The dynamics of B-cell reconstitution post allogeneic hematopoietic stem cell transplantation: A real-world study.

BACKGROUND: The immune reconstitution after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is crucial for preventing infections and relapse and enhancing graft-versus-tumor effects. B cells play an important role in humoral immunity and immune regulation, but their reconstitution after allo-HSCT has not been well studied. METHODS: In this study, we analyzed the dynamics of B cells in 252 patients who underwent allo-HSCT for 2 years and assessed the impact of factors on B-cell reconstitution and their correlations with survival outcomes, as well as the development stages of B cells in the bone marrow and the subsets in the peripheral blood. RESULTS: We found that the B-cell reconstitution in the bone marrow was consistent with the peripheral blood (p = 0.232). B-cell reconstitution was delayed by the male gender, age >50, older donor age, the occurrence of chronic and acute graft-versus-host disease, and the infections of fungi and cytomegalovirus. The survival analysis revealed that patients with lower B cells had higher risks of death and relapse. More importantly, we used propensity score matching to obtain the conclusion that post-1-year B-cell reconstitution is better in females. Meanwhile, using mediation analysis, we proposed the age-B cells-survival axis and found that B-cell reconstitution at month 12 posttransplant mediated the effect of age on patient survival (p = 0.013). We also found that younger patients showed more immature B cells in the bone marrow after transplantation (p = 0.037). CONCLUSION: Our findings provide valuable insights for optimizing the management of B-cell reconstitution and improving the efficacy and safety of allo-HSCT.

DNA repair pathways-targeted cyclovirobuxine inhibits castration-resistant prostate cancer growth by promoting cell apoptosis and cycle arrest.

BACKGROUND: Castration-resistant prostate cancer (CRPC) is a deadly malignancy without effective therapeutics. Cyclovirobuxine (CVB) can play an anticancer role by inhibiting mitochondrial function, regulating tumor cell apoptosis, dysregulating autophagy, and other mechanisms. This study aimed to examine the function and mechanism of CVB in CRPC to provide new insights into CRPC treatment. METHODS: The effect of CVB on PC3 and C4-2 cell viability was determined using a CCK8 assay. Core therapeutic targets of CVB in CRPC cells were identified using RNA sequencing, online database, and PPI network analyses. Western blotting, RT-qPCR and molecular docking were performed to evaluate the regulation of core targets by CVB. Utilizing GO and KEGG enrichment analyses, the probable anti-CRPC mechanism of CVB was investigated. Immunofluorescence, flow cytometry and colony formation assays were used to verify the potential phenotypic regulatory role of CVB in CRPC. RESULTS: CVB inhibited CRPC cell activity in a concentration-dependent manner. Mechanistically, it primarily regulated BRCA1-, POLD1-, BLM-, MSH2-, MSH6- and PCNA-mediated mismatch repair, homologous recombination repair, base excision repair, Fanconi anemia repair, and nucleotide excision repair pathways. Immunofluorescence, Western blot, flow cytometry and colony formation experiments showed that CVB induced DNA damage accumulation, cell apoptosis, and cell cycle arrest and inhibited CRPC cell proliferation. CONCLUSION: CVB can induce DNA damage accumulation in CRPC cells by targeting DNA repair pathways and then induce cell apoptosis and cell cycle arrest, eventually leading to inhibition of the long-term proliferation of CRPC cells.

Evolutionary Implications of the RNA N6-Methyladenosine Methylome in Plants.

