ABSTRACT
In spatially resolved transcriptomics, Stereo-seq facilitates the analysis of large tissues at the single-cell level, offering subcellular resolution and centimeter-level field-of-view. Our previous work on StereoCell introduced a one-stop software using cell nuclei staining images and statistical methods to generate high-confidence single-cell spatial gene expression profiles for Stereo-seq data. With advancements allowing the acquisition of cell boundary information, such as cell membrane/wall staining images, we updated our software to a new version, STCellbin. Using cell nuclei staining images, STCellbin aligns cell membrane/wall staining images with spatial gene expression maps. Advanced cell segmentation ensures the detection of accurate cell boundaries, leading to more reliable single-cell spatial gene expression profiles. We verified that STCellbin can be applied to mouse liver (cell membranes) and Arabidopsis seed (cell walls) datasets, outperforming other methods. The improved capability of capturing single-cell gene expression profiles results in a deeper understanding of the contribution of single-cell phenotypes to tissue biology. Availability & Implementation: The source code of STCellbin is available at https://github.com/STOmics/STCellbin.
ABSTRACT
Objectives: The accurate prediction of osteoarthritis (OA) severity in patients can be helpful to make the proper decision of intervention. This study aims to build up a powerful model to assess predictive risk factors and severity of knee osteoarthritis (KOA) in the clinical scenario. Methods: A total of 4796 KOA cases and 1205 features were selected by feature selections from the public OA database, Osteoarthritis Initiative (OAI). Six machine learning-based models were constructed and compared for the accuracy of OA prediction. The gradient-boosting decision tree was used to identify important prediction features in the extreme gradient boosting (XGBoost) model. The performance of models was evaluated by F1-score. Results: Twenty features were determined as predictors for KOA risk and severity, including the subject characteristics, knee symptoms/risk factors and physical exam. The XGBoost model demonstrated 100% prediction accuracy for 54.7% of examined samples, and the remaining 45.3% of samples showed Kellgren and Lawrence (KL) gradings very close to the actual levels. It showed the highest prediction accuracy with an F1-score of 0.553 among the tested six models. Conclusions: We demonstrate that the XGBoost is the best model for the prediction of KOA severity in the six examined models. In addition, 20 risk features were determined as the essential predictors of KOA, including the physical exam, knee symptoms/risk factors and subject characteristics, which may be useful for the identification of high-risk KOA cases and for making appropriate treatment decisions as well.
ABSTRACT
Starch accounts for up to 90% of the dry weight of rice endosperm and is a key determinant of grain quality. Although starch biosynthesis enzymes have been comprehensively studied, transcriptional regulation of starch-synthesis enzyme-coding genes (SECGs) is largely unknown. In this study, we explored the role of a NAC transcription factor, OsNAC24, in regulating starch biosynthesis in rice. OsNAC24 is highly expressed in developing endosperm. The endosperm of osnac24 mutants is normal in appearance as is starch granule morphology, while total starch content, amylose content, chain length distribution of amylopectin and the physicochemical properties of the starch are changed. In addition, the expression of several SECGs was altered in osnac24 mutant plants. OsNAC24 is a transcriptional activator that targets the promoters of six SECGs; OsGBSSI, OsSBEI, OsAGPS2, OsSSI, OsSSIIIa and OsSSIVb. Since both the mRNA and protein abundances of OsGBSSI and OsSBEI were decreased in the mutants, OsNAC24 functions to regulate starch synthesis mainly through OsGBSSI and OsSBEI. Furthermore, OsNAC24 binds to the newly identified motifs TTGACAA, AGAAGA and ACAAGA as well as the core NAC-binding motif CACG. Another NAC family member, OsNAP, interacts with OsNAC24 and coactivates target gene expression. Loss-of-function of OsNAP led to altered expression in all tested SECGs and reduced the starch content. These results demonstrate that the OsNAC24-OsNAP complex plays key roles in fine-tuning starch synthesis in rice endosperm and further suggest that manipulating the OsNAC24-OsNAP complex regulatory network could be a potential strategy for breeding rice cultivars with improved cooking and eating quality.
