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The utility of circulating tumor DNA (ctDNA) in classifying the cell origin of diffuse large B-cell lymphoma (DLBCL) has not been explored in the Chinese population. In this study, we aimed to investigate the genetic characteristics of DLBCL based on both tumor and ctDNA sequencing and to assess the predictive value of ctDNA in DLBCL. A targeted sequencing panel of 413 genes was applied to tumor biopsies and paired plasma samples obtained from 30 patients with DLBCL before therapeutic intervention (pretreatment). The concordance between plasma genotyping classification and traditional cell-of-origin classification using tumor tissue was 80.0% (20/25). Patients with higher baseline plasma ctDNA levels had poorer survival compared to those with lower ctDNA levels (2-year progression survival rate: 40.0% vs. 80.0%, p = 0.011; 5-year overall survival rate: 30.5% vs. 70.0%, p = 0.004). Collectively, our results demonstrated that pretreatment ctDNA analysis could assist origin determination and prognosis prediction clinically.

Primordial follicle pool established perinatally is a non-renewable resource which determines the female fecundity in mammals. While the majority of primordial follicles in the primordial follicle pool maintain dormant state, only a few of them are activated into growing follicles in adults in each cycle. Excessive activation of the primordial follicles accelerates follicle pool consumption and leads to premature ovarian failure. Although previous studies including ours have emphasized the importance of keeping the balance between primordial follicle activation and dormancy via molecules within the primordial follicles, such as TGF-β, E-Cadherin, mTOR, and AKT through different mechanisms, the homeostasis regulatory mechanisms of primordial follicle activation remain unclear. Here, we reported that HDAC6 acts as a key negative regulator of mTOR in dormant primordial follicles. In the cytoplasm of both oocytes and granulosa cells of primordial follicles, HDAC6 expressed strong, however in those activated primordial follicles, its expression level is relatively weaker. Inhibition or knockdown of HDAC6 significantly promoted the activation of limited primordial follicles while the size of follicle pool was not affected profoundly in vitro. Importantly, the expression level of mTOR in the follicle and the activity of PI3K in the oocyte of the follicle were simultaneously up-regulated after inhibiting of HDAC6. The up-regulated mTOR leads to not only the growth and differentiation of primordial follicles granulosa cells (pfGCs) into granulosa cells (GCs), but the increased secretion of KITL in these somatic cells. As a result, inhibition of HDAC6 awaked the dormant primordial follicles of mice in vitro. In conclusion, HDAC6 may play an indispensable role in balancing the maintenance and activation of primordial follicles through mTOR signaling in mice. These findings shed new lights on uncovering the epigenetic factors involved physiology of sustaining female reproduction.

Background/aim TP53 mutation is recognized as a negative prognostic factor for patients with diffuse large B-cell lymphoma (DLBCL). Here, we present the characteristics of TP53 mut DLBCL patients following investigation of the effect of a treatment approach on survival of TP53 mut DLBCL patients. Methods A total of 44 DLBCL patients with TP53 mut and treated with an R-CHOP regimen were included for analysis. Patients who failed to achieve a complete response (CR) to initial treatment or relapsed in the first 6 months after initial CR were deemed to have primary refractory disease. Results Among 44 patients harboring TP53 mutations who underwent upfront R-CHOP or R-CHOP-like treatment, 21 (47.7%) had limited-stage and 23 (52.3%) presented advanced-stage disease. Apart from the seven patients receiving upfront surgical resection, 37 had measurable disease under the R-CHOP regimen, with 59.1% (n=26) developing primary refractory disease. Seven limited-stage patients after early complete resection and one with residue resection remained event-free at median follow-up of 37 months. Multivariate analysis revealed that elevated baseline lactate dehydrogenase (LDH), extranodal involvement (two or more), Ann Arbor stage, and locoregional treatment (surgery or radiation therapy) were independent indicators for progression-free survival (PFS). After adjustment for baseline LDH and extranodal involvement, adding locoregional treatment including surgery and radiation to the R-CHOP regimen significantly improved PFS (p=0.008) and overall survival (p=0.017) in limited-stage TP53 mut DLBCL patients compared to R-CHOP-only treatment. Conclusion This study presents the characteristics of TP53-mutated DLBCL and implies a potential benefit of locoregional treatment in limited-stage DLBCL patients with TP53 mutations.

Diffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous malignancy. Following front-line immunochemotherapy, 30–40% of DLBCL patients develop relapsed or refractory (r/r) disease, which can be treated with ibrutinib. It has been previously reported that MYD88MUT affects the response to ibrutinib in patients with r/r DLBCL. Here, we aimed to gather understanding of MYD88MUT in r/r DLBCL patients and to evaluate its influence on response to ibrutinib. In this study, tissue samples from DLBCL patients (n = 212) were retrospectively collected and sequenced by target-capturing panels of either 413 or 112 genes that are frequently mutated in non-Hodgkin’s lymphoma. Sixty patients with MYD88 mutations and available clinical information were included for further analysis. Seven MYD88MUT variants were identified, L265P (65.0%, n = 39), S219C (13.3%, n = 8), S243N (8.3%, n = 5), P258L (6.7%, n = 4), F283V (1.7%, n = 1), P141R (1.7%, n = 1), and V217F (1.7%, n = 1). One patient had MYD88 amplification. In addition, mutations in PIM1 (67%, n = 40), IGH fusion (48%, n = 29), CD79B (43%, n = 26), KMT2D (30%, n = 18), and TP53 (27%, n = 17) were identified. For patients with L265P, IRF4 (p = 0.011) was frequently mutated. Otherwise, TET2 (p = 0.016), NOTCH2 (p = 0.044), MET (p = 0.037), SOCS1 (p = 0.011), TNFRSF14 (p = 0.011), EZH2 (p = 0.037), and BCL6 (p

In female mammals, the majority of primordial follicles (PFs) are physiologically quiescent, and only a few of them are activated and enter the growing follicle pool. Specific molecules, such as ma...

Aiming at the problem of insufficient automatic control of temperature and humidity detection in material storage warehouses, this design proposes a temperature and humidity control system based on ARM11. Using ARM11 controller as the core processor, combined with WiFi wireless communication technology and touch LCD screen. With the help of temperature and humidity sensors, the temperature and humidity of the material storage warehouse are collected, and the PID algorithm is introduced to correct the system circuit. Experiments show that this system design can effectively collect, process and display the temperature and humidity in the farm shed. And can be automated.

Diffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous malignancy. Following front-line immunochemotherapy, 30-40% of DLBCL patients develop relapsed or refractory (r/r) disease, which can be treated with ibrutinib. It has been previously reported that MYD88Here, we aimed to gather understanding of MYD88In this study, tissue samples from DLBCL patients (n = 212) were retrospectively collected and sequenced by target-capturing panels of either 413 or 112 genes that are frequently mutated in non-Hodgkin's lymphoma. Sixty patients with MYD88 mutations and available clinical information were included for further analysis.Seven MYD88This study adds clinical observations with MYD88

