The aldolase family members involved in metabolism and glycolysis are present in three isoforms: ALDOA, ALDOB, and ALDOC. Aldolases are differentially expressed in human tissues, and aberrant ...expression has been observed in several human diseases and cancer types. However, non-enzymatic functions through protein–protein interactions or epigenetic modifications have been reported in recent years. Using high-throughput screening and -omics database integration, aldolase has been validated as an independent clinical prognostic marker of human cancers. Therefore, the aim of this review was to provide potential clinical value from in silico predictions and also summarize well-known signaling axes or phenotypes in various cancer types. Finally, we discuss the role of aldolase in the treatment of human diseases and cancers.
The enzymatic and non-enzymatic functions of glycolysis promote tumor cell growth, cell cycle, and cancer metastasis.
Isoforms of aldolases are abundant in the human body and play roles in glycolysis, fructolysis, and the synthesis of glyceraldehyde and ATP.
The expression of aldolase family members is associated with poor survival rates or multiple clinical parameters in several cancer types.
In silico analysis assesses the clinical value of aldolase family members as prognostic and diagnostic markers of human cancers and diseases.
The non-enzymatic functions of aldolases reveal novel phenotypes or signaling through protein–protein interactions.
Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick‐borne virus, causing thrombocytopenia and hemorrhagic fever, with a fatality rate ranging from 12% to 30%. SFTSV ...possesses Gn and Gc glycoproteins, which are responsible for host cell receptor attachment and membrane fusion, respectively, to infect host cells. We have previously reported a protein subunit vaccine candidate (sGn‐H‐FT) of the SFTSV soluble Gn head region (sGn‐H) fused with self‐assembling ferritin (FT) nanoparticles, displaying strong protective immunogenicity. In this study, we present messenger RNA (mRNA) vaccine candidates encoding sGn‐H or sGn‐H‐FT, both of which exhibit potent in vivo immunogenicity and protection capacity. Mice immunized with either sGn‐H or sGn‐H‐FT mRNA lipid nanoparticle (LNP) vaccine produced strong total antibodies and neutralizing antibodies (NAbs) against sGn‐H. Importantly, NAb titers remained high for an extended period. Finally, mice immunized with sGn‐H or sGn‐H‐FT mRNA LNP vaccine were fully protected from a lethal dose of SFTSV challenge, showing no fatality. These findings underscore the promise of sGn‐H and sGn‐H‐FT as vaccine antigen candidates capable of providing protective immunity against SFTSV infection.
The rapid dissemination of the 2009 pandemic influenza virus underscores the need for universal influenza vaccines that elicit protective immunity to diverse viral strains. Here, we show that ...vaccination with plasmid DNA encoding H1N1 influenza hemagglutinin (HA) and boosting with seasonal vaccine or replication-defective adenovirus 5 vector encoding HA stimulated the production of broadly neutralizing influenza antibodies. This prime/boost combination increased the neutralization of diverse H1N1 strains dating from 1934 to 2007 as compared to either component alone and conferred protection against divergent H1N1 viruses in mice and ferrets. These antibodies were directed to the conserved stem region of HA and were also elicited in nonhuman primates. Cross-neutralization of H1N1 subtypes elicited by this approach provides a basis for the development of a universal influenza vaccine for humans.
Cancer metabolic reprogramming promotes tumorigenesis and metastasis; however, the underlying molecular mechanisms are still being uncovered. In this study, we show that the glycolytic enzyme ...aldolase A (ALDOA) is a key enzyme involved in lung cancer metabolic reprogramming and metastasis. Overexpression of ALDOA increased migration and invasion of lung cancer cell lines
and formation of metastatic lung cancer foci
. ALDOA promoted metastasis independent of its enzymatic activity. Immunoprecipitation and proteomic analyses revealed γ-actin binds to ALDOA; blocking this interaction using specific peptides decreased metastasis both
and
. Screening of clinically available drugs based on the crystal structure of ALDOA identified raltegravir, an antiretroviral agent that targets HIV integrase, as a pharmacologic inhibitor of ALDOA-γ-actin binding that produced antimetastatic and survival benefits in a xenograft model with no significant toxicity. In summary, ALDOA promotes lung cancer metastasis by interacting with γ-actin. Targeting this interaction provides a new therapeutic strategy to treat lung cancer metastasis. SIGNIFICANCE: This study demonstrates the role of aldolase A and its interaction with γ-actin in the metastasis of non-small lung cancer and that blocking this interaction could be an effective cancer treatment.
Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, is overexpressed and activated in many cancer types. FAK regulates diverse cellular processes, including growth factor signaling, cell ...cycle progression, cell survival, cell motility, angiogenesis, and the establishment of immunosuppressive tumor microenvironments through kinase-dependent and kinase-independent scaffolding functions in the cytoplasm and nucleus. Mounting evidence has indicated that targeting FAK, either alone or in combination with other agents, may represent a promising therapeutic strategy for various cancers. In this review, we summarize the mechanisms underlying FAK-mediated signaling networks during tumor development. We also summarize the recent progress of FAK-targeted small-molecule compounds for anticancer activity from preclinical and clinical evidence.