Subject(s)
Endosperm , Oryza , Endosperm/genetics , Endosperm/metabolism , Oryza/metabolism , Plant Breeding , Starch/metabolism , Amylopectin/metabolism , Amylose/metabolism , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
The aberrantly up-regulated CDK9 can be targeted for cancer therapy. The CDK inhibitor dinaciclib (Dina) has been found to drastically sensitizes cancer response to TRAIL-expressing extracellular vesicle (EV-T). However, the low selectivity of Dina has limited its application for cancer. We propose that CDK9-targeted siRNA (siCDK9) may be a good alternative to Dina. The siCDK9 molecules were encapsulated into EV-Ts to prepare a complexed nanodrug (siEV-T). It was shown to efficiently suppress CDK9 expression and overcome TRAIL resistance to induce strikingly augmented apoptosis in lung cancer both in vitro and in vivo, with a mechanism related to suppression of both anti-apoptotic factors and nuclear factor-kappa B pathway. Therefore, siEV-T potentially constitutes a novel, highly effective and safe therapy for cancers.
Subject(s)
Lung Neoplasms , NF-kappa B , Humans , NF-kappa B/genetics , NF-kappa B/metabolism , Apoptosis , Cell Line, Tumor , RNA, Small Interfering/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , TNF-Related Apoptosis-Inducing Ligand/genetics , TNF-Related Apoptosis-Inducing Ligand/pharmacology , Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics , Cyclin-Dependent Kinase 9/geneticsABSTRACT
The clinical outcomes of lung cancer remain poor, mainly due to the chemoresistance and low bioavailability of systemically delivered drugs. Therefore, novel therapeutic strategies are urgently needed. The TNF-related apoptosis-inducing ligand (TRAIL)-armed extracellular vesicle (EV-T) has proven to be highly synergistic for the killing of cancer cells with the potent cyclin-dependent kinase (CDK) inhibitor Dinaciclib (Dina). However, both optimal drug formulations and delivery strategies are yet to be established to facilitate the clinical application of the combination of EV-T and Dina. We hypothesize that Dina can be encapsulated into EV-T to produce a complexed formulation, designated EV-T-Dina, which can be nebulized for pulmonary delivery to treat lung cancer with potentially improved efficacy and safety. The prepared EV-T-Dina shows good stability both in vitro and in vivo and is very efficient at killing two highly TRAIL-resistant cancer lines. The ability to overcome TRAIL resistance is associated with the concomitant downregulation of the expression of cFLIP, MCL-1, and Survivin by Dina. The EV-T-Dina solution is nebulized for inhalation, showing unique deposition in animal lungs and importantly it demonstrates a significant suppression of the growth of orthotopic A549 tumors without any detectable adverse side events. In conclusion, the aerosolized EV-T-Dina constitutes a novel therapy, which is highly effective and safe for the treatment of lung cancers.
ABSTRACT
Keloid disease is a nodular lesion, tumor-like but not cancerous, and characterized of excessive proliferation of fibroblasts and deposition of extracellular matrix (ECM) components. This condition often causes itching, pain and cosmetic disfigurement, significantly reducing patient quality of life. To date, no universally effective therapies are available, possibly due to inadequate understanding of keloid pathogenesis. As an oral small-molecule inhibitor of certain tyrosine kinase receptors, sunitinib has shown significant therapeutic effects in renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST). However, it has never been tested if keloid therapy can be effective for the management of keloids. This study thus aims to explore the potential of sunitinib for keloid treatment. Keloid-derived fibroblasts (KFs) were successfully isolated and demonstrated proliferative advantage to normal skin-derived fibroblasts (NFs). Additionally, sunitinib showed specific cytotoxicity and inhibition of invasion, and induced cell cycle arrest and significant apoptosis in KFs. These effects were accompanied by complete suppression of ECM component expression, including collagen types 1 and 3, upregulation of autophagy-associated LC3B and significant suppression of the Akt/PI3K/mTOR pathway. Moreover, a keloid explant culture model was successfully established and used to test the therapeutic efficacy of sunitinib on keloid formation in nude mice. Sunitinib was found to induce complete regression of keloid explant fragments in nude mice, showing significantly higher therapeutic efficacy than the most commonly used intralesional drug triamcinolone acetonide (TAC). These data suggest that sunitinib effectively inhibits keloid development through suppression of the Akt/PI3K/mTOR pathway and thus can be potentially developed as a monotherapy or combination therapy for the effective treatment of keloid disease.