Background: Blood-based biomarker such as circulating tumor DNA (ctDNA) has emerged as a promising tool for assessment of response to immunotherapy in solid tumors; But in hematological malignances, evidences are still lacking to support its clinical utility. In current study the feasibility of ctDNA for prediction and monitoring of response to anti-PD-1 therapy in Chinese patients with relapsed or refractory classical Hodgkin lymphoma (r/r cHL) was assessed. Methods: A total of 192 plasma samples from 75 patients with r/r cHL were collected at baseline and upon therapeutic evaluation. ctDNA were sequenced by targeting panels capturing frequently mutated genes in cHL and other hematological malignancies and then quantified. Analysis on: 1) Gene mutation profile and association of the gene mutations with progression-free survival; 2) Association of pre- and post-treatment ctDNA variant allelic frequencies with clinical outcome; (3) Correlation of the mutated genes with treatment resistance; were performed. Findings: Somatic mutations were detected in 50 out of 61 patients by ctDNA genotyping. The mutations of CHD8 was significantly higher in patients with PFS ≥ 12 months. Baseline ctDNA was significantly higher in responders and a decrease of ctDNA ≥ 40% from baseline indicated superior clinical outcome. Strong agreement between ctDNA dynamic and radiographic response change during therapy was observed in majority of the patients. Furthermore, the mutations of B2M, TNFRSF14 and KDM2B were found to be associated with acquired resistance. Interpretation: ctDNA could be an informative biomarker for anti-PD-1 immunotherapy in r/r cHL. Funding: This work was supported by Innovent Biologics, Eli Lilly and Companyhttps://doi.org/10.13039/501100002852, China National New Drug Innovation Program (2014ZX09201041-001 and 2017ZX09304015), Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-001) and National Key Scientific Program Precision Medicine Research Fund of China (2017YFC0909801). The funders had no role in study design, data collection, data analysis, interpretation or writing. Keywords: Circulating tumor DNA, Immunotherapy, anti-PD-1, Biomarker, Classical hodgkin lymphoma, Sintilimab

In female mammals, the majority of primordial follicles (PFs) are physiologically quiescent, and only a few of them are activated and enter the growing follicle pool. Specific molecules, such as mammalian target of rapamycin (mTOR) and the serine/threonine kinase Akt (AKT), have been proven to be important for PF activation. However, how the transcription of these genes is regulated is not clear. Although activators of mTOR or AKT have been successfully used to rescue the fertility of patients with premature ovarian insufficiency, the low efficacy and unclear safety profile of these drugs hinder their clinical use in the

To compare the visualization of the lesions of diabetic retinopathy (DR) using multicolour scanning laser imaging (MSLI) and conventional colour fundus photography (CFP). The paired images of diabetic patients who underwent same-day MSLI and CFP examinations were reviewed. Combined multicolour (MC) images were acquired simultaneously using three laser wavelengths: blue reflectance (BR, λ = 488 nm), green reflectance (GR, λ = 518 nm) and infrared reflectance (IR, λ = 820 nm). The number of positive DR lesions was calculated using fundus fluorescein angiography as the reference standard. The visibility of the microaneurysms (Mas) was graded using a scale, and the number of Mas for each method was counted by two masked readers. Eighty eyes of 42 diabetic patients were included. The average grading score for Mas visualization was significantly higher with MC (1.50 ± 0.71) and GR (1.55 ± 0.69) than with CFP (0.95 ± 0.81). The average number of Mas was also significantly higher with MC (11.41 ± 14.02) and GR (11.93 ± 13.43) than with CFP (6.43 ± 9.39). The number of positive Mas, diabetic macular edema (DME) and epiretinal membranes (ERM) were significantly higher with MC than CFP (P 0.05), while the numbers of cotton wool spots, haemorrhages, hard exudates, venous beading and abnormal new vessels were not significantly different (P 0.05). Mas and ERM were most effectively detected on GR images, and an elevated greenish shift was clearly visualized in patients with DME on the MC images. MSLI can effectively visualize Mas and other pathological lesions of DR compared with CFP. MSLI with superior resolution may be a useful complement for DME and ERM detection.

G protein-coupled receptor 91 (GPR91) is a succinate-specific receptor and activation of GPR91 could initiate a complex signal transduction cascade and upregulate inflammatory and pro-angiogenic cytokines. In the retina, GPR91 is predominately expressed in ganglion cells, a major cellular entity involved in the pathogenesis of diabetic retinopathy (DR) and other hypoxic retinal diseases. During the development of DR and retinopathy of prematurity (ROP), chronic hypoxia causes an increase in the levels of local succinate. Succinate-mediated GPR91 activation upregulates vascular endothelial growth factor (VEGF) through ERK1/2-C/EBP β (c-Fos) and/or ERK1/2-COX-2/PGE2 signaling pathways, which in turn, leads to the breakdown of blood-retina barriers in these disorders. In this review, we will have a brief introduction of GPR91 and its biological functions and a more detailed discussion about the role and mechanisms of GPR91 in DR and ROP. A better understanding of GPR91 regulation may be of great significance in identifying new biomarkers and drug targets for the prediction and treatment of DR, ROP, and hypoxic retinal diseases.