Epigenetic modifications play important roles in genome evolution and innovation. However, most analyses have focused on the evolutionary role of DNA modifications, and little is understood about the influence of posttranscriptional RNA modifications on genome evolution. To explore the evolutionary significance of RNA modifications, we generated transcriptome-wide profiles of N6-methyladenosine (m6A), the most prevalent internal modification of mRNA, for 13 representative plant species spanning over half a billion years of evolution. These data reveal the evolutionary conservation and divergence of m6A methylomes in plants, uncover the preference of m6A modifications on ancient orthologous genes, and demonstrate less m6A divergence between orthologous gene pairs with earlier evolutionary origins. Further investigation revealed that the evolutionary divergence of m6A modifications is related to sequence variation between homologs from whole-genome duplication and gene family expansion from local-genome duplication. Unexpectedly, a significant negative correlation was found between the retention ratio of m6A modifications and the number of family members. Moreover, the divergence of m6A modifications is accompanied by variation in the expression level and translation efficiency of duplicated genes from whole- and local-genome duplication. Our work reveals new insights into evolutionary patterns of m6A methylomes in plant species and their implications, and provides a resource of plant m6A profiles for further studies of m6A regulation and function in an evolutionary context.

The abnormal expression of chromosomal region maintenance 1 (CRM1)-survivin axis in ovarian cancer and its related mechanisms regulating proliferation and apoptosis of ovarian cancer cells.

Ovarian cancer (OC) is the main type of cancer that affects the female reproductive system and has a high morbidity and mortality rate. This study aimed to explore the regulatory effect of the chromosomal region maintenance 1 (CRM1)-survivin axis on the progression of OC. Ovarian cancer cells were transfected with pcDNA3.1-survivin and short hairpin RNA (sh)-CRM1. Cell proliferation was analyzed by cell counting kit-8 (CCK8), 5-ethynyl-2´-deoxyuridine (EdU) staining, and colony formation assays. Apoptosis was detected using flow cytometry. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were performed to analyze the expression of RNA and protein, respectively. qRT-PCR and prognostic correlation analyses revealed that CRM1 is highly expressed in OC cells and related to survival. The results of qRT-PCR, CCK8, colony formation test, EdU staining, flow cytometry, and Western blotting showed that CRM1 silencing inhibited the proliferation and colony formation of OVCAR 3 and SKOV3 cells and promoted cell apoptosis by promoting Caspase-3 activation. Survivin was positively regulated by CRM1 and promoted the development of OC. The results of the rescue experiment showed that overexpression of survivin reversed the inhibitory effect of CRM1 knockdown on the proliferation of ovarian cancer cells and its inhibitory effect on apoptosis. Our findings confirm the role of the CRM1-survivin signal transduction axis in OC by regulating the proliferation and apoptosis of OC cells, and may thus serve as a potential therapeutic target for OC.

ceRNA Networks: The Backbone Role in Neoadjuvant Chemoradiotherapy Resistance/Sensitivity of Locally Advanced Rectal Cancer.

Approximately 40% of rectal cancers during initial diagnosis are identified as locally advanced rectal cancers (LARCs), for which the standardized treatment scenario is total mesorectal excision following neoadjuvant chemoradiotherapy (nCRT). nCRT can lead to discernible reductions in local relapse rate and distant metastasis rate in LARC patients, in whom previously inoperable tumors may potentially be surgically removed. However, only 4% to 20% cases can attain pathological complete response, and the remaining patients who are unresponsive to nCRT have to suffer from the side effects plus toxicities and may encounter poor survival outcomes due to the late surgical intervention. As such, employing potential biomarkers to differentiate responders from nonresponders before nCRT implementation appears to be the overarching goal. Well-defined competing endogenous RNA (ceRNA) networks include long noncoding RNA (lncRNA)-microRNA (miRNA)-mRNA and circRNA-miRNA-mRNA networks. As ceRNAs, lncRNAs, and circRNAs sponge miRNAs to indirectly suppress miRNAs downstream of oncogenic mRNAs or tumor-suppressive mRNAs. The abnormal expression of mRNAs regulates the nCRT-induced DNA damage repair process through pluralistic carcinogenic signaling pathways, thereby bringing about alterations in the nCRT resistance/sensitivity of tumors. Moreover, many molecular mechanisms relevant to cell proliferation, metastasis, or apoptosis of cancers (eg, epithelial-mesenchymal transition and caspase-9-caspase-3 pathway) are influenced by ceRNA networks. Herein, we reviewed a large group of abnormally expressed mRNAs and noncoding RNAs that are associated with nCRT resistance/sensitivity in LARC patients and ultimately pinpointed the backbone role of ceRNA networks in the molecular mechanisms of nCRT resistance/sensitivity.

