First Report of Botrytis cinerea Causing Stem Rot on Hydrangea macrophylla in China.

Hydrangea (Hydrangea macrophylla), commonly referred to as big leaf hydrangea, is a species within the Hydrangeaceae family notable for its ornamental value. Characterized by its vividly colored sepals and lush, striking inflorescences, this species is globally esteemed as both a potted and landscape plant. Notably, in 2022, an alarming incidence of stem rot was observed in approximately 40% of H. macrophylla plants aged between six and twelve months within 16 greenhouses situated in Nanjing City (N 31°14', E 118°22'), Jiangsu Province, China. Initial symptoms of the disease manifested as wet gray-black spots at the base of the seedlings and stems, progressing to a necrotic gray-white discoloration in the stems and accompanied by the growth of gray mold on the affected parts. This infection ultimately led to the wilting of the leaves and the death of the seedlings. For pathogen identification, stem tissues at the interface of diseased and healthy sections were excised, surface-sterilized with 75 % ethanol for 30 s, followed by a 2 - 3 min treatment with 3% sodium hypochlorite, and subsequently rinsed three times with sterile water before air drying. Sections measuring 2 - 3 mm were then cultured on potato dextrose agar (PDA) medium, supplemented with 50 mg/mL rifampicin (RFP), and incubated at 25 ℃ for 3 - 5 d (Zhou et al. 2022). Upon 2 - 3 days of incubation, notable growth of fungal colonies was observed. Mycelial clusters from the periphery of these colonies were subsequently transferred to fresh PDA plates and incubated at 25 ℃ for an additional 5 - 7 d. A particular colony, designated JSNJ2022-2 and now preserved at the Jiangsu Academy of Agricultural Sciences, was selected for detailed examination. This colony exhibited a flocculent texture, with a coloration ranging from grey-white to light brown. It was characterized by the presence of irregularly formed, hard sclerotia within the hyphae. The conidiophores were observed to be slender and erect, featuring dendritic branches at their extremities. The conidia were clustered on the conidiophore like grapes. These conidia were generally colorless or grey, oval in shape, smooth and transparent, and measured between 6.4 - 12.2 × 7.3 - 18.2 µm (n = 50). For genetic analysis, genomic DNA (gDNA) was extracted using the DNA secure Plant Kit (Tiangen Biotech, Beijing, China). Polymerase chain reaction (PCR) amplification was performed using a set of universal primers of ITS1/ITS4 (White et al. 1990), primers corresponding to the specific sequences of glyceraldehyde-3-phosphate dehydrogenase (G3PDH), heat-shock protein 60 (HSP60), and DNA-dependent RNA polymerase subunit II (RPB2) (Yang et al. 2020). The resultant PCR products were sequenced, and the resulting sequences were submitted to the GenBank database, under the accession numbers OP131597, OP142320, OP142321, and OP142322, respectively. BLAST analysis of the sequences obtained from the isolate JSNJ2022-2 revealed a high degree of genetic similarity, ranging from 99 to 100%, with known sequences of Botrytis cinerea (accessions MK051124.1, MH796662.1, MH479931.1, and KU760986.1). To elucidate the phylogenetic position of the isolate, a phylogenetic tree was constructed using the maximum likelihood method, supported by 1,000 bootstrap replications, in the Mega7 software (Kumar et al. 2016). The results of this analysis confirmed that the strains under study clustered within the same branch as B. cinerea. To establish the pathogenicity of the isolate, Koch's postulates (Falkow 1988) were employed. Healthy potted H. macrophylla seedlings, approximately three months old, were wound inoculated at the base of the seedlings with a 6 mm diameter mycelium plug of JSNJ2002-2 cultivated on PDA for 3 days, which was subsequently covered with moistened degreasing cotton. Control plants were treated with moistened degreasing cloths minus the pathogen. Post-inoculation, these plants were placed in a growth chamber maintained at 25 ℃ with a relative humidity range of 60 - 80%. After a 3-d incubation period, the inoculated plants displayed symptoms identical to those initially observed in the greenhouse. The pathogen was successfully re-isolated from these inoculated plants and was morphologically re-confirmed as B. cinerea, thus satisfying the criteria of Koch's postulates. To our knowledge, this report represents the first documented incidence of B. cinerea causing stem rot in H. macrophylla in China.