Subject(s)
Keloid , Mice , Animals , Keloid/drug therapy , Keloid/metabolism , Keloid/pathology , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Sunitinib/pharmacology , Sunitinib/therapeutic use , Sunitinib/metabolism , Mice, Nude , Quality of Life , Apoptosis , Signal Transduction , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism , Fibroblasts/metabolism , Cell ProliferationABSTRACT
Grain size and the endosperm starch content determine grain yield and quality in rice. Although these yield components have been intensively studied, their regulatory mechanisms are still largely unknown. In this study, we show that loss-of-function of OsNAC129, a member of the NAC transcription factor gene family that has its highest expression in the immature seed, greatly increased grain length, grain weight, apparent amylose content (AAC), and plant height. Overexpression of OsNAC129 had the opposite effect, significantly decreasing grain width, grain weight, AAC, and plant height. Cytological observation of the outer epidermal cells of the lemma using a scanning electron microscope (SEM) revealed that increased grain length in the osnac129 mutant was due to increased cell length compared with wild-type (WT) plants. The expression of OsPGL1 and OsPGL2, two positive grain-size regulators that control cell elongation, was consistently upregulated in osnac129 mutant plants but downregulated in OsNAC129 overexpression plants. Furthermore, we also found that several starch synthase-encoding genes, including OsGBSSI, were upregulated in the osnac129 mutant and downregulated in the overexpression plants compared with WT plants, implying a negative regulatory role for OsNAC129 both in grain size and starch biosynthesis. Additionally, we found that the expression of OsNAC129 was induced exclusively by abscisic acid (ABA) in seedlings, but OsNAC129-overexpressing plants displayed reduced sensitivity to exogenous brassinolide (BR). Therefore, the results of our study demonstrate that OsNAC129 negatively regulates seed development and plant growth, and further suggest that OsNAC129 participates in the BR signaling pathway.
ABSTRACT
Hepatocellular carcinoma (HCC) is an aggressive malignancy, and its effective treatment has been hampered by drug resistance. Extracellular vesicle (EV) delivery of TNF-related apoptosis-inducing ligand (TRAIL) (EV-T) was demonstrated to be superior to recombinant TRAIL (rTRAIL) for cancer treatment previously. And AZD5582, a potent antagonist of inhibitors of apoptosis proteins (IAPs) can potentiate apoptosis-based cancer therapies. However, the combination of EV-T and AZD5582 has never been examined for their possible apoptosis inducing synergism in cancers. In this study, we proposed and tested the combination of EV-T and AZD5582 as a potential novel therapy for effective treatment of HCC. Two HCC lines Huh7 and HepG2 that are both resistant to rTRAIL were examined. The results confirmed that AZD5582 and EV-T are synergistic for apoptosis induction in some cancer lines including Huh7 and HepG2 while sparing normal cells. More importantly, this study revealed that TRAIL sensitization by AZD5582 is mediated through the concomitant suppression of anti-apoptotic factors including cFLIP, MCL-1, and IAPs (XIAP, Survivin and cIAP-1). Particularly the downregulation of cFLIP and IAP's appeared to be essential and necessary for the synergism between AZD5582 and TRAIL. In vivo, we first time demonstrated that the combined therapy with low doses of AZD5582 and EV-Ts triggered drastically enhanced apoptosis leading to the complete eradication of Huh7 tumor development without any apparent adverse side effects examined. We thus have unraveled the important molecular mechanism underlying TRAIL sensitization by AZD5582, rationalizing the next development of a combination therapy with AZD5582 and EV-T for HCC treatment. KEY MESSAGES: It confirmed the TRAIL sensitization by AZD5582, a potent antagonist of IAPs in hepatocarcinoma. It revealed that the sensitization is via the concomitant suppression of antiapoptotic factors including cFLIP, MCL-1, and IAPs. The downregulation of cFLIP and IAPs like Survivin appeared to be essential and necessary for the synergism between AZD5582 and nanosomal TRAIL. In vivo the combined therapy with AZD5582 and nanosomal TRAIL led to complete eradication of hepatocarcinoma tumors. This study has rationalized the next development of a combination therapy with AZD5582 and nanosomal TRAIL for cancer treatment.
