Abstract This meta-analysis aimed to assess the prophylactic effects of honey use on the management of radio/chemotherapy-induced mucositis. PubMed, Cochrane Library, Science Direct, China National ...Knowledge Infrastructure (CNKI), VIP (Chinese scientific journal database), and China Biology Medicine (CBM) were searched for relevant articles without language restriction. Two reviewers searched and evaluated the related studies independently. Statistical analyses were performed using Stata 11.0, calculating the pooled risk ratio (RR) with the corresponding 95% confidence interval (CI). Begg's funnel plot was used together with Egger's test to detect publication bias. A total of seven randomized controlled trials were finally included. Quality assessment showed one article to have a low risk of bias, two to have a moderate risk, and four to have a high risk. Meta-analysis showed that, compared with blank control, honey treatment could reduce the incidence of oral mucositis after radio/chemotherapy (RR 0.35, 95% CI 0.18–0.70, P = 0.003). No meta-analysis was applied for honey vs. lidocaine or honey vs. golden syrup. The sensitivity analysis showed no significant change when any one study was excluded. No obvious publication bias (honey vs. blank control) was detected. In conclusion, honey can effectively reduce the incidence of radio/chemotherapy-induced oral mucositis; however, further multi-centre randomized controlled trials are needed to support the current evidence.
Inner-ear hair cell differentiation requires Atoh1 function, while Eya1, Six1, and Sox2 are coexpressed in sensory progenitors and mutations in these genes cause sensorineural hearing loss. However, ...how these genes are linked functionally and the transcriptional networks controlling hair cell induction remain unclear. Here, we show (1) that Eya1/Six1 are necessary for hair cell development, and their coexpression in mouse cochlear explants is sufficient to induce hair cell fate in the nonsensory epithelium expressing low-level Sox2 by activating not only Atoh1-dependent but also Atoh1-independent pathways and (2) that both pathways induce Pou4f3 to promote hair cell differentiation. Sox2 cooperates with Eya1/Six1 to synergistically activate Atoh1 transcription via direct binding to the conserved Sox- and Six-binding sites in Atoh1 enhancers, and these proteins physically interact. Our findings demonstrate that direct and cooperative interactions between the Sox2, Six1, and Eya1 proteins coordinate Atoh1 expression to specify hair cell fate.
► Direct and cooperative interactions of Sox2/Six1/Eya1 coordinate Atoh1 activation ► Sox2 and Six1 directly bind to Atoh1 enhancers ► Sox2 antagonizes factors downstream of Atoh1 to inhibit hair cell differentiation ► Eya1/Six1 are necessary for Atoh1 expression and hair cell development in vivo
Atoh1 initiates induction of auditory hair cells in the developing inner ear. Ahmed et al. define transcriptional complexes containing Eya1/Six1 and Sox2 transcription factors as crucial regulators of Atoh1 and Atoh1-independent hair cell formation. Misexpression of these transcription factors induces hair cells de novo.
Noninvasive prenatal testing using fetal DNA in maternal plasma is an actively researched area. The current generation of tests using massively parallel sequencing is based on counting plasma DNA ...sequences originating from different genomic regions. In this study, we explored a different approach that is based on the use of DNA fragment size as a diagnostic parameter. This approach is dependent on the fact that circulating fetal DNA molecules are generally shorter than the corresponding maternal DNA molecules. First, we performed plasma DNA size analysis using pairedend massively parallel sequencing and microchip-based capillary electrophoresis. We demonstrated that the fetal DNA fraction in maternal plasma could be deduced from the overall size distribution of maternal plasma DNA. The fetal DNA fraction is a critical parameter affecting the accuracy of noninvasive prenatal testing using maternal plasma DNA. Second, we showed that fetal chromosomal aneuploidy could be detected by observing an aberrant proportion of short fragments from an aneuploid chromosome in the paired-end sequencing data. Using this approach, we detected fetal trisomy 21 and trisomy 18 with 100% sensitivity (T21: 36/36; T18: 27/27) and 100% specificity (non-T21: 88/88; non-T18: 97/97). For trisomy 13, the sensitivity and specificity were 95.2% (20/21) and 99% (102/103), respectively. For monosomy X, the sensitivity and specificity were both 100% (10/10 and 8/8). Thus, this study establishes the principle of size-based molecular diagnostics using plasma DNA. This approach has potential applications beyond noninvasive prenatal testing to areas such as oncology and transplantation monitoring.