Insights into the involvement of long non-coding RNAs in doxorubicin resistance of cancer.

Doxorubicin is one of the most classical chemotherapeutic drugs for the treatment of cancer. However, resistance to the cytotoxic effects of doxorubicin in tumor cells remains a major obstacle. Aberrant expression of long non-coding RNAs (lncRNAs) has been associated with tumorigenesis and development via regulation of chromatin remodeling, transcription, and post-transcriptional processing. Emerging studies have also revealed that dysregulation of lncRNAs mediates the development of drug resistance through multiple molecules and pathways. In this review, we focus on the role and mechanism of lncRNAs in the progress of doxorubicin resistance in various cancers, which mainly include cellular drug transport, cell cycle disorder, anti-apoptosis, epithelial-mesenchymal transition, cancer stem cells, autophagy, tumor microenvironment, metabolic reprogramming and signaling pathways. This review is aimed to provide potential therapeutic targets for future cancer therapy, especially for the reversal of chemoresistance.

Enhanced 3D Pose Estimation in Multi-Person, Multi-View Scenarios through Unsupervised Domain Adaptation with Dropout Discriminator.

Data-driven pose estimation methods often assume equal distributions between training and test data. However, in reality, this assumption does not always hold true, leading to significant performance degradation due to distribution mismatches. In this study, our objective is to enhance the cross-domain robustness of multi-view, multi-person 3D pose estimation. We tackle the domain shift challenge through three key approaches: (1) A domain adaptation component is introduced to improve estimation accuracy for specific target domains. (2) By incorporating a dropout mechanism, we train a more reliable model tailored to the target domain. (3) Transferable Parameter Learning is employed to retain crucial parameters for learning domain-invariant data. The foundation for these approaches lies in the H-divergence theory and the lottery ticket hypothesis, which are realized through adversarial training by learning domain classifiers. Our proposed methodology is evaluated using three datasets: Panoptic, Shelf, and Campus, allowing us to assess its efficacy in addressing domain shifts in multi-view, multi-person pose estimation. Both qualitative and quantitative experiments demonstrate that our algorithm performs well in two different domain shift scenarios.

Long non-coding RNA H19: a potential biomarker and therapeutic target in human malignant tumors.

Long non-coding RNAs play important roles in cellular functions and disease development. H19, as a long non-coding RNA, is pervasively over-expressed in almost all kinds of human malignant tumors. Although many studies have reported that H19 is closely associated with tumor cell proliferation, apoptosis, invasion, metastasis, and chemoresistance, the role and mechanism of H19 in gene regulation and tumor development are largely unclear. In this review, we summarized the recent progress in the study of the major functions and mechanisms of H19 lncRNA in cancer development and progression. H19 possesses both oncogenic and tumor-suppressing activities, presumably through regulating target gene transcription, mRNA stability and splicing, and competitive inhibition of endogenous RNA degradation. Studies indicate that H19 may involve in cell proliferation and apoptosis, tumor initiation, migration, invasion, metastasis and chemoresistance and may serve as a potential biomarker for early diagnosis, prognosis, and novel molecular target for cancer therapy.

Genetic Diversity and Population Genetic Structure of Setosphaeria turcica From Sorghum in Three Provinces of China Using Single Nucleotide Polymorphism Markers.