Subject(s)
Carcinoma, Hepatocellular , Extracellular Vesicles , Liver Neoplasms , Alkynes , Apoptosis , Apoptosis Regulatory Proteins/metabolism , CASP8 and FADD-Like Apoptosis Regulating Protein/genetics , CASP8 and FADD-Like Apoptosis Regulating Protein/metabolism , CASP8 and FADD-Like Apoptosis Regulating Protein/pharmacology , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Extracellular Vesicles/metabolism , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Oligopeptides , Survivin/metabolism , Survivin/pharmacology , TNF-Related Apoptosis-Inducing Ligand/metabolism , TNF-Related Apoptosis-Inducing Ligand/pharmacologyABSTRACT
Extracellular vesicle (EV) delivery of TNF-related apoptosis-inducing ligand (TRAIL) (EV-T) has been shown to be highly efficient for cancer treatment when combined with the potent cyclin-dependent kinase (CDK) inhibitor dinaciclib (SCH727965, Dina). However, only topical administration was previously tested for cancer treatment, leaving unknown the efficacy of systemic therapy by EV-T and Dina. In this study we hypothesize that the systemic application of EV-T and Dina can be performed through EV-mediated co-delivery of TRAIL and Dina. Dina was first post-loaded into EV-Ts by sonication to prepare EV-mediated co-delivery of TRAIL and Dina, designated Dina@EV-T. Then Dina@EV-Ts were shown to be stable, readily endocytosed into cancer cells, and highly effective at inducing intensive apoptosis in resistant cancer lines but not in normal cells. Moreover, systemically infused Dina@EV-Ts showed evident tumor tropism suggesting their good potential for tumour-targeted delivery of therapeutics. Importantly, the systemic therapy with Dina@EV-Ts showed the best efficacy in vivo when compared with other treatments. The augmented therapeutic efficacy appeared to be associated with the concomitant suppression of prosurvival CDK1 and anti-apoptotic proteins including CDK9, cFLIP, MCL-1, BCL-2 and Survivin by Dina@EV-T treatment. Additionally, there were no adverse side effects observed for the systemic Dina@EV-T therapy. In conclusion, our data suggest that the co-delivery of TRAIL and Dina by EVs potentially constitutes a novel tumour-targeted therapy, which is highly effective and safe for the treatment of refractory tumors.