Stereotactic Biopsy for Brainstem Lesions: A Meta-analysis with Noncomparative Binary Data.

OBJECTIVES: To evaluate the diagnostic yield and safety of brainstem stereotactic biopsy for brainstem lesions. METHODS: We performed a meta-analysis of English articles retrieved from the PubMed, Web of Science, Cochrane Library, and APA psycInfo databases up to May 12, 2021. A binary fixed-effect model, the inverse variance method, or a binary random-effect model, the Dersimonian Laird method, were utilized for pooling the data. This meta-analysis was registered with INPLASY, INPLASY202190034. FINDINGS: A total of 41 eligible studies with 2792 participants were included. The weighted average diagnostic yield was 97.0% (95% confidential interval [CI], 96.0-97.9%). The weighted average proportions of temporary complications, permanent deficits, and deaths were 6.2% (95% CI, 4.5-7.9%), .5% (95% CI, .2-.8%), and .3% (95% CI, .1-.5%), respectively. The subgroup analysis indicated a nearly identical weighted average diagnostic yield between MRI-guided stereotactic biopsy and CT-guided stereotactic biopsy (95.9% vs 95.8%) but slightly increased proportions of temporary complications (7.9% vs 6.0%), permanent deficits (1.9% vs .2%), and deaths (1.1% vs .4%) in the former compared to the latter. Moreover, a greater weighted average diagnostic yield (99.2% vs 97.6%) and lower proportions of temporary complications (5.1% vs 6.8%) and deaths (.7% vs 1.5%) were shown in the pediatric patient population than in the adult patient population. CONCLUSIONS: Brainstem stereotactic biopsy demonstrates striking accuracy plus satisfying safety in the diagnosis of brainstem lesions. The diagnostic yield, morbidity, and mortality mildly vary based on the diversity of assistant techniques and subject populations.

Breast Cancer Subtypes and Mortality of Breast Cancer Patients With Brain Metastasis at Diagnosis: A Population-Based Study.

BACKGROUND: Brain metastasis is an important cause of breast cancer-related death. AIM: We evaluated the relationships between breast cancer subtype and prognosis among patients with brain metastasis at the initial diagnosis. METHODS: The Surveillance, Epidemiology, and End Results database was searched to identify patients with brain metastasis from breast cancer between 2010 and 2015. Multivariable Cox proportional hazard models were used to identify factors that were associated with survival among patients with initial brain metastases. The Kaplan-Meier method was used to compare survival outcomes according to breast cancer subtype. RESULTS: Among 752 breast cancer patients with brain metastasis at diagnosis, 140 patients (18.6%) underwent primary surgery and 612 patients (81.4%) did not undergo surgery, while 460 patients (61.2%) received chemotherapy and 292 patients (38.8%) did not receive chemotherapy. Multivariable analysis revealed that, relative to HR+/HER2- breast cancer, HR-/HER2- breast cancer was associated with significantly poorer overall survival (hazard ratio: 2.52, 95% confidence interval: 1.99-3.21), independent of age, sex, race, marital status, insurance status, grade, liver involvement, lung involvement, primary surgery, radiotherapy, and chemotherapy. The median overall survival intervals were 12 months for HR+/HER2-, 19 months for HR+/HER2+, 11 months for HR-/HER2+, and 6 months for HR-/HER2- (P < .0001). Relative to HR+/HER2- breast cancer, HR-/HER2- breast cancer was associated with a significantly higher risk of mortality among patients, and the association was stronger among patients who received chemotherapy (p for interaction = .005). CONCLUSIONS: Breast cancer subtype significantly predicted overall survival among patients with brain metastasis at diagnosis.

IL-27 as a potential biomarker for distinguishing between necrotising enterocolitis and highly suspected early-onset food protein-induced enterocolitis syndrome with abdominal gas signs.