Setosphaeria turcica is a heterothallic fungus that is the causal agent of northern leaf blight (NLB), which is a devastating foliar disease of sorghum and maize. Despite of its adversary to crop production, little is known about the genetic diversity and population genetic structure of this pathogen from sorghum. In this study, we explored the utilization of single nucleotide polymorphism (SNP) molecular markers and three mating type-specific primers to analyze the genetic diversity, population genetic structure, and mating type distribution of 87 S. turcica isolates that had been collected in sorghum production areas from three provinces, including Henan, Shaanxi, and Shanxi in China. The populations are featured with moderate genetic diversity and relatively equal mating type distribution of MAT1-1 and MAT1-2. The genetic differentiation was significant (p < 0.05) among different populations except those from Henan and Shanxi provinces that showed particularly frequent gene flow between them. Neither the maxinum likelihood phylogenetic tree, nor principal coordinate analysis, nor genetic structure analysis was able to completely separate the three populations. The relatively low genetic distance and high genetic identification were also observed among the three populations. Nevertheless, the genetic variation within populations was the major source of variation as revealed by AMOVA analysis. The findings of this study have improved our current understanding about the genetic diversity, population genetic structure, and the distribution of mating type of S. turcica, which are useful for unraveling the epidemiology of NLB and developing effective disease management strategies.

Apatinib in the treatment of gastric cancer in Henan Province: a multicenter prospective real-world observational study (Ahead-HAP01).

Background: Apatinib is approved in China for the treatment of advanced gastric adenocarcinoma that had progressed or relapsed after standard systemic chemotherapy treatments. However, the effectiveness of Apatinib under real-world condition has not been evaluated and the drug performance under ideal and controlled circumstances has not been validated. In fact, genetic factors, poor healthcare access, social economic status, comorbidities compliance and other factors play significant role in drug performance under "real-world" conditions. Real-world experience can help validate the safety and efficacy of apatinib. Methods: In this observational, prospective study we evaluated the safety and efficacy of Apatinib in patient treated in China. Between March 2018 and March 2019, a total of 943 patients with gastric cancer treated with Apatinib were enrolled. Response Evaluation Criteria in Solid Tumors, version 1.1 and Common Terminology Criteria for Adverse Events, version 4.0 were used to evaluate efficacy and adverse effects. Results: The median progression-free survival (PFS) was 5.65 months (5.22-6.05 months), and the median overall survival (OS) was 11.47 months (10.41-12.52 months). Apatinib in combination with more than two agents was superior to single agent apatinib in overall response rate (ORR) [18.18% vs. 9.43%, 95% confidence interval (CI): 1.03-5.90] and disease control rate (DCR) (82.82% vs. 77.87%, 95% CI: 1.21-2.59). Apatinib in combination with single agent chemotherapy was also superior to apatinib alone with DCR (86.29% vs. 77.87%, 95% CI: 1.47-2.99) irrespective of the dose (250 or 500 mg). In the patient cohort who received a starting dose of 250 mg, the DCRs of the combined treatment and monotherapy groups were 86.22% vs. 80.00% (95% CI: 1.18-3.09), respectively. The most common treatment-emergent adverse events were anemia, anorexia and thrombocytopenia (66.28%, 37.75%, 36.06%, respectively). Conclusions: Efficacy of Apatinib in this observational study is promising and toxicities are manageable. Combination of Apatinib with chemotherapy agents has a higher response rate and better disease control at the expense of increased serious adverse events. Better OS can be achieved by receiving apatinib treatment earlier. As a supplement and further validation of explanatory randomized controlled trials, the real-world study reflects the real efficacy of apatinib in practical application.

Vibrio vulnificus infection attributed to bee sting: a case report.

Vibrio vulnificus is a pathogenic marine bacteria associated with high mortality. Changes in climate and the global seafood trade have increased the prevalence of marine and freshwater systems affected by V. vulnificus. As a result, the incidence of land animals, plants, and insects contacting V. vulnificus and acting as disease vectors is on the rise. We report the case of a 53-year-old male who was infected with V. vulnificus as the result of a bee sting. The patient had no history of contact with the sea or fresh water or aquatic organisms or products. Due to bacterial pathogenicity and the patient's underlying diseases, his condition deteriorated rapidly and eventually resulted in death. Here, we review the pathogenic mechanisms and treatment of V. vulnificus. We determined that V. vulnificus has spread from seawater to freshwater and that individuals may become infected from insects, even in the absence of direct contact with infected water. This case report will inform clinicians about the possible sources of V. vulnificus infection and indicates the possibility that more insects may transmit V. vulnificus in the future.

Clinical observation and analysis on the significance of quick sequential organ failure assessment in 74 non-ICU patients with sepsis.