Subject(s)
Extracellular Vesicles , Indolizines , Apoptosis , Cell Line, Tumor , Cyclic N-Oxides , Extracellular Vesicles/metabolism , Indolizines/pharmacology , Pyridinium Compounds , TNF-Related Apoptosis-Inducing Ligand/metabolism , TNF-Related Apoptosis-Inducing Ligand/pharmacologyABSTRACT
Neuroblastoma is a metastatic brain tumor particularly common in children. The cure rate is below 50% for patients of high-risk condition. Novel therapeutic agents and approaches are needed to improve the cure rate. Tumor necrosis factor-related and apoptosis-inducing ligand (TRAIL) is a promising proapoptotic factor that rapidly induces apoptosis preferentially in transformed and cancerous cells. Unfortunately, the common TRAIL resistance in cancers has hampered the clinical application of the ligand. Previously we prepared a novel TRAIL-armed ER derived nanosomal agent (ERN-T) that overcomes TRAIL resistance in some cancer lines when combined with a synthetic antagonist of inhibitors of apoptosis proteins (IAPs), AZD5582. However, how AZD5582 sensitizes cancer cells to ERN-T remains not well understood. In this study we continued to test the therapeutic efficacy of the combinatory therapy of ERN-T and AZD5582 on neuroblastoma, aiming to reveal the molecular mechanism underlying the synergism between AZD5582 and ERN-T. The obtained data revealed that ERN-Ts overcame TRAIL resistance and showed significant cytotoxicity on the resistant neuroblastoma line SH-SH5Y when combined with AZD5582 whilst sparing normal cells. The combination of low doses of ERN-Ts and AZD5582 induced intensive apoptosis in SH-SY5Y but not in normal skin fibroblasts (NSFs). Importantly we discovered that TRAIL sensitization in SH-SY5Y was associated with the concomitant downregulation of antiapoptotic factors cFLIP, MCL-1 and IAPs and upregulation of proapoptotic protein BAX and the death receptor 5 (DR5) by the cotreatment of ERN-T and AZD5582. In vivo study demonstrated that the combination of ERN-T and AZD5582 constituted a highly effective and safe therapy for subcutaneous SH-SY5Y xenograft neuroblastoma in nude mice. In conclusion, we identified that the concomitant regulation of both antiapoptotic and proapoptotic factors and DR5 is an essential molecular mechanism for overcoming TRAIL resistance in SH-SY5Y and the combination of ERN-T and AZD5582 potentially constitutes a novel therapeutic strategy, which is highly effective and safe for neuroblastoma.
Subject(s)
Neuroblastoma , TNF-Related Apoptosis-Inducing Ligand , Alkynes , Animals , Apoptosis , Cell Line, Tumor , Humans , Mice , Mice, Nude , Neuroblastoma/drug therapy , Neuroblastoma/metabolism , Neuroblastoma/pathology , Oligopeptides , TNF-Related Apoptosis-Inducing Ligand/pharmacology , TNF-Related Apoptosis-Inducing Ligand/therapeutic useABSTRACT
Rice is a major food crop that sustains approximately half of the world population. Recent worldwide improvements in the standard of living have increased the demand for high-quality rice. Accurate identification of quantitative trait loci (QTLs) for rice grain quality traits will facilitate rice quality breeding and improvement. In the present study, we performed high-resolution QTL mapping for rice grain quality traits using a genotyping-by-sequencing approach. An F2 population derived from a cross between an elite japonica variety, Koshihikari, and an indica variety, Nona Bokra, was used to construct a high-density genetic map. A total of 3,830 single nucleotide polymorphism markers were mapped to 12 linkage groups spanning a total length of 2,456.4 cM, with an average genetic distance of 0.82 cM. Seven grain quality traits-the percentage of whole grain, percentage of head rice, percentage of area of head rice, transparency, percentage of chalky rice, percentage of chalkiness area, and degree of chalkiness-of the F2 population were investigated. In total, 15 QTLs with logarithm of the odds (LOD) scores >4 were identified, which mapped to chromosomes 6, 7, and 9. These loci include four QTLs for transparency, four for percentage of chalky rice, four for percentage of chalkiness area, and three for degree of chalkiness, accounting for 0.01%-61.64% of the total phenotypic variation. Of these QTLs, only one overlapped with previously reported QTLs, and the others were novel. By comparing the major QTL regions in the rice genome, several key candidate genes reported to play crucial roles in grain quality traits were identified. These findings will expedite the fine mapping of these QTLs and QTL pyramiding, which will facilitate the genetic improvement of rice grain quality.