Purpose: TP53 mutation was recognized as a negative prognostic factor for patients with diffuse large B-cell lymphoma (DLBCL). Exploratory therapy for this group of patients is in great need for potential clinical benefit. Here, we investigated the effect of adding surgical procedure to standard immunochemotherapy on survival of TP53 MUT DLBCL patients. Methods: Capture-based targeted sequencing was performed on 214 DLBCL patients, of which 47 was detected TP53MUT and included for further analysis. Refractory patients were defined as individuals did not achieve complete remission (CR) or develop relapse after 6 months in response to initial treatment. Findings: For 47 patients confirmed with TP53 mutation, 44 (93·6%) received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or R-CHOP-like regime were included for survival analysis with a median follow-up of 13 months. The median progression-free survival (PFS) and overall survival (OS) were 10.0 months (95%CI, 6·7-13·3) and 46.0 months (95%CI, 11·8-80·2). Among them, 26 patients developed refractory and received second-line chemotherapy. Seven limited-stage patients after early complete resection and one patient with residue resection remained event free with a median follow-up of 37 months. A multivariate analysis showed adding surgery to R-CHOP regime significantly improved PFS of TP53 MUT DLBCL patients compared to R-CHOP only treatment (p=0·039, HR=0·109, 95%CI=0·013-0·894). Conclusions: TP53 mutation is associated with unfavorable prognosis in DLBCL patients. Our study showed surgical resection may provide additional clinical benefit, which offered new treatment consideration for this group of patients. Funding Statement: This study was supported by National Key Technology Support Program (2014BAI09B12), CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-001), and National New Drug Innovation Program (2017ZX09304015). Declaration of Interests: JL is an employee of Burning Rock Biotech. All other authors declare no conflicts of interest. Ethics Approval Statement: The study was approved by the local ethic committee and was conducted in accordance with the Declaration of Helsinki.

In this study, Cr3+-doped MgAl2O4 nanophosphors have been prepared via a facile high-temperature calcination route. The structure and morphology of the products were characterized by x-ray diffraction (XRD), scanning electron microscope (SEM) and transmission electron microscopy (TEM) techniques, which confirmed the typical spinel MgAl2O4 phase and sphere-like shape with particle size distribution of 50–80 nm. It was found that the Cr3+-doped MgAl2O4 can be efficiently excited by visible light and exhibits intense red emission peaking at 695 nm, corresponding to the 2Eg→4A2g transition of Cr3+ ions. The evolution of the luminescent properties on the Cr-doping concentration (0, 0.5, 1, 2, 3, 4 and 6 mol%) was then investigated and the optimal concentration was 3.0 mol%. It is believed that active intermediates and gases created in the calcining process play important roles not only on the formation of the monodispersed nanoparticles, but also on the homogeneous doping of Cr3+ at high concentration.

