HG deleted and cells with miR-31 deleted identified 17 candidate genes that seem to be modulated by MIR31HG in OSCC cells. A TCGA database algorithm pinpointed MMP1, BMP2 and Limb-Bud and Heart development (LBH) as effector genes controlled by MIR31HG during OSCC. Exogenous LBH expression decreases tumor cell invasiveness, while knockdown of LBH reverses the oncogenic suppression present in MIR31HG deletion subclones. The study provides novel insights demonstrating the contribution of the MIR31HG-LBH cascade to oral carcinogenesis.

Entangling capacities and the geometry of quantum operations.

Quantum operations are the fundamental transformations on quantum states. In this work, we study the relation between entangling capacities of operations, geometry of operations, and positive partial transpose (PPT) states, which are an important class of states in quantum information. We show a method to calculate bounds for entangling capacity, the amount of entanglement that can be produced by a quantum operation, in terms of negativity, a measure of entanglement. The bounds of entangling capacity are found to be associated with how non-PPT (PPT preserving) an operation is. A length that quantifies both entangling capacity/entanglement and PPT-ness of an operation or state can be defined, establishing a geometry characterized by PPT-ness. The distance derived from the length bounds the relative entangling capability, endowing the geometry with more physical significance. We also demonstrate the equivalence of PPT-ness and separability for unitary operations.

Querying large graphs in biomedicine with colored graphs and decomposition.

In graph networks, graph structural analytics such as betweenness centrality has played an important role in finding the most central vertices in graph data. Hence, betweenness centrality has been heavily applied to discover the most important genes with respect to multiple diseases in biomedicine research. Considering color as a property of graph data to represent different categories for the nodes and edges in the graph, we may investigate the betweenness centrality of each colored subgraph composed of a specific color. However, as investigators may be interested in querying betweenness centrality on multiple combinations of the colored subgraphs, the total execution time on all the subgraphs may be excessively long, considering all the possible combinations. In addition, the performance could be worse when the size of the graph grows larger. In this research, we propose an approach to computing betweenness centrality by incorporating node colors and edge colors. We propose that the node with the highest betweenness centrality can be computed for a very large and colored graph by decomposing the graph into colored subgraphs and merging the result from the base cases. Furthermore, we compare our approach with the conventional approaches in the experiments, and we demonstrate that our scalable approach is more efficient when finding the global backbone node with the highest betweenness centrality.

miR-187* Enhances SiHa Cervical Cancer Cell Oncogenicity Via Suppression of WWOX.

BACKGROUND/AIM: Cervical cancer is one of the most common cancers worldwide and a major cause of cancer-related mortality among women. Previous studies have reported that microRNA-miR-187*, which is one of the non-coding parts of the genome producing small conserved ribonucleic acids, is associated with various cancers. In this study, we explored the function of miR-187* in cervical cancer cells. MATERIALS AND METHODS: miR-187* mimic, WWOX reporter constructs, siRNA and overexpression constructs were transfected into SiHa cells to investigate the function and regulatory mechanisms of miR-187*. RESULTS: Exogenous miR-187* was found to increase the oncogenic phenotypes of SiHa cells. The tumor suppressor gene WWOX is a novel target of miR-187* in SiHa cells. WWOX siRNA suppressed endogenous WWOX expression and increased the oncogenic phenotypes of SiHa cells. Exogenous WWOX expression was able to suppress the oncogenic phenotypes of SiHa cells and rescue cells from miR-187*-induced migration. CONCLUSION: miR-187* seems to enhance SiHa cervical cancer cell oncogenicity via suppression of the WWOX pathway.

MicroRNA miR-31 targets SIRT3 to disrupt mitochondrial activity and increase oxidative stress in oral carcinoma.

MicroRNA miR-31 is implicated in the neoplastic process of various malignancies including oral squamous cell carcinoma (OSCC). Silent information regulator 3 (Sirtuin3 or SIRT3) is a NAD-dependent deacetylase that regulates metabolic process. Suppressor role of SIRT3 has been found in neoplasms. This study investigates the disruptions of miR-31-SIRT3 cascade to explore their potential association with metabolic change in OSCC. We identified that miR-31 directly targeted SIRT3 in OSCC cells, and a reverse correlation between miR-31 expression and SIRT3 expression was noted in OSCC tumors. SIRT3 expression attenuated the miR-31 enhanced tumor cell migration and invasion. It also reduced the tumorigenic potential of FaDu cell line. miR-31-SIRT3 impaired the mitochondrial membrane potential and structural integrity. The dis-regulation of this axis also contributed to the genesis of oxidative stress. In addition, miR-31 switched tumor cells from aerobic metabolism to glycolytic metabolism. This study provides novel evidences demonstrating the presence of miR-31-mediated post-transcriptional regulation of SIRT3 in OSCC. The disruption of miR-31-SIRT3 cascade and the consequential metabolic aberrances are involved in OSCC progression.

Establishing of mouse oral carcinoma cell lines derived from transgenic mice and their use as syngeneic tumorigenesis models.