ABSTRACT
Tongue cancer is the most prevalent type of oral cancer. Our previous study revealed that JAG1 exerted an oncogenic effect on tongue carcinoma through the JAG1/Notch pathway. In this study, a lncRNA PTTG3P which was upregulated in tongue cancer, was found to be positively correlated with JAG1. In CAL-27 and SCC4 cells, PTTG3P silencing significantly decreased JAG1 proteins and the ability of tongue tumor cells to proliferate and migrate. PTTG3P overexpression exhibited the opposite effect on CAL-27 and SCC4 cells. PPTG3P directly bound miR-142-5p, and miR-142-5p directly bound 3'UTR of JAG1 and inhibited the expression levels of JAG1. As opposed to PTTG3P silencing, miR-142-5p inhibition increased JAG1 protein levels and tongue cancer cell proliferation and migration; moreover, miR-142-5p inhibition substantially reversed the effects of PTTG3P silencing. Finally, the PPTG3P/miR-142-5p axis regulated the level of NICD, Notch downstream c-myc, and cyclin D1, as well as EMT markers Snail, Twist, and Vimentin. In conclusion, the PTTG3P/miR-142-5p axis modulates tongue cancer aggressiveness through JAG1, potentially through a JAG1/Notch signaling pathway.
Subject(s)
Jagged-1 Protein , MicroRNAs , RNA, Long Noncoding , Tongue Neoplasms , Humans , Jagged-1 Protein/genetics , MicroRNAs/genetics , Phenotype , RNA, Long Noncoding/genetics , Receptor, Notch1/genetics , Signal Transduction/genetics , Tongue Neoplasms/geneticsABSTRACT
Objective @# To study the effect of fluoride varnish, glass ionomer and resin sealant on the prevention of pit and fissure caries in young children, and to identify an a method to reduce the sensitivity of operation technique to prevent pit and fissure caries in young children with limited moisture isolation.@*Methods@# A self-control design was used to select 370 young children aged 3 to 5. Eight molars in the mouth were distributed in four quadrants, and each quadrant was randomly allocated to the blank group, fluoride varnish Duraphat group, glass ionomer GC FujiⅦ group, and resin ClinproTM Sealant group. The retention rate of pit and fissure sealant and the incidence of primary molar caries were observed in the 6th, 12th, 24th and 36th months respectively.@* Results @# In the 6th month, 12th month and 24th month, there were no significant differences in the material retention rate between the GC Fuji Ⅶ group and ClinproTM Sealant group. In the 36th month, the retention rate of the ClinproTM sealant group was better than that of the GC Fuji Ⅶ group (P < 0.05). In the 6th month, the caries incidence in the Duraphat group, GC Fuji Ⅶ group and ClinproTM sealant group was significantly lower than that in the blank group (P < 0.001). There was no significant difference between the Duraphat group, GC Fuji Ⅶ group and ClinproTM sealant group. In the 12th month, 24th month and 36th month, the incidence of caries in the GC Fuji Ⅶ group and ClinproTM sealant group was lower than that in the Duraphat group and blank group (P < 0.001), but there was no significant difference between the blank group and Duraphat group, and there was no significant difference in caries incidence between the GC Fuji Ⅶ group and ClinproTM sealant group.@*Conclusion @#The GC Fuji Ⅶ and ClinproTM sealant treatments continuously and effectively prevented pit and fissure caries compared with simple fluoride application. However, in cases of limited cooperation and poor moisture isolation in young children, the preventive measures of glass ionomer pits and fissure sealants (GC Fuji Ⅶ) are simpler and more feasible.
ABSTRACT
Although mesenchymal stem cells (MSCs) can be engineered to deliver the TNF-related apoptosis-inducing ligand (TRAIL) as an effective anticancer therapy, the clinical application is hampered by the costly manufacturing of therapeutic MSCs. Therefore, it is needed to find an alternative cell-free therapy. In this study, TRAIL-armed endoplasmic reticulum (ER)-derived nanosomes (ERN-T) are successfully prepared with an average size of 70.6 nm in diameter from TRAIL transduced MSCs. It is demonstrated that the ERN-T is significantly more efficient for cancer cell killing than the soluble recombinant TRAIL (rTRAIL). AZD5582 is an antagonist of the inhibitors of apoptosis proteins (IAPs), and its combination with ERN-T induces strikingly enhanced apoptosis in cancerous but not normal cells. AZD5582 sensitizes resistant cancer cells to TRAIL through concomitant downregulation of IAP members like XIAP and the Bcl2 family member Mcl-1. Intravenously infused ERN-Ts accumulate in tumors for over 48 h indicating good tumor tropism and retention. The combination of ERN-T and AZD5582 drastically promotes therapeutic efficacy comparing with the cotreatment by rTRAIL and AZD5582 in a subcutaneous MDA-MB-231 xenograft tumor model. The data thus demonstrate that ERN-T can be a novel cell-free alternative to TRAIL-expressing MSC-based anticancer therapy and its efficacy can be drastically enhanced through combination with AZD5582.