BACKGROUND: Sepsis is an important disease that endangers human health and is the main cause of death in ICU patients, which has been a focus of clinical treatment. This study aims to evaluate the significance of the readily available quick sequential organ failure assessment (qSOFA) score in clinical cases of sepsis. METHODS: A retrospective cross-sectional study of patients with sepsis treated in the Department of Infectious Diseases, the Affiliated Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology from January 2015 to December 2016 was conducted, and the patients were divided into a high-score group (≥2 points) and the low-score group (<2 points) according to the diagnostic criteria for sepsis (Sepsis 3.0). The differences in disease outcome and inflammatory indicators were compared between groups. RESULTS: A total of 74 patients with sepsis were included in this study. When the cutoff qSOFA score was 2 points, the patients in the high-score group showed a higher mortality rate (71.43%), and the patients in the low-score group showed a higher improvement rate (87.76%). The inflammatory indicators did not show statistically significant differences between the two groups. CONCLUSIONS: The qSOFA score can better predict the prognoses of non-ICU patients with sepsis compared with traditional inflammatory indicators. Clinicians should raise their awareness about qSOFA and improving its accuracy.

Effects of CORO2A on Cell Migration and Proliferation and Its Potential Regulatory Network in Breast Cancer.

Coronin 2A (CORO2A) is a novel component of the N-CoR (nuclear receptor co-repressor) complex. Abnormal CORO2A expression is associated with carcinogenesis. We used databases from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), and analyzed CORO2A expression and gene regulation networks in breast cancer. Expression was analyzed using GEO and TCGA database and further validated in breast cancer samples collected in our clinic. The prognostic value of CORO2A was explored by using the Kaplan-Meier survival analysis and Cox proportional hazards regression analysis. LinkedOmics was used to identify coexpressed genes associated with CORO2A. After analyzing the intersection of coexpressed genes correlated with CORO2A and differentially expressed genes after CORO2A silencing, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of the intersecting genes were conducted by using FunRich software. Transwell assays were performed in breast cancer cells to determine the effect of CORO2A on cell migration. MTS, colony formation, and cell cycle distribution assays were performed in breast cancer cells to determine the effect of CORO2A on cell proliferation. Gene enrichment analysis was employed to explore the target networks of transcription factors and miRNAs. We found that CORO2A was upregulated and that the elevated expression of CORO2A was associated with poor overall survival (OS) and relapse-free survival (RFS) in TNBC patients. Further bioinformatics analysis of public sequencing data and our own RNA-Seq data revealed that CORO2A was probably involved in the epithelial-to-mesenchymal transition process and might have a significant effect on the migration of breast cancer cells, which might be mediated via pathways involving several miRNAs and MYC transcription factors. Functionally, the knockdown of CORO2A inhibited cell migration, decreased viability, and colony formation and induced cell cycle arrest in the G0/G1 phase in breast cancer cells. These results demonstrate that bioinformatics-based analysis efficiently reveals information about CORO2A expression and its potential regulatory networks in breast cancer, laying a foundation for further mechanistic research on the role of CORO2A in carcinogenesis. Moreover, CORO2A promotes the migration and proliferation of breast cancer cells and may have an important function in breast cancer progression. CORO2A is a potential prognostic predictor for TNBC patients. Targeting CORO2A may provide promising therapy strategies for breast cancer treatment.

Identification of Candidate Genes Associated with Breast Cancer Prognosis.