3124 Background: Recognition of tumor neoantigen is the key to generating immune response. The expression and integrity of human leukocyte antigen (HLA) are the prerequisites for neoantigen presentation, and loss of heterozygosity in HLA (HLA LOH) may facilitate immune evasion. However, the incidence of HLA LOH in Chinese cancer patients is unknown. Methods: In this study, 45 samples sequenced with both 1021-gene panel and whole-exome sequencing(WES) were used to evaluate the consistency of HLA LOH in the two testing strategies. The prevalence of HLA LOH analysis was performed in 1546 advanced patients across 10 diverse cancer types and 114 early-stage lung cancer patients who had undergone tumor profiling using 1021-gene panel. Exon 2, exon 3 and bilateral introns of HLA-A/B/C genes were well covered in 1021-gene panel. HLA LOH were analysis using LOHHLA algorithm (McGranahan, et al. 2017). Results: In the HLA LOH analysis of 45 samples, the consistency of 1021-gene panel and WES was 95.6% (43/45). Among the 1660 samples, 1.3% (21) were detected as HLA homozygous at all of the three site. HLA LOH was found in 45.1%(697/1546) of all the advanced patients, range from 24.1% to 59.7%. In colorectal cancer, the HLA LOH ratio of MSS samples was significantly higher than that of MSI-H samples (46.2%, 61/132 vs 16.7%, 3/18 p =0.0214). For NSCLC, the proportion of HLALOH in early-stage (I-IIIa) lung adenocarcinoma and lung squamous cell carcinoma was 25.7% (18/70) and 65.9% (29/44), respectively, consistent with the report. However, advanced (IIIa-IV) lung adenocarcinoma and lung squamous cell carcinoma were 49.4%(168/340) and 58.7%(179/305), respectively. The reason for the difference between early-stage lung adenocarcinoma and advanced lung adenocarcinoma needs further study. In 43.8% of cases (326/744), LOH occurred simultaneously in HLA-A, B and C,suggesting that the Class I locus was often lost together. Conclusions: We can use multi-gene panel for HLA LOH analysis, provided that the relevant regions are well captured. The prevalenceof HLA LOHpresent differences among cancer types.Understanding these distributions may provide more information for immunotherapy research. [Table: see text]

Clonal hematopoiesis (CH) is characterized by clonal expansion of hematopoietic stem/progenitor cells with the capability of multilineage differentiation and can be detected through the biomarker of genetic mutations. Bone marrow failure (BMF) diseases including idiopathic cytopenia of undetermined significance (ICUS), aplastic anemia (AA), paroxysmal nocturnal hemoglobinuria (PNH) and myelodysplasia syndrome (MDS) are reported to partially coexist with CH. However, till now, the CH and genetic mutations in acquired BMF diseases are still not very clear. Therefore, we designed a panel that contains more than 500 candidate genes to perform a targeted sequencing of bone marrow cells isolated from 48 BMF patients, taking their mucosal cells as controls. In total, 75 somatic mutations and two germline mutations (PTCH1 c.1177G>A, CHEK2 c.1240C>T) were profiled in 30 patients, including 5 ICUS (also termed CCUS (clonal cytopenia of undetermined significance)), 14 AA, 3 PNH and 7 MDS patients. 67.53% missense mutations, 10.39% nonsense mutations, 10.39% frameshift mutations, 1.30% splicing mutations, 7.79% cds-del mutations, 2.60% CNV (copy number variations) can be found in our sequenced mutations. In comparison, the genetic mutation burden is relatively lower in AA and ICUS but higher in PNH and MDS, suggesting that the extent of CH possibly correlated with disease progression. Genetic mutations in our assay also implicated insightful views in the pathogenesis of BMF diseases. We can functionally divide genetic mutations into several types such as signaling transduction (21.6%), transcriptional regulation (19.6%), epigenetic regulation (15.5%), cell cycle regulation (7.2%), DNA repair (3.1%), cohesion complex (2.1%), immunity (3.1%), RNA splicing (4.1%) and others (3.1%). Specifically, we found a serial of novel genetic mutations. For example, the mutations in extracellular membrane receptors such as Notch (Notch1 c.4759A>C , Notch2 c.4819C>T, Notch3 c.3592A>C), CXCR4(c.598C>T), IGF1(c.341C>T), MPL(c.611C>T) suggest bone marrow environment is possibly associated with BMF diseases. In detail, Notch, IGF1, CXCR4 and MPL-mediated signaling are critical for HSC niche regulation, suggesting niche signals serve as a promoting factor for acquired BMF pathogenesis, which is consistent with previous reports. Also, we found the immunity-related mutations in HLA-A(c.750_751delGG) and CD58(c.475T>G), which are closely related with specific T cell recognition, implicated that clonal hematopoiesis and evolution to malignancies can be partially attributed to immune evasion possibly. The mutation ERBB4 (c.3424C>T), a membrane receptor which binds to and is activated by nerve cell released neuregulins, implicated that nerve fiber might involve in BMF. Additionally, we also found novel mutations in epigenetic factors such as KDM5C (c.265delA) and CHD3 (cds-del c.222GCC [7>6]) in PNH and MDS patients. Interestingly, LRP1B (c.13771G>A) that plays an important role in lipid metabolism was found in PNH patient firstly. These gene mutations provide clues for potential biomarkers for BMF diagnosis and prognosis and need more functional investigations. To systemically observe the clonal hematopoiesis at individual patient-level, we delineated the mutational composition in 30 individual BMF patients. We found that 56.7% patients have more than two mutations (eg. MDS 85.71%, PNH 100%, CCUS 60% and AA 35.7%), suggesting that multiple gene mutations-driven clonal expansion constitutes a complex mutational composition and their interaction possibly influences disease progression. At individual patient-level, mutational composition better promotes our understanding on BMF pathogenesis and clinical diagnosis. For example, an MDS patient bearing several mutations in ASXL (non-sense mutation, c.3187C>T, VAF: 18.2%), DNMT3A (missense mutation, c.2644C>T, VAF: 3.01%) and RUNX1 (missense, c.602G>A, VAF: 2.08%) suggested a complex pathological process and poor prognosis. Therefore, mutational composition structure can be revealed in individual acquired BMF patients, promoting precise diagnosis and prognosis. In conclusion, our study not only found a serial of novel genetic mutations that need further investigations, but also provided potential clues for the identification of biomarkers in acquired BMF diseases. Figure Disclosures No relevant conflicts of interest to declare.