The up-regulation of fucosyltransferase 8 (FUT8), the only enzyme catalyzing α1,6-fucosylation in mammals, has been observed in several malignant cancers including liver, ovarian, thyroid, and ...colorectal cancers. However, the pathological role and the regulatory mechanism of FUT8 in cancers remain largely unknown. In the current study, we report that the expression of FUT8 is up-regulated in nonsmall cell lung cancer (NSCLC) and correlates with tumor metastasis, disease recurrence, and poor survival in patients with NSCLC. Knocking down FUT8 in aggressive lung cancer cell lines significantly inhibits their malignant behaviors including in vitro invasion and cell proliferation, as well as in vivo metastasis and tumor growth. The results of glycoproteomic and microarray analyses show that FUT8 globally modifies surface antigens, receptors, and adhesion molecules and is involved in the regulation of dozens of genes associated with malignancy, suggesting that FUT8 contributes to tumor progression through multiple mechanisms. Moreover, we show that FUT8 is up-regulated during epithelial–mesenchymal transition (EMT), a critical process for malignant transformation of tumor, via the transactivation of β-catenin/lymphoid enhancer-binding factor-1 (LEF-1). These results provide a model to illustrate the relation between FUT8 expression and lung cancer progression and point to a promising direction for the prognosis and therapy of lung cancer.
Fatty infiltration of the pancreas has been shown to interfere with insulin secretion. Both insulin sensitivity and secretion are important in the pathogenesis of diabetes and prediabetes. However, ...the relationship between diabetes, prediabetes, and fatty pancreas remains unknown. We aim to investigate the relationships that fatty pancreas and nonalcoholic fatty liver disease (NAFLD) have with prediabetes and diabetes in a Chinese population.
This was a cross-sectional study. A total of 7,464 subjects were recruited. NAFLD and fatty pancreas were assessed by sonography. Clinico-metabolic parameters were compared among subjects with normoglycemia, prediabetes, and diabetes. Multinomial logistic regression was used to evaluate the relationship between fatty pancreas and NAFLD and diabetes or prediabetes with adjustment for cardiometabolic risk factors.
With an increase in glycemia, a significantly greater proportion of subjects had NAFLD and fatty pancreas (test for trend p<0.05). Similar trends were also found for hypertension, general and central obesity, low-HDL cholesterol, and hypertriglyceridemia. In the logistic regression analysis, age, hypertension, male gender, hypertriglyceridemia, and central obesity were significantly associated with prediabetes and diabetes. Furthermore, the ORs of prediabetes and diabetes for NAFLD were 1.798 (95% CI 1.544-2.094) and 2.578 (95% CI 2.024-3.284), respectively. In addition, fatty pancreas was independently related to diabetes (OR, 1.379; 95% CI, 1.047-1.816) and prediabetes (OR, 1.222; 95% CI, 1.002-1.491) in male subjects.
Both NAFLD and fatty pancreas were associated with diabetes independent of age, gender, adiposity, and other cardiometabolic risk factors. Fatty pancreas was also related to prediabetes in males.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In linear support vector regression (SVR), the regularization and error sensitivity parameters are used to avoid overfitting the training data. A proper selection of parameters is very essential for ...obtaining a good model, but the search process may be complicated and time-consuming. In an earlier work by Chu et al. (2015), an effective parameter-selection procedure by using warm-start techniques to solve a sequence of optimization problems has been proposed for linear classification. We extend their techniques to linear SVR, but address some new and challenging issues. In particular, linear classification involves only the regularization parameter, but linear SVR has an extra error sensitivity parameter. We investigate the effective range of each parameter and the sequence in checking the two parameters. Based on this work, an effective tool for the selection of parameters for linear SVR has been available for public use.
The present article investigates the interactions between the pilot and main flames in a novel stratified swirl burner using both experimental and numerical methods. Experiments are conducted in a ...test rig operating at atmospheric conditions. The system is equipped with the BASIS (Beihang Axial Swirler Independently-Stratified) burner fuelled with premixed methane-air mixtures. To illustrate the interactions between the pilot and main flames, three operating modes are studied, where the burner works with: (i) only the pilot flame, (ii) only the main flame, and (iii) the stratified flame (with both the pilot and main flames). We found that: (1) in the pilot flame mode, the flame changes from V-shape to M-shape when the main stage is switched from closed to supplying a pure air stream. Strong oscillations in the M-shape flame are found due to the dilution of the main air to the pilot methane flame. (2) In the main flame mode, the main flame is lifted off from the burner if the pilot stage is supplied with air. The temperature of the primary recirculation zone drops substantially and the unsteady heat release is intensified. (3) In the stratified flame mode, unique beating oscillations exhibiting dual closely-spaced frequencies in the pressure spectrum is found. This is observed within over narrow window of equivalence ratio combinations between the pilot and main stages. Detailed analysis of the experimental data shows that flame dynamics and thermoacoustic couplings at these two frequencies are similar to those of the unstable pilot flame and the attached main flame cases, respectively. Large Eddy Simulations (LESs) are carried out with OpenFOAM to understand the mechanisms of the time-averaged flame shapes in different operating modes. Finally, a simple acoustic analysis is proposed to understand the acoustic mode nature of the beating oscillations.
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