BACKGROUND: The initial clinical manifestations and abdominal imaging findings of neonates with necrotising enterocolitis (NEC) and food protein-induced enterocolitis syndrome (FPIES) are sometimes similar; however, their prognosis and therapies are different. We aimed to evaluate the utility of interleukin (IL)-27 as a differentiation marker between NEC and highly suspected early onset (HSEO)-FPIES. METHODS: All samples used in this study were obtained from the neonatal diagnosis centre of Children's Hospital of Chongqing Medical University. In the case-control study, neonates with NEC (n = 13), HSEO-FPIES (n = 9), and jaundice (control, n = 8) were enroled to determine the serum IL-27 levels using commercial enzyme-linked immunosorbent assay (ELISA) kits. In the validation cohort study, the NEC (n = 87), HSEO-FPIES (n = 62), and jaundice (control, n = 54) groups were included to analyse the diagnostic efficiency of IL-27 for discriminating between NEC and HSEO-FPIES using a receiver operating characteristic (ROC) curve. FINDINGS: In the case-control study, IL-27 levels were higher in the NEC group than in the HSEO-FPIES group (p = 0·005). In the cohort study, the area under the ROC curve (AUC) of IL-27 for differentiating NEC from HSEO-FPIES was 0·878, which was higher than the AUCs of IL-6 (0·761), C-reactive protein (0·800), white blood cell count (0·637), neutrophils (0·765), lymphocytes (0·782), neutrophil to lymphocyte ratio (0·781), and platelet count (0·729). INTERPRETATION: Serum IL-27 is a novel biomarker that may potentially discriminate NEC from HSEO-FPIES in neonates. FUNDING: None.

The Antifouling and Drag-Reduction Performance of Alumina Reinforced Polydimethylsiloxane Coatings Containing Phenylmethylsilicone Oil.

Fouling-release coatings reinforced with micro-alumina and nano-alumina were prepared based on polydimethylsiloxane (PDMS) containing phenylmethylsilicone oil. The surface properties, mechanical properties, leaching behavior of silicone oil, anti-fouling and drag-reduction performance of the coating were studied. The results show that the addition of alumina can significantly improve the tensile strength, elastic modulus and Shore's hardness of the coating. The adhesion experiments of marine bacteria and Navicula Tenera show that the addition of alumina can reduce the antifouling performance of the coating, which is related to the stripping mode of fouling organisms. The fouling organisms leave the coating surface by shearing, and the energy required for shearing is proportional to the elastic modulus of the coating. At 800-1400 rpm, the addition of alumina will reduce the drag reduction performance of the coating, which is related to the drag reduction mechanism of PDMS. PDMS counteracts part of the resistance by surface deformation. The larger the elastic modulus is, the more difficult the surface deformation is. The experiment of silicone oil leaching shows that the increase of alumina addition amount and the decrease of particle size will inhibit the leaching of silicone oil.

Ligustilide Prevents Radiation Enteritis by Targeting Gch1/BH4/eNOS to Improve Intestinal Ischemia.

There is a high incidence of radiation enteritis (RE) after abdominal radiotherapy. The occurrence of RE seriously affects the treatment and quality of life of patients; however, its pathogenesis is complex and there are no effective drugs for its prevention or treatment. Intestinal ischemia plays an important role in the occurrence of enteritis. Previous studies have shown that targeting GTP-cyclohydrolase 1 (Gch1) to improve intestinal ischemia could be a new strategy to prevent and treat RE. A high content of the naturally occurring phthalide derivative ligustilide (LIG) has been found in the plant drug Rhizoma Ligustici Chuanxiong for the treatment of cardiovascular diseases. The purpose of this study was to evaluate the protective effects of LIG on RE. Ionizing radiation (IR) rat and endothelial cell models were used to observe and record rat body weights and stool morphologies, measure intestinal blood perfusion by laser Doppler blood flow imaging, determine the diastolic functions of mesenteric arteries, detect the levels of Gch1/BH4/eNOS pathway-related proteins and regulatory molecules in the mesenteric arteries and endothelial cells, and predict affinity by molecular docking technology. The results showed that LIG significantly improved the body weights, loose stools, intestinal villi lengths, intestinal perfusion and vasodilatory functions of IR rats. LIG also significantly improved Gch1 protein and BH4 levels in the mesenteric arteries and endothelial cells after IR, increased the NO content, reduced superoxide accumulation, and improved p-eNOS (Ser1177) levels in endothelial cells. LIG has good affinity for Gch1, which significantly improves its activity. These results indicate that LIG is the preferred compound for the prevention and treatment of RE by improving intestinal ischemia through the Gch1/BH4/eNOS pathway. This study provides a theoretical basis and new research ideas for the development of new drugs for RE.