Breast cancer (BC) is the most malignant tumor in women. The molecular mechanisms underlying tumorigenesis still need to be further elucidated. It is necessary to investigate novel candidate genes involved in breast cancer progression and prognosis. In this study, we commit to explore candidate genes that associate with prognosis and therapy in BC by a comprehensive bioinformatic analysis. Four GEO datasets (GSE5764, GSE7904, GSE20711, and GSE29431) and the BC-related transcriptome data in TCGA database were downloaded and used to identify the differently expressed genes (DEGs). The function of DEGs was analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis. The protein-protein interaction (PPI) network of DEGs was constructed to identify hub genes. Prognostic candidate genes were identified through survival analysis. In addition, potential therapeutic targets were identified by constructed gene-drug interaction network through Comparative Toxicogenomics Database. A total of 547 DEGs (302 up and 245 down) were identified. Three core-subnetwork and 25 hub genes were identified in PPI network. Seven genes (namely COL12A1, QPRT, MRPL13, KRT14, KRT15, LAMB3, and MYBPC1) were identified as crucial prognostic candidate genes, which significantly associated with breast cancer overall survival. Furthermore, two representative candidate genes (COL12A1 and LAMB3) were optionally chosen for verification by reverse transcription and quantitative real-time polymerase chain reaction (RT-PCR). What's more, the gene-drugs interaction analysis indicates several antitumor drugs that could affect the expression of these prognostic markers, such as doxorubicin, cisplatin, and tamoxifen. These results identified seven crucial candidate genes that may serve as prognosis biomarkers and novel therapeutic targets of breast cancer, which may facilitate further understanding the molecular pathogenesis and providing potential therapeutic strategies for BC.

Statins induce cell apoptosis through a modulation of AKT/FOXO1 pathway in prostate cancer cells.

BACKGROUND: In recent years, statins have been frequently investigated in neoplasms. However, the potential roles of statins on prostate cancer cells and the underlying mechanisms have not been fully elucidated. In current study, we explored the effect and molecular mechanism of statins on cell proliferation and apoptosis in prostate cancer cells. METHODS: Prostate cancer cell were treated with gradient doses of simvastatin and fluvastatin for 24-72 h. Cell proliferation was analyzed by using MTS assay and colony formation. Cell apoptosis was measured by Hoechst staining, flow cytometry and caspase-3 activity. Western blotting was used to evaluate the proteins levels. RESULTS: Both simvastatin and fluvastatin produced a dose- and time-dependent inhibition of cell viability and colony formation while a promotion of cell apoptosis as evident with increases in caspase-3 activity, cleaved-caspase-3, cleaved-caspase-8 and cleaved-PARP levels in PC3 cells. Similar statin effects were observed in DU145 prostate cancer cells. Furthermore, statins produced a time- and dose-dependent reduction of phosphorylated-AKT and phosphorylated-FOXO1 levels in PC3 cells, and pretreatment of cells with an AKT phosphorylation inhibitor, MK2206, potentiated statins' effect. CONCLUSION: Statins decrease cell proliferation and induce cell apoptosis, probably mediated via a downregulation of AKT/FOXO1 phosphorylation in prostate cancer cells, which may have a potential benefit in prostate cancer prevention and therapy.

Long non-coding RNAs in prostate cancer: Functional roles and clinical implications.

Long noncoding RNAs (lncRNAs) are defined as RNA transcripts longer than 200 nucleotides that do not encode proteins. LncRNAs have been documented to exhibit aberrant expression in various types of cancer, including prostate cancer. Currently, screening for prostate cancer results in overdiagnosis. The consequent overtreatment of patients with indolent disease in the clinic is due to the lack of appropriately sensitive and specific biomarkers. Thus, the identification of lncRNAs as novel biomarkers and therapeutic targets for prostate cancer is promising. In the present review, we attempt to summarize the current knowledge of lncRNA expression patterns and mechanisms in prostate cancer. In particular, we focus on lncRNAs regulated by the androgen receptor and the specific molecular mechanism of lncRNAs in prostate cancer to provide a potential clinical therapeutic strategy for prostate cancer.

Identification of Potential Crucial Genes and Key Pathways in Breast Cancer Using Bioinformatic Analysis.