Subject(s)
Neoplasms , TNF-Related Apoptosis-Inducing Ligand , Alkynes , Apoptosis , Cell Line, Tumor , Endoplasmic Reticulum , Humans , OligopeptidesABSTRACT
Tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) is a promising anti-cancer agent that rapidly induces apoptosis in cancer cells. Unfortunately, the clinical application of recombinant TRAIL (rTRAIL) has been hampered by its common cancer resistance. Naturally TRAIL is delivered as a membrane-bound form by extracellular vesicles (EV-T) and is highly efficient for apoptosis induction. SCH727965 (dinaciclib), a potent cyclin-dependent kinase (CDK) inhibitor, was shown to synergize with other drugs to get better efficacy. However, it has never been investigated if dinaciclib coordinates with EV-T to enhance therapeutic results. This study explores the potential of combination therapy with EV-T and dinaciclib for cancer treatment. EV-T was successfully derived from human TRAIL transduced cells and shown to partially overcome resistance of A549 cells. Dinaciclib was shown to drastically enhance EV-T killing effects on cancer lines that express good levels of death receptor (DR) 5, which are associated with suppression of CDK1, CDK9 and anti-apoptotic proteins. Combination therapy with low doses of EV-T and dinaciclib induced strikingly enhanced apoptosis and led to complete regression in A549 tumors without any adverse side effects observed in a subcutaneous xenograft model. Tumor infiltration of mass NK cells and macrophages was also observed. These observations thus indicate that the combination of EV-T with dinaciclib is a potential novel therapy for highly effective and safe cancer treatment.
ABSTRACT
Tongue cancer remains a massive threat to public health due to the high rate of metastasis. Tumor cell epithelial-mesenchymal transition (EMT), which can be induced by transforming growth factor ß1 (TGFß1), has been regarded as a significant contributor to cancer invasion and migration. In our previous study, long noncoding RNA (lncRNA) MALAT1/miR-124/JAG1 axis modulates the growth of tongue cancer. In addition to metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), another lncRNA, urothelial cancer associated 1 (UCA1), can promote EMT and cancer metastasis. In the present study, UCA1 was overexpressed in tongue cancer tissues and cell lines. UCA1 overexpression was correlated to the poorer prognosis of patients with tongue cancer. UCA1 knockdown significantly suppressed TGFß1-induced tongue cancer cell invasion and EMT by decreasing vimentin and increasing E-cadherin. Regarding the molecular mechanism, UCA1 could directly bind to microRNA-124 (miR-124) and negatively regulate each other. UCA1 knockdown ameliorated, whereas miR-124 inhibition exacerbated TGFß1-induced EMT and invasion in tongue cancer cells through miR-124 downstream jagged 1 (JAG1) and Notch signaling. Moreover, miR-124 inhibition partially impaired the effect of UCA1 knockdown. In tongue cancer tissues, miR-124 expression was remarkably decreased, whereas JAG1 mRNA expression was increased. miR-124 was negatively correlated with UCA1 and JAG1. UCA1 and JAG1 were positively correlated. In summary, we provided a novel mechanism by which the EMT process and cancer cell invasion in tongue cancer could be modulated from the perspective of lncRNA-miRNA-mRNA regulation.