Microstructure and Properties of Poly(ethylene glycol)-Segmented Polyurethane Antifouling Coatings after Immersion in Seawater.

Polyurethane has a microphase separation structure, while polyethylene glycol (PEG) can form a hydrated layer to resist protein adsorption. In this paper, PEG was introduced to polyurethane to improve the antifouling properties of the polyurethane, providing a new method and idea for the preparation of new antifouling polyurethane materials. The mechanical properties, hydrophilicity, swelling degree, microphase separation and antifouling performance of the coatings were evaluated. The response characteristics of the polyurethane coatings in a seawater environment were studied, and the performance changes of coatings in seawater were tested. The results showed that the crystallized PEG soft segments increased, promoting microphase separation. The stress at 100% and the elasticity modulus of the polyurethane material also markedly increased, in addition to increases in the swelling degree in seawater, the water contact angle decreased. A total of 25% of PEG incorporated into a soft segment can markedly improve the antibacterial properties of the coatings, but adding more PEG has little significant effect. After immersion in seawater, the coatings became softer and more elastic. This is because water molecules formed hydrogen bonding with the amino NH, which resulted in a weakening effect being exerted on the carbonyl C=O hydrogen bonding and ether oxygen group crystallization.

DLG1-AS1 is activated by MYC and drives the proliferation and migration of hepatocellular carcinoma cells through miR-497-5p/SSRP1 axis.

BACKGROUND: Long non-coding RNAs (lncRNAs) have been reported to be biological regulators in hepatocellular carcinoma (HCC). DLG1 antisense RNA 1 (DLG1-AS1) has been found to be up-regulated in cervical cancer. However, its function and underlying mechanism in HCC remains unknown. METHODS: DLG1-AS1 expression was assessed in HCC cells and normal cell by RT-qPCR. Luciferase reporter assay, RNA pull down assay and RIP assay were used to demonstrate the interaction between DLG1-AS1 and miR-497-5p. RESULTS: DLG1-AS1 was highly expressed in HCC cells. Silencing of DLG1-AS1 led to the inhibition of HCC cell growth and migration. Besides, MYC induced the transcriptional activation of DLG1-AS1. MYC could facilitate HCC cellular processes by up-regulating DLG1-AS1. MiR-497-5p could interact with DLG1-AS1 in HCC cells. Down-regulation of miR-497-5p could reverse the impacts of DLG1-AS1 silencing on HCC cells. SSRP1 expression could be positively regulated by DLG1-AS1 but was negatively regulated by miR-497-5p. Knockdown of DLG1-AS1 suppressed tumor growth in nude mice. CONCLUSIONS: DLG1-AS1 is activated by MYC and functions as an oncogene in HCC via miR-497-5p/SSRP1 axis.

Polysaccharides extracted from Rheum tanguticum ameliorate radiation-induced enteritis via activation of Nrf2/HO-1.