Aluminum oxynitride (AlON) powder was prepared using a carbothermal reduction and nitridation method. The products were characterized by x-ray diffraction (XRD) and scanning electron microscopy (SEM) techniques, which confirmed the typical spinel AlON phase with sub-micro particle size. UV–vis absorption spectra revealed that the AlON has a band-gap of about 5.2 eV and shows a weak absorption in the wavelength of 240–400 nm, which could be caused by defects in crystal. In addition, the AlON exhibits good photocatalytic properties for degrading methyl orange (MO) under UV light illumination, suggesting that AlON could be a potential photocatalyst. Based on the intrinsic non-stoichiometry properties of AlON, the photocatalytic ability of AlON is related to its defect microstructures, which can promote the effective separation of electron–hole pairs.

Hypoxia is the most important factor in the pathogenesis of diabetic retinopathy (DR). Our previous studies demonstrated that G protein-coupled receptor 91(GPR91) participated in the regulation of vascular endothelial growth factor (VEGF) secretion in DR. The present study induced OIR model in newborn rats using exposure to alternating 24-hour episodes of 50% and 12% oxygen for 14 days. Treatment with GPR91 shRNA attenuated the retinal avascular area, abnormal neovascularization and pericyte loss. Western blot and qRT-PCR demonstrated that CoCl2 exposure promoted VEGF expression and secretion, activated the ERK1/2 signaling pathways and upregulated C/EBP and AP-1. Knockdown of GPR91 inhibited ERK1/2 activity. GPR91 siRNA transduction and the ERK1/2 inhibitor U0126 inhibited the increases in C/EBP β, C/EBP δ, c-Fos and HIF-1α. Luciferase reporter assays and a chromatin immunoprecipitation (ChIP) assay demonstrated that C/EBP β and c-Fos bound the functional transcriptional factor binding site in the region of the VEGF promoter, but not C/EBP δ. Knockdown of C/EBP β and c-Fos using RNAi reduced VEGF expression. Our data suggest that activation of the GPR91-ERK1/2-C/EBP β (c-Fos, HIF-1α) signaling pathway plays a tonic role in regulating VEGF transcription in rat retinal ganglion cells.

