RNA helicase DHX15 decreases cell apoptosis by NF-κB signaling pathway in Burkitt lymphoma.

BACKGROUND: DHX15 is one of the RNA helicase family members involving in several biological processes. Studies have reported that overexpression of DHX15 is related to cancer progression. However, the role of DHX15 in Burkitt lymphoma (BL) and latent Epstein-Barr virus (EBV) infection remains to be elucidated. METHODS: Expression of DHX15 was measured in BL patient by immunohistochemical staining. In vitro study, a CCK-8 assay was used to analyze cell proliferation and flow cytometry was performed to assess cell cycle, apoptosis and mitochondria membrane potential. Members of NF-κB signaling pathway and apoptotic-related proteins expression were measured by western-blot. EBV latent infection products and RNA polymerase III transcripts expression were determined by quantitative real-time PCR and western-blot. In vivo study, HE, IHC, TUNEL and ISH assays were used to analyze the effect of DHX15 on subcutaneous tumor nodes formation. RESULTS: DHX15 was overexpressed in Burkitt lymphoma patients and tends to be associated with poor progression-free survival and poor overall survival. Knockdown of DHX15 significantly inhibited BL tumor growth, reduced cell proliferation, induced cell cycle arrest and increased cell apoptosis. Further analysis showed that canonical NF-κB signaling and its downstream targets, mitochondria and Caspase were involved in the increased cell apoptosis after DHX15 gene knockdown. Furthermore, knockdown of DHX15 reduced EBV latent infection products expression and inhibited RNA polymerase III activity. CONCLUSION: DHX15 may be an oncogene in the development of BL and a potential therapeutic target for the treatment of BL and latent EBV infection.

Dhx15 regulates zebrafish definitive hematopoiesis through the unfolded protein response pathway.

Gene alterations are recognized as important events in acute myeloid leukemia (AML) progression. Studies on hematopoiesis of altered genes contribute to a better understanding on their roles in AML progression. Our previous work reported a DEAH box helicase 15 (DHX15) R222G mutation in AML patients, and we showed DHX15 overexpression is associated with poor prognosis in AML patients. In this work, we further study the role of dhx15 in zebrafish developmental hematopoiesis by generating dhx15-/- zebrafish using transcription activator-like effector nuclease technology. Whole-mount in situ hybridization (WISH) analysis showed hematopoietic stem/progenitor cells were dramatically perturbed when dhx15 was deleted. Immunofluorescence staining indicated inhibited hematopoietic stem/progenitor cell (HSPC) proliferation instead of accelerated apoptosis were detected in dhx15-/- zebrafish. Furthermore, our data showed that HSPC defect is mediated through the unfolded protein response (UPR) pathway. DHX15 R222G mutation, a recurrent mutation identified in AML patients, displayed a compromised function in restoring HSPC failure in dhx15-/- ; Tg (hsp: DHX15 R222G) zebrafish. Collectively, this work revealed a vital role of dhx15 in the maintenance of definitive hematopoiesis in zebrafish through the unfolded protein respone pathway. The study of DHX15 and DHX15 R222G mutation could hold clinical significance for evaluating prognosis of AML patients with aberrant DHX15 expression.

PPM1H is an independent prognostic biomarker of non-small cell lung cancer.

Protein phosphatase 1H (PPM1H) is the metal-dependent protein phosphatase, however, its role in tumorigenesis and tumor progression remains controversial. Non-small-cell lung cancer (NSCLC) is the most common histological type of lung cancer but the expression and clinical significance of PPM1H in NSCLC is unknown. In our study, we detected the mRNA of PPM1H in 25 pairs of NSCLC tissues and their corresponding adjacent tissues with qRT-PCR. Moreover, we investigated PPM1H expression in 474 NSCLC tissues and divided them into subgroups with low and high PPM1H. We further evaluated its correlation with the clinicopathological factors. The correlation between PPM1H and other biomarkers involved in tumor progression including chromosome segregation 1-like protein (CSE1L), p53, and Ki67 was also estimated. In addition, the prognostic significance of PPM1H was investigated by univariate and multivariate analyses. The mRNA levels of PPM1H in NSCLCs were significantly higher than those in tumor-adjacent tissues. Patients with low and high PPM1H expression accounted for 54.64% (259/474) and 45.36% (215/474) respectively in all the NSCLCs. PPM1H expression (p=0.012), patients' sex (p=0.009), tumor size (p<0.001), histological grade (p=0.026), T stage (p=0.002), N stage (p<0.001), M stage (p=0.011), and TNM stage (p<0.001) were all associated with the poor prognosis. With multivariate analysis, PPM1H was determined as an independent prognostic factor of NSCLC (HR=1.42, 95% CI=1.14-1.75, p=0.001). Moreover, high PPM1H was significantly with high Ki67 (p=0.022), indicating the oncogenic role of PPM1H. PPM1H is an independent prognostic factor indicating an unfavorable prognosis of NSCLC. Our results indicated that PPM1H was an important supplement of NSCLC molecular profile and detecting PPM1H may help recognize the high-risk patients for further treatment.

