RAS and RHO proteins, which contribute to tumorigenesis and metastasis, undergo posttranslational modification with an isoprenyl lipid by protein farnesyltransferase (FTase) or protein geranylgeranyltransferase-I (GGTase-I). Inhibitors of FTase and GGTase-I were developed to block RAS-induced malignancies, but their utility has been difficult to evaluate because of off-target effects, drug resistance, and toxicity. Moreover, the impact of FTase deficiency and combined FTase/ GGTase-I deficiency has not been evaluated with genetic approaches. We found that inactivation of FTase eliminated farnesylation of HDJ2 and H-RAS, prevented H-RAS targeting to the plasma membrane, and blocked proliferation of primary and K-RAS G12D -expressing fibroblasts. FTase inactivation in mice with K-RAS-induced lung cancer reduced tumor growth and improved survival, similar to results obtained previously with inactivation of GGTase-I. Simultaneous inactivation of FTase and GGTase-I markedly reduced lung tumors and improved survival without apparent pulmonary toxicity. These data shed light on the biochemical and therapeutic importance of FTase and suggest that simultaneous inhibition of FTase and GGTase-I could be useful in cancer therapeutics.mouse models | non-small-cell lung cancer | protein farnesyltransferase | protein geranylgeranyltransferase type I

The aim of this study was to explore the signatures of oral microbiome associated with OSCC using a random forest (RF) model. Patients and Methods: A total of 24 patients with OSCC were enrolled in the study. The oral microbiome was assessed in cancerous lesions and matched paracancerous tissues from each patient using 16S rRNA gene sequencing. Signatures of mucosal microbiome in OSCC were identified using a RF model. Results: Significant differences were found between OSCC lesions and matched paracancerous tissues with respect to the microbial profile and composition. Linear discriminant analysis effect size analyses (LEfSe) identified 15 bacteria genera associated with cancerous lesions. Fusobacterium, Treponema, Streptococcus, Peptostreptococcus, Carnobacterium, Tannerella, Parvimonas and Filifactor were enriched. A classifier based on RF model identified a microbial signature comprising 12 bacteria, which was capable of distinguishing cancerous lesions and paracancerous tissues (AUC = 0.82). The network of the oral microbiome in cancerous lesions appeared to be simplified and fragmented. Functional analyses of oral microbiome showed altered functions in amino acid metabolism and increased capacity of glucose utilization in OSCC. Conclusion: The identified microbial signatures may potentially be used as a biomarker for predicting OSCC or for clinical assessment of oral cancer risk.

Aim: Galectin-3 (Gal-3) is a member of the carbohydrate-binding protein family that contributes to neoplastic transformation, tumor survival, angiogenesis, and metastasis. The aim of this study is to investigate the role of Gal-3 in human tongue cancer progression. Methods: Human tongue cancer cell lines (SCC-4 and CAL27) were transfected with a small-interfering RNA against Gal-3 (Gal-3-siRNA). The migration and invasion of the cells were examined using a scratch assay and BD BioCoat Matrigel Invasion Chamber, respectively. The mRNA and protein levels of β-catenin, Akt/pAkt, GSK-3β/pGSK-3β, MMP-9 in the cells were measured using RT-PCR and Western blotting, respectively. Results: Transient silencing of Gal-3 gene for 48 h significantly suppressed the migration and invasion of both SCC-4 and CAL27 cells. Silencing of Gal-3 gene significantly decreased the protein level of β-catenin, leaving the mRNA level of β-catenin unaffected. Furthermore, silencing Gal-3 gene significantly decreased the levels of phosphorylated Akt and GSK-3β, and suppressed the mRNA and protein levels of MMP-9 in the cells. Conclusion: Our data suggest that Gal-3 mediates the migration and invasion of tongue cancer cells in vitro via regulating the Wnt/ β-catenin signaling pathway and Akt phosphorylation.

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) has been shown to play a pivotal role in the regulation of mitochondrial biogenesis in diseases. Resveratrol (RSV), a natural polyphenolic reagent, has powerful antioxidant properties and the ability to scavenge mitochondrial reactive oxygen species (ROS) in a variety of central nervous system diseases. However, the underlying molecular mechanisms of RSV on mitochondrial biogenesis in early brain injury (EBI) following subarachnoid hemorrhage (SAH) remain poorly understood. This study aimed to explore the potential neuroprotective effects of RSV on mitochondrial biogenesis and function by activation of the PGC-1α signaling pathway in a prechiasmatic cistern SAH model. PGC-1α expression and related mitochondrial biogenesis were detected. Amounts of nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM) were determined to evaluate the extent of mitochondrial biogenesis. Increased PGC-1α and mitochondrial biogenesis after SAH were observed in the temporal cortex. Resveratrol increased the expression of PGC-1α, NRF1, and TFAM, and promoted PGC-1α nuclear translocation. Moreover, RSV could scavenge excess ROS, increase the activity of superoxide dismutase (SOD), enhance the potential of mitochondrial membrane and ATP levels, reduce the number of mitochondrial DNA copy, and decrease the level of malondialdehyde (MDA). RSV significantly ameliorated the release of apoptosis-related cytokines, namely P53, cleaved caspase-3, cytochrome c, and BAX, leading to the amelioration of neuronal apoptosis, brain edema, and neurological impairment 24 h after SAH. These results indicate that resveratrol promotes mitochondrial biogenesis and function by activation of the PGC-1α signaling pathway in EBI following SAH.