Head and neck squamous cell carcinoma is the sixth most common cancer worldwide and has high heterogeneity and unsatisfactory outcomes. To better characterize the tumor progression trajectory, we ...perform single-cell RNA sequencing of normal tissue, precancerous tissue, early-stage, advanced-stage cancer tissue, lymph node, and recurrent tumors tissue samples. We identify the transcriptional development trajectory of malignant epithelial cells and a tumorigenic epithelial subcluster regulated by TFDP1. Furthermore, we find that the infiltration of POSTN
fibroblasts and SPP1
macrophages gradually increases with tumor progression; their interaction or interaction with malignant cells also gradually increase to shape the desmoplastic microenvironment and reprogram malignant cells to promote tumor progression. Additionally, we demonstrate that during lymph node metastasis, exhausted CD8
T cells with high CXCL13 expression strongly interact with tumor cells to acquire more aggressive phenotypes of extranodal expansion. Finally, we delineate the distinct features of malignant epithelial cells in primary and recurrent tumors, providing a theoretical foundation for the precise selection of targeted therapy for tumors at different stages. In summary, the current study offers a comprehensive landscape and deep insight into epithelial and microenvironmental reprogramming throughout initiation, progression, lymph node metastasis and recurrence of head and neck squamous cell carcinoma.
To evaluate the prevalence, awareness, treatment and control of hypertension and its risk factors in Dehui City of Jilin Province in China. The study was performed among 3778 subjects (male=1787) in ...Dehui City, Jilin Province of China. The subjects completed a standard questionnaire, biochemical tests and physical examinations. Logistic regression analyses were used to identify risk factors for hypertension. The prevalence of hypertension was 41.00% in this area. The awareness, treatment and the control of hypertension were 21.82, 15.56 and 1.10%, respectively, with city areas being significantly higher than rural areas. Significant risk factors for hypertension included age, sex, central obesity, alcohol consumption, family history of hypertension, dyslipidemia, education level and type of work. Further analysis showed that diabetes for urban participants and cigarette smoking for rural participants were risk factors but were not statistically significant at the multi-variate level. The prevalence of hypertension in Dehui Ctiy of Jilin Province is higher than in other areas of China. In addition, rates of awareness and treatment of the condition are much lower than in other populations, with the control rate only 1.10%.
The nuclear export receptor, Exportin 1 (XPO1), mediates transport of growth-regulatory proteins, including tumor suppressors, and is overactive in many cancers, including chronic lymphocytic ...leukemia (CLL), acute myeloid leukemia (AML) and aggressive lymphomas. Oral selective inhibitor of nuclear export (SINE) compounds that block XPO1 function were recently identified and hold promise as a new therapeutic paradigm in many neoplasms. One of these compounds, KPT-330 (selinexor), has made progress in Phase I/II clinical trials, but systemic toxicities limit its administration to twice-per-week and requiring supportive care. We designed a new generation SINE compound, KPT-8602, with a similar mechanism of XPO1 inhibition and potency but considerably improved tolerability. Efficacy of KPT-8602 was evaluated in preclinical animal models of hematological malignancies, including CLL and AML. KPT-8602 shows similar in vitro potency compared with KPT-330 but lower central nervous system penetration, which resulted in enhanced tolerability, even when dosed daily, and improved survival in CLL and AML murine models compared with KPT-330. KPT-8602 is a promising compound for further development in hematological malignancies and other cancers in which upregulation of XPO1 is seen. The wider therapeutic window of KPT-8602 may also allow increased on-target efficacy leading to even more efficacious combinations with other targeted anticancer therapies.