Background: The molecular mechanism of tumorigenesis remains to be fully understood in breast cancer. It is urgently required to identify genes that are associated with breast cancer development and prognosis and to elucidate the underlying molecular mechanisms. In the present study, we aimed to identify potential pathogenic and prognostic differentially expressed genes (DEGs) in breast adenocarcinoma through bioinformatic analysis of public datasets. Methods: Four datasets (GSE21422, GSE29431, GSE42568, and GSE61304) from Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) dataset were used for the bioinformatic analysis. DEGs were identified using LIMMA Package of R. The GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses were conducted through FunRich. The protein-protein interaction (PPI) network of the DEGs was established through STRING (Search Tool for the Retrieval of Interacting Genes database) website, visualized by Cytoscape and further analyzed by Molecular Complex Detection (MCODE). UALCAN and Kaplan-Meier (KM) plotter were employed to analyze the expression levels and prognostic values of hub genes. The expression levels of the hub genes were also validated in clinical samples from breast cancer patients. In addition, the gene-drug interaction network was constructed using Comparative Toxicogenomics Database (CTD). Results: In total, 203 up-regulated and 118 down-regulated DEGs were identified. Mitotic cell cycle and epithelial-to-mesenchymal transition pathway were the major enriched pathways for the up-regulated and down-regulated genes, respectively. The PPI network was constructed with 314 nodes and 1,810 interactions, and two significant modules are selected. The most significant enriched pathway in module 1 was the mitotic cell cycle. Moreover, six hub genes were selected and validated in clinical sample for further analysis owing to the high degree of connectivity, including CDK1, CCNA2, TOP2A, CCNB1, KIF11, and MELK, and they were all correlated to worse overall survival (OS) in breast cancer. Conclusion: These results revealed that mitotic cell cycle and epithelial-to-mesenchymal transition pathway could be potential pathways accounting for the progression in breast cancer, and CDK1, CCNA2, TOP2A, CCNB1, KIF11, and MELK may be potential crucial genes. Further, it could be utilized as new biomarkers for prognosis and potential new targets for drug synthesis of breast cancer.

Neurexophilin and PC-esterase domain family member 4 (NXPE4) and prostate androgen-regulated mucin-like protein 1 (PARM1) as prognostic biomarkers for colorectal cancer.

Owing to the high morbidity and mortality, novel biomarkers in the occurrence and development of colorectal cancer (CRC) are needed nowadays. In this study, the CRC-related datasets were downloaded from the Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA) database. After screening the differentially expressed genes (DEGs) in R software, a total of 238 upregulated and 199 downregulated DEGs were revealed simultaneously. Then the Kaplan-Meier survival analysis and Cox regression analysis were used to reveal the prognostic function of these DEGs. Neurexophilin and PC-esterase domain family member 4 (NXPE4) and prostate androgen-regulated mucin-like protein 1 (PARM1) were two outstanding independent overall survival (OS) and relapse-free survival (RFS) prognostic genes of CRC in TCGA database. We next verified the expression of NXPE4 and PARM1 messenger RNA (mRNA) levels were significantly lower in CRC tumor tissue than in the adjacent noncancerous tissue in our clinical samples, and NXPE4 mRNA expression level was related to the tumor location and tumor size, while PARM1 was related to tumor location, lymph nodes metastasis, and tumor size. This study demonstrated that NXPE4 and PARM1 might be two potential novel prognostic biomarkers for CRC.

Inhibition of PI3K/Akt/mTOR signaling pathway alleviates ovarian cancer chemoresistance through reversing epithelial-mesenchymal transition and decreasing cancer stem cell marker expression.

BACKGROUND: Ovarian cancer is the most common malignant tumor of the female reproductive tract. Chemoresistance is a major challenge for current ovarian cancer therapy. However, the mechanism underlying epithelial ovarian cancer (EOC) chemoresistance is not completely uncovered. The phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling is an important intracellular pathway in regulating cell cycle, quiescence, and proliferation. The aim of this study is to investigate the role of PI3K/Akt/mTOR signaling pathway and its association with epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) marker expression in EOC chemoresistance. METHODS: The expressions of EMT and CSC markers were detected by immunofluorescence, western blot, and quantitative real-time PCR. BEZ235, a dual PI3K/mTOR inhibitor, was employed to investigate the role of PI3K/Akt/ mTOR signaling in regulating EMT and CSC marker expression. Students' t test and one-way ANOVA with Tukey's post-hoc test were used to compare the data from different groups. RESULTS: We found that EMT and CSC marker expression were significantly enhanced in chemoresistant EOC cells, which was accompanied by the activation of PI3K/Akt/mTOR signaling. Compared with single cisplatin treatment, combined treatment with BEZ235 and cisplatin significantly disrupted the colony formation ability, induced higher ROS level and more apoptosis in chemoresistant EOC cells. Furthermore, the combination approach effectively inhibited PI3K/Akt/mTOR signaling pathway, reversed EMT, and decreased CSC marker expression in chemoresistant EOC cells compared with cisplatin mono-treatment. CONCLUSIONS: Our results first demonstrate that EMT and enhanced CSC marker expression triggered by activated PI3K/Akt/mTOR signaling are involved in the chemoresistance of EOC, and BEZ235 in combination with cisplatin might be a promising treatment option to reverse EOC chemoresistance.