Radiation-induced enteritis is a major side effect in cancer patients undergoing abdominopelvic radiotherapy. The Nrf2/HO-1 pathway is a critical endogenous antioxidant stress pathway, but its precise role in radiation-induced enteritis remains to be clarified. Polysaccharides extracted from Rheum tanguticum (RTP) can protect the intestinal cells from radiation-induced damage, but the underlying mechanism is unknown. SD rats and IEC-6 cells were exposed to 12 or 10 Gy X-ray radiation. Rat survival, and histopathological and immunohistochemical profiles were analyzed at different time points. Indicators of oxidative stress and inflammatory response were also assessed. Cell viability, apoptosis and Nrf2/HO-1 expression were evaluated at multiple time points. Significant changes were observed in the physiological and biochemical indexes of rats after radiation, accompanied by significant oxidative stress response. The mRNA and protein expression of Nrf2 peaked at 12 h after irradiation, and HO-1 expression peaked at 48 h after irradiation. RTP administration reduced radiation-induced intestinal damage, upregulated Nrf2/HO-1, improved physiological indexes, significantly decreased apoptosis and inflammatory factors, and upregulated HO-1, particularly at 48 h after irradiation. In conclusion, Nrf2 is activated in the early stage of radiation-induced intestinal injury and plays a protective role. RTP significantly ameliorates radiation-induced intestinal injury via the regulation of Nrf2 and its downstream protein HO-1.

Comparison of the Oncological Efficacy Between Intraoperative Radiotherapy With Whole-Breast Irradiation for Early Breast Cancer: A Meta-Analysis.

BACKGROUND: Intraoperative radiotherapy (IORT) and whole-breast irradiation (WBI) are both effective radiotherapeutic interventions for early breast cancer patients undergoing breast-conserving surgery; however, an issue on whether which one can entail the better prognosis is still controversial. Our study aimed to investigate the 5-year oncological efficacy of the IORT cohort and the WBI cohort, respectively, and compare the oncological efficacy between the cohorts. MATERIALS AND METHODS: We conducted a computerized retrieval to identify English published articles between 2000 and 2021 in the PubMed, the Web of Science, the Cochrane Library, and APA PsycInfo databases. Screening, data extraction, and quality assessment were performed in duplicate. RESULTS: A total of 38 studies were eligible, with 30,225 analyzed participants. A non-comparative binary meta-analysis was performed to calculate the weighted average 5-year local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and overall survival (OS) in the two cohorts, respectively. The LRFS, DMFS, and OS (without restriction on the 5-year outcomes) between the two cohorts were further investigated by a comparative binary meta-analysis. The weighted average 5-year LRFS, DMFS, and OS in the IORT cohort were 96.3, 96.6, and 94.1%, respectively, and in the WBI cohort were 98.0, 94.9, and 94.9%, respectively. Our pooled results indicated that the LRFS in the IORT cohort was significantly lower than that in the WBI cohort (pooled odds ratio [OR] = 2.36; 95% confidential interval [CI], 1.66-3.36). Nevertheless, the comparisons of DMFS (pooled OR = 1.00; 95% CI, 0.76-1.31), and OS (pooled OR = 0.95; 95% CI, 0.79-1.14) between the IORT cohort with the WBI cohort were both not statistically significant. CONCLUSIONS: Despite the drastically high 5-year oncological efficacy in both cohorts, the LRFS in the IORT cohort is significantly poorer than that in the WBI cohort, and DMFS and OS do not differ between cohorts.

Ionizing radiation induces BH4 deficiency by downregulating GTP-cyclohydrolase 1, a novel target for preventing and treating radiation enteritis.

Radiation enteritis (RE) is a common side effect after radiotherapy for abdominal cancer. RE pathogenesis is complicated, with no drugs available for prevention or treatments. Intestinal ischemia is a key factor in the occurrence and development of enteritis. The effect of ionizing radiation (IR) on intestinal ischemia is unknown. Deficiency of tetrahydrobiopterin (BH4) produced by GTP-cyclohydrolase 1 (Gch1) is important in ischemic diseases. This study focused on the relationship of Gch1/BH4 between intestinal ischemia in radiation enteritis. BH4 levels were analyzed by high-performance liquid chromatography in humans and rats after radiotherapy. Intestinal blood perfusion was measured by laser doppler flow imaging. Vascular ring tests determined the diastolic functions of rat mesenteric arteries. Gene, protein, and immunohistochemical staining experiments and inhibitor interventions were used to investigate Gch1 and endothelial NOS (eNOS) in rat mesenteric arteries and endothelial cells. The results showed that IR decreased BH4 levels in patients and rats after radiotherapy and decreased intestinal blood perfusion in rats. The degree of change in intestinal ischemia was consistent with intestinal villus injury. Gch1 mRNA and protein levels and nitric oxide (NO) production significantly decreased, while eNOS uncoupling in arterial and vascular endothelial cells strongly increased. BH4 supplementation improved eNOS uncoupling and NO levels in vascular endothelia after IR. The results of this study showed that downregulation of Gch1 in intestinal blood vessels after IR is an important target in RE. BH4 supplementation may prevent intestinal ischemia and improve vascular endothelial function after IR. These findings have clinical significance for the prevention and treatment of RE.