ETS1 and SP1 drive DHX15 expression in acute lymphoblastic leukaemia.

DHX15 plays a role in leukaemogenesis and leukaemia relapse. However, the mechanism underlying the transcriptional regulation of DHX15 in ALL has not been elucidated. Our present study aimed to explore the functional promoter region of DHX15 and to investigate the transcription factors controlling the transcription of this gene. A luciferase assay performed with several truncated constructs identified a 501-bp region as the core promoter region of DHX15. Site-directed mutagenesis, electrophoretic mobility shift and chromatin immunoprecipitation assays showed that ETS1 and SP1 occupied the DHX15 promoter. Furthermore, knockdown of ETS1 and SP1 resulted in suppression of DHX15, whereas the overexpression of these genes led to up-regulation of DHX15. Interestingly, in samples obtained from patients with ALL at diagnosis, both ETS1 and SP1 correlated positively with DHX15 expression. Additionally, differences in methylation of the DHX15 core promoter region were not observed between the patients and controls. In conclusion, we identified the core promoter region of DHX15 and demonstrated that ETS1 and SP1 regulated DHX15 expression in ALL.

[Genetic Analysis of a Chinese Pedigree with Hereditary Spherocytosis Caused by Copy Number Variation Deletion of SPTB Gene].

OBJECTIVE: To investigate the molecular mechanism of the disease based on the clinical characterization and genetic mutation analysis in a family with hereditary spherocytosis. METHODS: The proband with jaundice and anemia was referred to Yidu Central Hospital of Weifang in May 2021. Peripheral blood samples were collected from six members of the family. Second-generation sequencing was used to screen the pathological mutations, and the clinically significant variant sites were selected. Then the relevant databases were used to analyze the variant sites, and RT-qPCR was used to detect the relative mRNA levels of candidate gene. The structure and function of SPTB protein were analyzed by UniProt and SMART databases. RESULTS: We infer that the SPTB gene copy number variation (CNV) deletion was co-segregated with the phenotype of the patients in this family based on the results of second-generation sequencing (about 700 target genes). The UCSC Genome Browser demonstrated that the deleted region was mainly located in exon2-3 of SPTB gene. The results of RT-qPCR showed that the relative SPTB mRNA levels of all patients were lower than the healthy control. UniProt and SMART databases analysis showed that SPTB protein without CH1 and CH2 domains could not bind to erythrocyte membrane actin. CONCLUSION: The CNV deletion of SPTB gene may be the reason for the hereditary spherocytosis in this family.

Primary B-cell non-Hodgkin lymphoma of the parotid gland: An analysis based on the SEER database.

Primary malignant lymphoma of the parotid gland is a rare entity. The disease is often misdiagnosed, and its survival factors remain unclear. This study included patients diagnosed with primary B-cell non-Hodgkin lymphoma of the parotid gland from 1987 to 2016 in the surveillance, epidemiology, and end results program. Univariate survival analysis was conducted using the Kaplan-Meier method, and multivariate analysis was performed using the Cox proportional hazards regression model. A competing risks regression model was applied to estimate the specific risks associated with parotid lymphoma mortality. A total of 1443 patients were identified. The overall survival of indolent primary B-cell lymphoma of the parotid gland was higher than that of aggressive lymphoma (hazard ratio 0.53, 95% confidence interval 0.44-0.64, P < .001), and older patients (≥70 years) exhibited inferior overall survival. Histological subtype and age are important prognostic factors in patients with primary B-cell non-Hodgkin lymphoma of the parotid gland.

Hand Exoskeleton Design and Human-Machine Interaction Strategies for Rehabilitation.

Stroke and related complications such as hemiplegia and disability create huge burdens for human society in the 21st century, which leads to a great need for rehabilitation and daily life assistance. To address this issue, continuous efforts are devoted in human-machine interaction (HMI) technology, which aims to capture and recognize users' intentions and fulfil their needs via physical response. Based on the physiological structure of the human hand, a dimension-adjustable linkage-driven hand exoskeleton with 10 active degrees of freedom (DoFs) and 3 passive DoFs is proposed in this study, which grants high-level synergy with the human hand. Considering the weight of the adopted linkage design, the hand exoskeleton can be mounted on the existing up-limb exoskeleton system, which greatly diminishes the burden for users. Three rehabilitation/daily life assistance modes are developed (namely, robot-in-charge, therapist-in-charge, and patient-in-charge modes) to meet specific personal needs. To realize HMI, a thin-film force sensor matrix and Inertial Measurement Units (IMUs) are installed in both the hand exoskeleton and the corresponding controller. Outstanding sensor-machine synergy is confirmed by trigger rate evaluation, Kernel Density Estimation (KDE), and a confusion matrix. To recognize user intention, a genetic algorithm (GA) is applied to search for the optimal hyperparameters of a 1D Convolutional Neural Network (CNN), and the average intention-recognition accuracy for the eight actions/gestures examined reaches 97.1% (based on K-fold cross-validation). The hand exoskeleton system provides the possibility for people with limited exercise ability to conduct self-rehabilitation and complex daily activities.