Polymorphisms in IGF2/H19 gene locus are associated with platinum-based chemotherapeutic response in Chinese patients with epithelial ovarian cancer.

AIM: The present study aimed to assess the association between IGF2/H19 genetic variants and susceptibility to platinum-based chemotherapy in epithelial ovarian cancer (EOC). METHODS: A total of 43 platinum-resistant (PR) and 138 platinum-sensitive (PS) EOC patients were recruited in our study. 21 polymorphisms in IGF2/H19 locus were genotyped by Sequenom MassARRAY assay. RESULTS: The frequencies of GG genotype in both rs3842761(C/G) and rs4244809(A/G) were significantly lower in PR group compared with those in PS group (9.76 vs 23.36%, p = 0.049; 9.76 vs 26.09%, p = 0.045; respectively). Compared with the AA genotype, rs4244809 GG genotype was associated with significantly reduced risk of platinum resistance (adjusted OR: 0.30; 95% CI: 0.10-0.91; p = 0.033). Further stratified analyses revealed that the SNPs of rs3842761 and rs4244809 were greatly related to PR risk in FIGO stage III-IV (rs3842761GG/CC+CG: adjusted OR: 0.15; 95% CI: 0.02-1.21; rs4244809 GG/AA+AG: adjusted OR: 0.24; 95% CI: 0.07-0.84; respectively) and serous adenocarcinoma subgroups (rs3842761 GG/CC+CG: adjusted OR: 0.21; 95% CI: 0.05-0.94; rs4244809 GG/AA+AG: adjusted OR: 0.19; 95% CI: 0.04-0.5; respectively), while rs7924316 polymorphism was associated with reduced risk of PR in serous adenocarcinoma subgroup as analyzed by a recessive model (rs7924316 GG/TT+TG: adjusted OR: 0.22; 95% CI: 0.05-0.98). In addition, both TCT haplotypes of rs3741206/rs3842761/rs7924316 and TC haplotype of rs3741206/rs3842761 were associated with elevated risk of PR (for the TCT haplotype of rs3741206/rs3842761/rs7924316: p = 0.049; OR: 1.69; 95% CI: 1.00-2.87; for the TC haplotype of rs3741206/rs3842761: p = 0.044; OR: 1.71; 95% CI: 1.01-2.88). CONCLUSION: These results suggest that polymorphisms in IGF2/H19 gene locus are associated with PR risk in EOC.

Emerging role of long non-coding RNAs in cisplatin resistance.

Cisplatin (CDDP) is one of the most commonly used chemotherapy drugs for the treatment of various cancers. Although platinum-based therapies are highly efficacious against rapidly proliferating malignant tumors, the development of CDDP resistance results in significant relapse as well as decreased overall survival rates, which is a significant obstacle in CDDP-based cancer therapy. Long non-coding RNAs (lncRNAs) are involved in cancer development and progression by the regulation of processes related to chromatin remodeling, transcription, and posttranscriptional processing. Emerging evidence has recently highlighted the roles of lncRNAs in the development of CDDP resistance. In this review, we discuss the roles and mechanisms of lncRNAs in CDDP chemoresistance, including changes in cellular uptake or efflux of a drug, intracellular detoxification, DNA repair, apoptosis, autophagy, cell stemness, and the related signaling pathways, aiming to provide potential lncRNA-targeted strategies for overcoming drug resistance in cancer therapy.