Objectives:Childhood obesity/underweight status and caries are both important public health problems. This study aims to investigate the caries status and its association with body weight in 8-year-old children in Qingdao, China.Materials and Methods:We initiated a cross-sectional investigation on 744 children aged 8 years during the Oral Health Survey in 2012. Dental caries assessments were carried out and weight status was recorded accordingly. The resulting caries status including caries prevalence, dmft (deciduous dentition), and (dmft + DMFT) (mixed dentition), as well as BMI indices were analyzed for comparison and correlation.Results:The prevalence of dental caries among the 744 children aged 8 years participating in this survey was 86.3%. The caries status represented by dmft (deciduous dentition) and (dmft + DMFT) (mixed dentition) values was 4.31 and 4.85, respectively, and the restoration rate was extremely low, which was no more than 3.0%. Significant difference was found in dmft/(dmft + DMFT) values between different BMI groups, and underweight individuals were found to have the highest dmft/(dmft + DMFT) value. An inverse relationship between body BMI and dmft/(dmft + DMFT) index was identified based on Pearson's correlation.Conclusions:A severe state of caries disease was revealed in 8-year-old children in the Chinese city of Qingdao, for whom urgent dental intervention and treatment were needed. Furthermore, underweight individuals were found with the most severe caries experience, indicating caries may affect the development and growth of the afflicted children. Thus, more emphasis should be placed on improving their dental health, with caries prevention being given the priority.

To construct a saliva-based caries risk assessment model, saliva samples from 176 severe early childhood caries (S-ECC) children and 178 healthy (H) children were screened by real-time PCR-based quantification of the selected species, including Streptococcus mutans, Prevotella pallens, Prevotella denticola and Lactobacillus fermentum. Host factors including caries status, dmft indices, age, gender, and geographic origin were assessed in their influence on abundance of the targeted species, which revealed host caries status as the dominant factor, followed by dmft indices (both P < 0.01). Moreover, levels of S. mutans and P. denticola in the S-ECC group were significantly higher than those in the healthy group (P < 0.001 for S. mutans and p < 0.01 for P. denticola). Interestingly, the co-occurrence network of these targeted species in the S-ECC group differed from that from the healthy group. Finally, based on the combined change pattern of S. mutans and P. pallens, we constructed an S-ECC diagnosis model with an accuracy of 72%. This saliva-based caries diagnosis model is of potential value for circumstances where sampling dental plague is difficult. Early childhood caries (ECC) is defined as the presence of one or more decayed, missing, or filled tooth surfaces in the primary dentition in children of 71 months or younger 1. Severe early childhood caries (S-ECC), an extraordinary form of ECC, is defined as the presence of decayed, missing, or filled score surfaces of either ≥4 (age 3 years), ≥5 (age 4 years), or ≥6 (age 5 years) 2. In USA, 23% of children between the ages of 2 and 5 are affected by ECC 3. In China, fresh reports from the Fourth National Oral Health Survey showed that over 70% of 5-year-old children carry dental caries in primary teeth 4. Unfortunately, childhood caries are wide-ranging, rapid-progressing and irreversible 5. Besides, severe caries can cause pulpal infection, as well as varieties of adverse physical and psychological effects, thus it affects children's development while posing a substantial economic burden on both families and society 6-8. Therefore, preventive measures and early diagnosis of ECC or S-ECC are of vital clinical and social importance. Many studies have shown that caries is a multifactorial disease 9,10 and pathogenic bacteria are the main cause of disease occurrence and progression 11. Streptococcus mutans (S. mutans) has been considered as a cariogenic bacterial agent in children 12-15 , due to its aciduric and acidogenic properties 16. Apart from this, Lactobacillus spp. was also linked to caries development and progression 16-18. Positive associations between certain Lactobacillus spp. (especially Lactobacillus fermentum) and the hard tissue changes were revealed in the process of caries progression 19,20. In addition, our past pyrosequencing of oral and plaque microbiota unveiled Prevotella spp's close relationship with caries, in both cross-sectional and longitudinal studies 21,22. Specifically, we proposed a caries

Mechanical overloading can lead to skeletal muscle damage instead of remodeling. This is attributed to the excessive apoptosis of myoblasts, mechanism of which remains to be elucidated. The present study aimed to investigate the involvement of endoplasmic reticulum stress (ERS) and caspase-12 in mediating the stretch-induced apoptosis of myoblasts. Myoblast apoptosis was evaluated by Hoechst staining, DNA fragmentation assay, Annexin V binding, and propidium iodide staining, as well as caspase-3 and poly-ADP-ribose polymerase 1 cleavage. First, our results showed that apoptosis was elevated in a time-dependent manner when myoblasts were subjected to cyclic mechanical stretch (CMS) for 12, 24, and 36 hr. Concomitantly, CMS triggered the ERS and caspase-12 cleavage; ERS inhibitor GSK 2606414 suppressed the CMS-induced cleavage of caspase-12 and myoblast apoptosis. Silencing caspase-12 attenuated the apoptosis of myoblasts under CMS. Furthermore, CMS-induced myoblast apoptosis was partially recovered by overexpressing wild-type caspase-12 in caspase-12-silenced myoblasts. In contrast, overexpressing mutant caspase-12 (D94N), which cannot be cleaved into the active caspase-12 fragments, failed to accomplish the same effect. Finally, C2C12 overexpressing truncated caspase-12 segment (TC-casp12-D94), which starts from Asp94 and ends at Asn419, underwent apoptosis under both static and stretched conditions. Interestingly, C2C12 myoblasts seemed to be resistant to stretch-induced apoptosis upon low-serum-induced differentiation. In conclusion, our study provided evidence that caspase-12 cleavage at Asp94, induced by ERS under mechanical stimuli, is the key molecule in initiating the stretch-triggered apoptosis of myoblasts.

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