BACKGROUND: The survival of OSCC patient needs to be further improved. miR-211 is oncogenic in OSCC and its upregulation is associated with tumor progression and poor patient survival. K14-EGFP-miR-211 transgenic mice also exhibit augmented potential for OSCC induction. METHODS: Four murine OSCC cell lines, designated MOC-L1 to MOC-L4, are established from tongue tumors induced by 4-nitroquinoline 1-oxide using the K14-EGFP-miR-211 transgenic mouse model. The genetic disruption, in vitro oncogenicity, and the eligibilities of tumorigenesis and metastasis of the cell lines are analyzed. RESULTS: All cell lines show green fluorescence and express a range of epithelial markers. The MOC-L1, MOC-L2 and MOC-L3 cells carry missense mutations in the DNA binding domain of the p53 gene. MOC-L1 exhibits a high level of epithelial-mesenchymal transition and has the aggressive characteristics associated with this. MOC-L1 and MOC-L2 are clonogenic in vitro as well as being tumorigenic when implanted into the dermis or tongue of syngeneic recipients. Nonetheless, only MOC-L1 exhibits immense potential for local regional and distal metastasis. Since the expression of miR-196b in MOC-L1 xenografts is drastically decreased on cisplatin treatment, it would seem that targeting of miR-196b might facilitate tumor abrogation. CONCLUSIONS: As cell lines established in this study originated from the C57BL/6 mouse, the strain most suitable for transgenic engineering, exploring the interplay of these OSCC cells with other genetically modified cells in immune-competent mice would provide important insights into OSCC pathogenesis.

miR-125b suppresses oral oncogenicity by targeting the anti-oxidative gene PRXL2A.

Oral squamous cell carcinoma (OSCC) is a globally prevalent malignancy. The molecular mechanisms of this cancer are not well understood and acquire elucidation. Peroxiredoxin like 2A (PRXL2A) has been reported to be an antioxidant protein that protects cells from oxidative stress. Our previous study identified an association between PRXL2A upregulation in OSCC and a worse patient prognosis. MicroRNAs (miRNAs) are small non-coding RNAs that are involved in the modulation of biological/pathological properties. The miR-125 family of genes drive pluripotent regulation across a wide variety of cancers. In this study, we identify the oncogenic eligibility of PRXL2A and clarify miR-125b as its upstream regulator. Downregulation of miR-125b can be observed in OSCC tumors. Lower miR-125b expression in tumors results in a worse patient prognosis at the relatively early stage. Reporter assays are able to validate that PRXL2A is a direct target of miR-125b. Exogenous miR-125b expression in OSCC cells results in increased oxidative stress, increased drug sensitivity, and suppressor activity that is paralleled by the knockout of PRXL2A gene. The suppressor activity of miR-125b is able to be rescued by PRXL2A, which suggests the existence of a miR-125b-PRXL2A regulatory axis that is part of OSCC pathogenesis. Nuclear factor-erythroid 2-related factor 2 (NRF2) was found to be a downstream effector of the miR-125b-PRXL2A cascade. As a whole, this study has pinpointed novel clues demonstrating that downregulation of miR-125b suppressor underlies upregulation of PRXL2A in OSCC, and this then protects the affected tumor cells from oxidative stress.

Supremum of block entanglement for symmetric Gaussian states.

For a system composed of permutationally symmetric Gaussian modes, by identifying the boundary of valid states and making necessary change of variables, the existence and exact value of the supremum of logarithmic negativity (and negativity likewise) between any two blocks can be shown analytically. Involving only the total number of interchangeable modes and the sizes of respective blocks, this result is general and easy to be applied for such a class of states.

Targeting of miR-31/96/182 to the Numb gene during head and neck oncogenesis.

BACKGROUND: MicroRNAs (miRNAs) play crucial roles in head and neck squamous cell carcinoma (HNSCC). This study investigates whether miR-31, miR-96, and miR-182 are involved in targeting Numb during HNSCC. METHODS: The expression of miR-31/96/182 in tumor tissues was analyzed. Reporter assay, knockdown, expression, and oncogenic analysis were carried out in cell lines. RESULTS: Upregulation of miR-31/96/182 was detected in tumor tissues. In addition, advanced tumors showed higher expression levels of these miRNAs. The expression of these miRNAs was upregulated after treatment with areca ingredients (P < .01 or P < .001). These miRNAs directly targeted the 3' untranslated region (UTR) sequence of the Numb gene. An increased migration and invasion of HNSCC cells was associated with the exogenous expression of miR-31/96/182 (P < .01 or P < .001), and this was reverted by expression of Numb. CONCLUSION: This study provides new evidence demonstrating that there is frequent and concordant upregulation of miR-31, miR-96, and miR-182 during HNSCC and these miRNAs co-target Numb.

Exact master equation and quantum decoherence of two coupled harmonic oscillators in a general environment.