LncRNA H19 is a major mediator of doxorubicin chemoresistance in breast cancer cells through a cullin4A-MDR1 pathway.

Development of chemoresistance is a persistent problem during cancer treatment. Long non-coding RNAs (LncRNAs) are currently emerging as an integral functional component of the human genome and as critical regulators of cancer development and progression. In the present study, we investigated the role and molecular mechanism of H19 lncRNA in chemoresistance development by using doxorubicin (Dox) resistance in breast cancer cells as a model system. H19 lncRNA expression was significantly increased in anthracycline-treated and Dox-resistant MCF-7 breast cancer cells. This H19 overexpression was contributed to cancer cell resistance to anthracyclines and paclitaxel as knockdown of H19 lncRNA by a specific H19 shRNA in Dox-resistant cells significantly improved the cell sensitivity to anthracyclines and paclitaxel. Furthermore, gene expression profiling analysis revealed that a total of 192 genes were associated with H19-mediated Dox resistance. These genes were enriched in multiple KEGG pathways that are related to chemoresistance. Using genetic and pharmacological approaches, we demonstrated that MDR1 and MRP4 were major effectors of H19-regulated Dox resistance in breast cancer cells as MDR1 and MRP4 expression was markedly elevated in Dox-resistant cells while dramatically reduced when H19 was knocked down. Moreover, we found that CUL4A, an ubiquitin ligase component, was a critical factor bridging H19 lncRNA to MDR1 expression, and a high tumor CUL4A expression was associated with low survival in breast cancer patients treated with chemotherapy. These data suggest that H19 lncRNA plays a leading role in breast cancer chemoresistance, mediated mainly through a H19-CUL4A-ABCB1/MDR1 pathway.

Long Non-Coding RNA as Potential Biomarker for Prostate Cancer: Is It Making a Difference?

Whole genome transcriptomic analyses have identified numerous long non-coding RNA (lncRNA) transcripts that are increasingly implicated in cancer biology. LncRNAs are found to promote essential cancer cell functions such as proliferation, invasion, and metastasis, with the potential to serve as novel biomarkers of various cancers and to further reveal uncharacterized aspects of tumor biology. However, the biological and molecular mechanisms as well as the clinical applications of lncRNAs in diverse diseases are not completely understood, and remain to be fully explored. LncRNAs may be critical players and regulators in prostate cancer carcinogenesis and progression, and could serve as potential biomarkers for prostate cancer. This review focuses on lncRNA biomarkers that are already available for clinical use and provides an overview of lncRNA biomarkers that are under investigation for clinical development in prostate cancer.

Proteomic identification of the lactate dehydrogenase A in a radioresistant prostate cancer xenograft mouse model for improving radiotherapy.

Radioresistance is a major challenge for prostate cancer (CaP) metastasis and recurrence after radiotherapy. This study aimed to identify potential protein markers and signaling pathways associated with radioresistance using a PC-3 radioresistant (RR) subcutaneous xenograft mouse model and verify the radiosensitization effect from a selected potential candidate. PC-3RR and PC-3 xenograft tumors were established and differential protein expression profiles from two groups of xenografts were analyzed using liquid chromatography tandem-mass spectrometry. One selected glycolysis marker, lactate dehydrogenase A (LDHA) was validated, and further investigated for its role in CaP radioresistance. We found that 378 proteins and 51 pathways were significantly differentially expressed between PC-3RR and PC-3 xenograft tumors, and that the glycolysis pathway is closely linked with CaP radioresistance. In addition, we also demonstrated that knock down of LDHA with siRNA or inhibition of LDHA activity with a LDHA specific inhibitor (FX-11), could sensitize PC-3RR cells to radiotherapy with reduced epithelial-mesenchymal transition, hypoxia, DNA repair ability and autophagy, as well as increased DNA double strand breaks and apoptosis. In summary, we identified a list of potential RR protein markers and important signaling pathways from a PC-3RR xenograft mouse model, and demonstrate that targeting LDHA combined with radiotherapy could increase radiosensitivity in RR CaP cells, suggesting that LDHA is an ideal therapeutic target to develop combination therapy for overcoming CaP radioresistance.