Neutron spectrum unfolding based on generalized regression neural networks for neutron fluence and neutron ambient dose equivalent estimations.

Neutron fluence and neutron ambient dose equivalent, H*(10), are important physical quantities for neutron radiation protection and monitoring. They can be deduced from neutron spectrum, which is usually measured by multisphere system with proper unfolding methods. Novel unfolding methods on the basis of artificial intelligence, mainly artificial neural networks (ANNs), have been researched and developed. However, without normalization on network inputs, ANNs can not be applied to accommodate demands of various neutron field measurements for neutron spectrum unfolding in practice, because the neutron spectra for training the ANNs are mostly extracted from IAEA (2001), the integrals of which over neutron energy are unit fluences. Moreover, derived from an unfolded normalized spectrum, the true values of neutron fluence and H*(10) are never to know. In this work, three normalization methods-zero-mean normalization method, min-max normalization method, and maximum-divided normalization method were used to process with the inputs of generalized regression neural networks (GRNNs), and a new method was proposed for neutron fluence and H*(10) estimations derived from unfolded neutron spectrum based on GRNNs for the first time. Sixty-three neutron spectra were unfolded based on GRNNs with use of three normalization methods, and the corresponding neutron fluences and H*(10) were obtained and compared. From the testing results, the GRNNs with the maximum-divided method is most effective to unfold neutron spectrum and to evaluate neutron fluence and H*(10). The feasibility of the method was further studied through experiments by using Bonner sphere spectrometer in well characterized 241Am-Be neutron field.

Prognostic value and susceptibility of BAX rs4645878 polymorphism in cancer: A systematic review and meta-analysis.

BACKGROUND: BCL-2 Associated X (BAX) is an important modulator of apoptosis. The associations between BAX gene polymorphism and cancer susceptibility and prognosis in different ethnic groups and types of cancer have yielded controversial results. To reconcile the results, a systematic review followed by meta-analysis was performed to assess the associations. METHODS: A systematic search of Medline database (PubMed), EMBASE, China Biology Medicine disc, China National Knowledge Infrastructure, Wanfang databases for publications on BAX polymorphisms, and susceptibility and prognosis was carried out until July 2017. Retrieved 14 articles met the inclusions. Summary odds ratios (ORs) and hazard ratios (HRs) with their 95% confidence intervals (CIs) were harnessed to determine the strength of correlation between BAX polymorphisms and cancer susceptibility and prognosis, which were combined using fixed- or random-effects models as appropriate. RESULTS: A total of 12 trials involving 3321 cases and 3209 controls were included in our pooled analysis regarding the polymorphisms and the susceptibility of cancers. Overall, results of the present meta-analysis demonstrated that there was no significant association between BAX polymorphisms and susceptibility of cancers (OR = 1.052, 95% CI: 0.827-1.339, P = .679, A vs G). Even in a stratified analysis by ethnicity and the sources of control groups, the results were consistent. Four retrospective studies of 549 cases qualified for meta-analysis were identified to set forth the associations of the polymorphisms with cancer prognosis. Our results suggested that BAX gene polymorphisms were significantly associated with unfavorable prognosis (HR = 1.735, 95% CI: 1.368-2.202, P = .000, GG vs GA/AA). CONCLUSION: There is no significant association between BAX gene polymorphism and cancer susceptibility, but it probably contributes to increased adverse prognosis to cancer.

[Effect of B Cell Differentiation Markers on the Prognosis of Primary Central Nervous System Lymphoma].

OBJECTIVE: To investigate the value of B-cell differentiation markers in prognosis evaluation of 119 patients with primary CNS lymphoma(PCNSL). METHODS: The expressions of BCL-2, BCL-6, CD10 and MUM1/IRF4 protein were determined by immunohistochemistry, and their relationship with the prognosis of primary central nervous system lymphoma was analyzed. RESULTS: Univariate analysis showed that BCL-6 positive means shorter PFS (P=0.047) and OS (P=0.035). Multivariate analysis showed that BCL-6 positive expression was related with shorter PFS (hazard ratio:1.95, 95% CI: 1.22- 3.12, P=0.005), but did not relate with OS (hazard ratio: 1.85, 95% CI: 0.71- 4.80, P=0.21). Classification based on Hans algorithm and expression status of the single B-cell markers BCL-2, CD10 and MUM1/IRF4 did not correlate with prognosis. CONCLUSION: BCL-6 may be an unfavorable prognostic biomarker for PCNSL.

Focal choroidal excavation and a traumatic macular hole secondary to accidental Q-switched Nd:YAG laser.

Today, the widespread use of laser instruments in various fields has resulted in many accidental retinal injuries. Here we describe a rare clinical case of full-thickness macular hole (MH) and focal choroidal excavation (FCE) caused by a 1064-nm Q-switched Nd:YAG laser. After pars plana vitrectomy and the following 14 months, consecutive optical coherence tomography imagings showed closure of the MH. Visual acuity improved even in the absence of the outer retina and in the presence of FCE. We speculate that different focusing effects of the unexpected Nd:YAG lasers which target different levels of retinal tissue generate diverse prognosis.