A comprehensive microarray analysis of hepatocellular carcinoma (HCC) revealed distinct synexpression patterns during intrahepatic metastasis. Recent evidence has demonstrated that synexpression ...group member genes are likely to be regulated by master control gene(s). Here we investigate the functions and gene regulation of the transcription factor SOX4 in intrahepatic metastatic HCC. SOX4 is important in tumor metastasis as RNAi knockdown reduces tumor cell migration, invasion, in vivo tumorigenesis and metastasis. A multifaceted approach integrating gene profiling, binding site computation and empirical verification by chromatin immunoprecipitation and gene ablation refined the consensus SOX4 binding motif and identified 32 binding loci in 31 genes with high confidence. RNAi knockdown of two SOX4 target genes, neuropilin 1 and semaphorin 3C, drastically reduced cell migration activity in HCC cell lines suggesting that SOX4 exerts some of its action via regulation of these two downstream targets. The discovery of 31 previously unidentified targets expands our knowledge of how SOX4 modulates HCC progression and implies a range of novel SOX4 functions. This integrated approach sets a paradigm whereby a subset of member genes from a synexpression group can be regulated by one master control gene and this is exemplified by SOX4 and advanced HCC.
Sustained, drug-free control of HIV-1 replication is naturally achieved in less than 0.5% of infected individuals (here termed 'elite controllers'), despite the presence of a replication-competent ...viral reservoir
. Inducing such an ability to spontaneously maintain undetectable plasma viraemia is a major objective of HIV-1 cure research, but the characteristics of proviral reservoirs in elite controllers remain to be determined. Here, using next-generation sequencing of near-full-length single HIV-1 genomes and corresponding chromosomal integration sites, we show that the proviral reservoirs of elite controllers frequently consist of oligoclonal to near-monoclonal clusters of intact proviral sequences. In contrast to individuals treated with long-term antiretroviral therapy, intact proviral sequences from elite controllers were integrated at highly distinct sites in the human genome and were preferentially located in centromeric satellite DNA or in Krüppel-associated box domain-containing zinc finger genes on chromosome 19, both of which are associated with heterochromatin features. Moreover, the integration sites of intact proviral sequences from elite controllers showed an increased distance to transcriptional start sites and accessible chromatin of the host genome and were enriched in repressive chromatin marks. These data suggest that a distinct configuration of the proviral reservoir represents a structural correlate of natural viral control, and that the quality, rather than the quantity, of viral reservoirs can be an important distinguishing feature for a functional cure of HIV-1 infection. Moreover, in one elite controller, we were unable to detect intact proviral sequences despite analysing more than 1.5 billion peripheral blood mononuclear cells, which raises the possibility that a sterilizing cure of HIV-1 infection, which has previously been observed only following allogeneic haematopoietic stem cell transplantation
, may be feasible in rare instances.
Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is expressed in the epithelial cells of a wide range of organs/tissues from which most cancers are derived. Although accumulating ...reports have indicated the association of cancer incidence with genetic variations in CFTR gene, the exact role of CFTR in cancer development and the possible underlying mechanism have not been elucidated. Here, we report that CFTR expression is significantly decreased in both prostate cancer cell lines and human prostate cancer tissue samples. Overexpression of CFTR in prostate cancer cell lines suppresses tumor progression (cell growth, adhesion and migration), whereas knockdown of CFTR leads to enhanced malignancies both in vitro and in vivo. In addition, we demonstrate that CFTR knockdown-enhanced cell proliferation, cell invasion and migration are significantly reversed by antibodies against either urokinase plasminogen activator (uPA) or uPA receptor (uPAR), which are known to be involved in various malignant traits of cancer development. More interestingly, overexpression of CFTR suppresses uPA by upregulating the recently described tumor suppressor microRNA-193b (miR-193b), and overexpression of pre-miR-193b significantly reverses CFTR knockdown-enhanced malignant phenotype and abrogates elevated uPA activity in prostate cancer cell line. Finally, we show that CFTR gene transfer results in significant tumor repression in prostate cancer xenografts in vivo. Taken together, the present study has demonstrated a previously undefined tumor-suppressing role of CFTR and its involvement in regulation of miR-193b in prostate cancer development.
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