Streptococcus pneumoniae aminopeptidase N contributes to bacterial virulence and elicits a strong innate immune response through MAPK and PI3K/AKT signaling.

Streptococcus pneumoniae is a Gram-positive pathogen with high morbidity and mortality globally but some of its pathogenesis remains unknown. Previous research has provided evidence that aminopeptidase N (PepN) is most likely a virulence factor of S. pneumoniae. However, its role in S. pneumoniae virulence and its interaction with the host remains to be confirmed. We generated a pepN gene deficient mutant strain and found that its virulence for mice was significantly attenuated as were in vitro adhesion and invasion of host cells. The PepN protein could induce a strong innate immune response in vivo and in vitro and induced secretion of IL-6 and TNF-α by primary peritoneal macrophages via the rapid phosphorylation of MAPK and PI3K/AKT signaling pathways and this was confirmed using specific pathway inhibitors. In conclusion, PepN is a novel virulence factor that is essential for the virulence of S. pneumoniae and induces host innate immunity via MAPK and PI3K/AKT signaling.

Evolution of the RNA N 6-Methyladenosine Methylome Mediated by Genomic Duplication.

RNA N 6-methyladenosine (m6A) modification is the most abundant form of RNA epigenetic modification in eukaryotes. Given that m6A evolution is associated with the selective constraints of nucleotide sequences in mammalian genomes, we hypothesize that m6A evolution can be linked, at least in part, to genomic duplication events in complex polyploid plant genomes. To test this hypothesis, we presented the maize (Zea mays) m6A modification landscape in a transcriptome-wide manner and identified 11,968 m6A peaks carried by 5,893 and 3,811 genes from two subgenomes (maize1 and maize2, respectively). Each of these subgenomes covered over 2,200 duplicate genes. Within these duplicate genes, those carrying m6A peaks exhibited significant differences in retention rate. This biased subgenome fractionation of m6A-methylated genes is associated with multiple sequence features and is influenced by asymmetric evolutionary rates. We also characterized the coevolutionary patterns of m6A-methylated genes and transposable elements, which can be mediated by whole genome duplication and tandem duplication. We revealed the evolutionary conservation and divergence of duplicated m6A functional factors and the potential role of m6A modification in maize responses to drought stress. This study highlights complex interplays between m6A modification and gene duplication, providing a reference for understanding the mechanisms underlying m6A evolution mediated by genome duplication events.

MicroRNA-152 inhibits tumor cell growth by directly targeting RTKN in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common form of adult liver cancer and accounts for approximately 90% of all cases of primary liver cancer annually. Rhotekin (RTKN), which functions as a cancer promoter, can be frequently detected in many human cancers, including gastric cancer, colorectal carcinoma and bladder carcinoma. The aim of this study was to investigate the role of RTKN in HCC. Using HCC cells and tissues from patients with liver cancer, we demonstrated that RTKN was significantly increased in HCC. To examine the effect of RTKN on HCC, RTKN overexpressed or silenced HepG2 and Hep3B cells were constructed. Cell proliferation and apoptosis were measured by RT-PCR and flow cytometry. The results showed that RTKN can function as an oncogene and promote the proliferation, while inhibiting apoptosis, of HepG2 and Hep3B cells. Furthermore, we identified that RTKN is a direct gene target of miR-152. miR-152 can reverse the growth promoting effect of RTKN on HCC cells through G2/M phase arrest and nuclear factor-κB (NF-κB) signal inhibition. In conclusion, our research identified that miRNA-152 can inhibit tumor cell growth by targeting RTKN in HCC.