AIM To assess the prevalence, causes, and risk factors for blindness and visual impairment among elderly (≥60 years of age) Chinese people in a metropolitan area of Shanghai, China. METHODS Random cluster sampling was conducted to identify participants among residents ≥60 years of age living in the Xietu Block, Xuhui District, Shanghai, China. Presenting visual acuity (PVA) and best-corrected visual acuity (BCVA) were checked by the Early Treatment Diabetic Retinopathy Study (ETDRS) visual chart. All eligible participants underwent a comprehensive eye examination. Blindness and visual impairment were defined according to World Health Organization (WHO) criteria. RESULTS A total of 4190 persons (1688 men and 2502 women) participated in the study, and the response rate was 91.1%. Based on PVA, the prevalence of blindness was 1.1% and that of visual impairment was 7.6%. Based on BCVA, the prevalence of blindness and visual impairment decreased to 0.9% and 3.9%, respectively. Older (≥80 years of age) women, with low educational levels and smoking habits, exhibited a significantly greater chance for blindness and visual impairment than did those with high educational levels and no smoking habits (P

MicroRNAs (miRNAs) - as negative regulators of target genes - are associated with various human diseases, but their precise role(s) in diabetic retinopathy (DR) remains to be elucidated. The aim of this study was to elucidate the involvement of miRNAs in early DR using in silico analysis to explore their gene expression patterns.We used the streptozotocin (STZ)-induced diabetic rat to investigate the roles of miRNAs in early DR. Retinal miRNA expression profiles from diabetic versus healthy control rats were examined by miRNA array analysis. Based on several bioinformatic systems, specifically, gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, we identified signatures of the potential pathological processes, gene functions, and signaling pathways that are influenced by dysregulated miRNAs. We used quantitative real-time polymerase chain reaction (qRT-PCR) to validate six (i.e. those with significant changes in expression levels) of the 17 miRNAs that were detected in the miRNA array. We also describe the significant role of the miRNA-gene network, which is based on the interactions between miRNAs and target genes.GO analysis of the 17 miRNAs detected in the miRNA array analysis revealed the most prevalent miRNAs to be those related to biological processes, olfactory bulb development and axonogenesis. These miRNAs also exert significant influence on additional pathways, including the mitogen-activated protein and calcium signaling pathways. Six of the seventeen miRNAs were chosen for qRT-PCR validation. With the exception of a slight difference in miRNA-350, our results are in close agreement with the differential expressions detected by array analysis.This study, which describes miRNA expression during the early developmental phases of DR, revealed extensive miRNA interactions. Based on both their target genes and signaling pathways, we suggest that miRNAs perform critical regulatory functions during the early stages of DR evolution.

7534 Background: A large fraction of patients with relapsed/refractory (r/r) Classic Hodgkin Lymphoma (cHL) enjoy a beneficial response induced by PD-1. However, no reliable predictive biomarkers for response or resistance are available. Sintilimab, an anti-PD1 agent, has recently demonstrated efficacy and safety in a multi-center, single-arm, phase II study of Chinese patients with r/r cHL (ORIENT-1). The predictive value of circulating tumor DNA (ctDNA) in longitudinal samples from patients in ORIENT-1 was investigated. Methods: A total of 192 plasma samples were collected from 75 patients prior to treatment and during therapy. After ctDNA extraction next-generation sequencing (NGS) was performed using the HiSeq Sequencing System to assess either a 619 or 659 gene panels at an average sequencing depth of 1260×. The panels include frequently mutated genes in cHL and other hematological malignancies. DNA from paired granulocytes was sequenced as presumptive germline control. Results: The genomic profiling of baseline ctDNA revealed a mean allele mutation frequency of 5.47%. Among the most frequently mutated genes in these cHL patients, PCLO and LRP1B are likely unique to Chinese r/r cHL patients. Truncating mutation of B2M, DNMT3, TNFRSF14 and KDM2B were found in patients with acquired resistance, of which TNFRSF14 and KDM2B have not been reported before and need to be confirmed in further study. The baseline ctDNA level was significantly different between objective response group (CR+PR, n = 41, median = 8.72) and non-responder group (SD+PD, n = 9, median = 2.9) ( p= 0.0070) Patients with ctDNA high achieved response earlier than others ( p< 0.05). A drop of 40% in ctDNA after three cycles of therapy confirmed as best cut-off to predict progression associated with clinical benefit, demonstrating 100% specificity. Patients with ctDNA drop ≥40% achieved response significantly earlier (median = 71 days) than others (median = 216 days, p= 0.0074). Conclusions: Our study demonstrated that ctDNA could serve as valuable biomarker for prediction of response or resistance to anti-PD1 immunotherapy.