Subject(s)
Epithelial-Mesenchymal Transition/genetics , MicroRNAs/genetics , RNA, Long Noncoding/genetics , Tongue Neoplasms/genetics , Cell Line, Tumor , Epithelial-Mesenchymal Transition/drug effects , Female , Gene Expression Regulation, Neoplastic , Humans , Jagged-1 Protein/metabolism , Kaplan-Meier Estimate , Lymphatic Metastasis/genetics , Male , MicroRNAs/metabolism , Middle Aged , RNA, Long Noncoding/metabolism , Receptors, Notch/genetics , Receptors, Notch/metabolism , Tongue Neoplasms/mortality , Tongue Neoplasms/pathology , Transforming Growth Factor beta1/metabolism , Transforming Growth Factor beta1/pharmacologyABSTRACT
Objective @#To summarize experience treating dog bites in the oral and maxillofacial regions of children and provide a reference for clinical practice.@*Methods @#Nineteen children with dog bite wounds in the maxillofacial region were treated from July 2011 to June 2018 with primary debridement and suturing. A rabies vaccine, tetanus vaccine and human immunoglobulin as a passive immune agent were given via intramuscular injection. Anti-inflammatory therapy with amoxicillin and clavulanate potassium or other antibiotics. Follow-up observation and a retrospective analysis of the treatment effect were carried out.@*Results@#After treatment, among the 19 pediatric patients, 18 cases showed primary healing and 1 case showed secondary healing. The follow-up period ranged from six months to seven and a half years. No cases of rabies occurred.@*Conclusion @#For the treatment of patients with maxillofacial dog bite wounds, the first stage debridement and suture can reduce the scar after operation and is beneficial to the recovery of face.
ABSTRACT
We wish to retract our research article entitled "Long noncoding RNA MALAT1 interacts with miR124 and modulates tongue cancer growth by targeting JAG1" published in Oncology Reports 37 20872094, 2017. Following the publication of this article, it was drawn to our attention that this paper bore numerous similarites with an article published previously in the journal OncoTargets and Therapy. Although all the data reported in our study were original, we recognize that it was not appropriate that we should have modelled our paper on previously published articles as a template on which to base the writing of our paper. Therefore, we have agreed to follow the Editor's recommendation that this paper be retracted from the publication. All the named authors agree to this retraction. We sincerely apologize to the Editor and the readership of the Journal for our action, and regret any inconvenience this has caused. [the original article was published in the Oncology Reports 37: 20872094, 2017; DOI: 10.3892/or.2017.5445].
ABSTRACT
This study evaluated the effect of temperature on methane production by CO2 reduction during microbial electrosynthesis (MES) with a mixed-culture biocathode. Reactor performance, in terms of the amount and rate of methane production, current density, and coulombic efficiency, was compared at different temperatures. The microbial properties of the biocathode at each temperature were also analyzed by 16S rRNA gene sequencing. The results showed that the optimum temperature for methane production from CO2 reduction in MES with a mixed-culture cathode was 50°C, with the highest amount and rate of methane production of 2.06±0.13mmol and 0.094±0.01mmolh-1, respectively. In the mixed-culture biocathode MES, the coulombic efficiency of methane formation was within a range of 19.15±2.31% to 73.94±2.18% due to by-product formation at the cathode, including volatile fatty acids and hydrogen. Microbial analysis demonstrated that temperature had an impact on the diversity of microbial communities in the biofilm that formed on the MES cathode. Specifically, the hydrogenotrophic methanogen Methanobacterium became the predominant archaea for methane production from CO2 reduction, while the abundance of the aceticlastic methanogen Methanosaeta decreased with increased temperature.
Subject(s)
Carbon Dioxide/metabolism , Electrochemistry/instrumentation , Methane/metabolism , Temperature , Bioelectric Energy Sources/microbiology , Carbon Dioxide/chemistry , Electrodes , RNA, Ribosomal, 16S/genetics , Sequence Analysis, RNAABSTRACT
@#Third molars, late-eruption permanent teeth in humans, have commonly been extracted in clinical treatments. However, with the development of oral medicine, the value of maxillary third molars in clinical treatments, as well as in oral prosthetics, orthodontics, and oral implant applications, has gradually become recognized. This paper summarizes the research on the morphology of the crown, root, root canal and root tip of the maxillary third molar in a review to facilitate related research and clinical treatments.