MicroRNA-381 increases radiosensitivity in esophageal squamous cell carcinoma.

BACKGROUND: Radiation resistance poses a major clinical challenge in treatment of esophageal squamous cell carcinoma (ESCC). However, the mechanisms of radioresistance has not been fully elucidated. Since accumulating evidence demonstrates that aberrant expression of microRNAs (miRNAs) contributes to cancer sensitivity to radiation, we aimed to identify miRNAs associated with radioresistance of ESCC. METHODS: In this study, we used GeneChip miRNA Array to perform an comparison of miRNAs expression in tissues from primary ESCC and recurrent ESCC in situ after radiotherapy. Differential expressions of miRNAs were comfirmed by quantitative Real-Time PCR in tissues and six ESCC cell lines. Cell radiosensitivity were determined by colony formation assay. Functional analyses of miRNA-381 in ESCC cells growth and metastasis were performed by MTT and Transwell Assays. In vivo assays of the functions of miRNA-381 were performed in tumor xenografts. RESULTS: One miRNA candidate, miRNA-381, was found to be downregulated in radiation resistance tissues and cells. Enforced expression of miRNA-381 increased radiosensitivity of ESCC cells and promoted nonaggressive phenotype including decreased cellular proliferation and migration. In contrast, inhibition of miRNA-381 in ESCC cells promoted radiation resistance and development of an aggressive phenotype. In vivo assays extended the significance of these results, showing that miRNA-381 overexpression decreased the tumor growth and the resistance to radiation treatment in tumor xenografts. CONCLUSIONS: Together, our work reveals miRNA-381 expression as a critical determinant of radiosensitivity in esophageal cancer cells.

Meta-analysis of MTHFR C677T and A1298C gene polymorphisms: association with the risk of hepatocellular carcinoma.

OBJECTIVE: Several studies have indicated an association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and the risk of hepatocellular carcinoma (HCC). However, the conclusions are inconsistent. Therefore, a meta-analysis was performed. METHODS: Databases like Pubmed, EMBASE, and EBSCO (up to September 2012) were searched to retrieve case-control trials about MTHFR (C677T or A1298C) polymorphisms and HCC. Literatures were independently screened by two researchers according to the inclusion and exclusion criteria. Data were extracted and analyzed by software STATA 11.0. RESULTS: Nine studies were included with 10 datasets and 5132 cases. C677T polymorphism was associated with HCC risk in a heterozygous model (TT vs. CT: OR=1.20, 95% CI: 1.02-1.40). For the A1298C polymorphism, a significantly decreased HCC risk was found in the dominant, heterozygous and homozygous models (CC vs. AA+AC: OR=0.52, 95% CI: 0.33-0.80; CC vs. AC: OR=0.50, 95% CI: 0.32-0.79; CC vs. AA: OR=0.52, 95% CI: 0.33-0.81). Subgroup analysis stratified by ethnicity and type of control further indicated decreased HCC risks in Asians (CC vs. AA+AC: OR=0.47, 95% CI: 0.26-0.84; CC vs. AC: OR=0.41, 95% CI: 0.24-0.71; CC vs. AA: OR=0.46, 95% CI: 0.27-0.78), studies with controls of healthy people (CC vs. AA: OR=0.54, 95% CI: 0.31-0.93; CC vs. AC: OR=0.54, 95% CI: 0.31-0.94; CC vs. AA+AC: OR=0.55, 95% CI: 0.32-0.94), and controls of non-HCC patients (CC vs. AC: OR=0.43, 95% CI: 0.19-0.96). CONCLUSIONS: Homozygous carriers of MTHFR C677T mutation are more susceptible to HCC, but homozygous mutations of MTHFR A1298C may play a protective role for developing HCC.