In this paper we derive an exact master equation for two coupled quantum harmonic oscillators interacting via bilinear coupling with a common environment at arbitrary temperature made up of many harmonic oscillators with a general spectral density function. We first show a simple derivation based on the observation that the two harmonic oscillator model can be effectively mapped into that of a single harmonic oscillator in a general environment plus a free harmonic oscillator. Since the exact one harmonic oscillator master equation is available [B. L. Hu, J. P. Paz, and Y. Zhang, Phys. Rev. D 45, 2843 (1992)], the exact master equation with all its coefficients for this two harmonic oscillator model can be easily deduced from the known results of the single harmonic oscillator case. In the second part we give an influence functional treatment of this model and provide explicit expressions for the evolutionary operator of the reduced density matrix which are useful for the study of decoherence and disentanglement issues. We show three applications of this master equation: on the decoherence and disentanglement of two harmonic oscillators due to their interaction with a common environment under Markovian approximation, and a derivation of the uncertainty principle at finite temperature for a composite object, modeled by two interacting harmonic oscillators. The exact master equation for two, and its generalization to N, harmonic oscillators interacting with a general environment are expected to be useful for the analysis of quantum coherence, entanglement, fluctuations, and dissipation of mesoscopic objects toward the construction of a theoretical framework for macroscopic quantum phenomena.

Oxidation of linear trinuclear ruthenium complexes [Ru(3)(dpa)(4)Cl(2)] and [Ru(3)(dpa)(4)(CN)(2)]: synthesis, structures, electrochemical and magnetic properties.

The neutral, monocationic, and dicationic linear trinuclear ruthenium compounds [Ru(3)(dpa)(4)(CN)(2)], [Ru(3)(dpa)(4)(CN)(2)][BF(4)], [Ru(3)(dpa)(4)Cl(2)][BF(4)], and [Ru(3)(dpa)(4)Cl(2)][BF(4)](2) (dpa=the anion of dipyridylamine) have been synthesized and characterized by various spectroscopic techniques. Cyclic voltammetric and spectroelectrochemical studies on the neutral and oxidized compounds are reported. These compounds undergo three successive metal-centered one-electron-transfer processes. X-ray structural studies reveal a symmetrical Ru(3) unit for these compounds. While the metal--metal bond lengths change only slightly, the metal--axial ligand lengths exhibit a significant decrease upon oxidation of the neutral complex. The electronic configuration of the Ru(3) unit changes as the axial chloride ligands are replaced by the stronger "pi-acid" cyanide axial ligands. Magnetic measurements and (1)H NMR spectra indicate that [Ru(3)(dpa)(4)Cl(2)] and [Ru(3)(dpa)(4)Cl(2)][BF(4)](2) are in a spin state of S=0 and [Ru(3)(dpa)(4)Cl(2)][BF(4)], [Ru(3)(dpa)(4)(CN)(2)], and [Ru(3)(dpa)(4)(CN)(2)][BF(4)] are in spin states of S=1/2, 1, and 3/2, respectively. These results are consistent with molecular orbital (MO) calculations.

Synthesis and properties of novel thiophene-based conjugated homologues: 9,9-diphenylfluorene-capped oligothiophenes.

[reaction: see text] A series of novel 9,9-diarylfluorene-capped oligothiophenes were synthesized by Suzuki coupling reactions in good yields. The color of the emissions can be controlled by varying the conjugation length of the oligothiophene core. The bulky and rigid terminal groups of the resulting oligomers are significantly beneficial for their high morphological and thermal stability. These new oligothiophenes exhibit intriguing reversible oxidation and reduction redox behavior.

Ter(9,9-diarylfluorene)s: highly efficient blue emitter with promising electrochemical and thermal stability.

Novel ter(9,9-diarylfluorene)s were synthesized by a Suzuki-coupling reaction of 2-bromofluorene (1) and 2,7-fluorenediboronic ester derivatives (3) with high isolated yields (63-86%). The X-ray structure analysis of ter(9,9'-spirobifluorene) (4aa) revealed that the conjugated chromophore adopts a helical conformation. This conformation effectively releases the steric interaction between the fluorene moieties and prevents inter-chromophore interactions. The introduction of aryl groups at the C9 position of fluorene was highly beneficial to the thermal and morphological stability of these oligomers. These terfluorenes exhibit intense blue fluorescence with excellent quantum yields both in solution ( approximately 100%) and in solid state (66-90%), and possess interesting reversible redox properties. Highly efficient blue light-emitting OLED devices were fabricated using 4aa and 4cc as emitters as well as hole transporters. The devices exhibit low turn-on voltage ( approximately 3 V) and high EL external quantum efficiency (2.5-3%).

Suzuki coupling approach for the synthesis of phenylene-pyrimidine alternating oligomers for blue light-emitting material.

[reaction: see text] Conjugated oligomers with an alternating phenylene-pyrimidine structure have been synthesized by the successive Suzuki coupling reaction starting from 2-bromo-5-iodopyrimidine. The photoluminescence properties and quasi-reversible redox behavior of these oligomers make them applicable as an active material for a light-emitting device. Blue light-emitting electroluminescent devices with an external quantum efficiency up to 1.8% have been fabricated.