e19053 Background: Tumor mutational burden (TMB) has emerged as a promising biomarker in melanoma, NSCLC, glioma, and likely across types of solid cancers. However, TMB distribution and influencing factors in non-Hodgkin's lymphoma are still unknown. Methods: In this study, we focused on tumor (tTMB) and peripheral blood TMB (bTMB) in different lymphoma subtypes and conducted a hybridization-capture methodology and targeted 1.1Mb or 1.7 Mb of genomic coding sequence. Analysis of 188 tumors and 98 plasma samples matching oral epithelial normal samples was performed to characterize the landscape of somatic mutations between the TMB high (TMB-H) and TMB low (TMB-L) groups. Results: In our cohort, tTMB and bTMB ranged from 0 to 42.48, and 0.59 to 37.17, respectively. The top quartile TMB distribution (tTMB:12.34, bTMB:13.20) was used as the cut-off value to define TMB-H. DLBCL had significantly higher tTMB than small B cell lymphoma and peripheral T-cell lymphoma (p < 0.0001). 34.09% of DLBCL had TMB-H, and minority of patients had TMB-H in small B cell lymphoma (3.70%), and peripheral T-cell lymphoma (3.85%). The bTMB had the similar distribution to tTMB. Among all the tumor and plasma samples we detected 8 gene mutations having a significant correlation with high TMB including BTG2, PIM1, DUSP2, HIST1H1E, BTG1, SOCS1, HIST1H1C, CD70 ( p< 0.05) . Table TMB distribution of different lymphoma subtypes Conclusions: Compared to other lymphoma subtypes, DLBCL had higher TMB. Particular gene mutation had correlation with high TMB.[Table: see text]

The size of the primordial follicle pool determines the reproductive potential of mammalian females and establishment of the pool is highly dependent on specific genes expression. However, the molecular mechanisms by which the essential genes are regulated coordinately to ensure primordial follicle assembly remain a mystery. Here, we show that the small GTPase Rac1 plays an indispensable role in controlling the formation of primordial follicles in mouse ovary. Employing fetal mouse ovary organ culture system, we demonstrate that disruption of Rac1 retarded the breakdown of germline cell cysts while Rac1 overexpression accelerated the formation of primordial follicles. In addition, in vivo inhibitor injection resulted in the formation of multi-oocyte follicles. Subsequent investigation showed that Rac1 induced nuclear import of STAT3 by physical binding. In turn, nuclear STAT3 directly activated the transcription of essential oocyte-specific genes, including Jagged1, GDF9, BMP15 and Nobox. Further, GDF9 and BMP15 regulated the translation of Notch2 via mTORC1 activation in pregranulosa cells. Overexression or addition of Jagged1, GDF9 and BMP15 not only reversed the effect of Rac1 disruption, but also accelerated primordial follicle formation via Notch2 signaling activation. Collectively, these results indicate that Rac1 plays important roles as a key regulator in follicular assembly.

e19527Background: BCL6 translocations (3q27) are the most common chromosomal abnormalities in diffuse large B-cell lymphoma (DLBCL), with numerous immunoglobulin (Ig) and non-Ig genes as partners. ...

Purpose To compare intra-retinal layer thickness measurements between eyes with no or mild diabetic retinopathy (DR) and age-matched controls using Spectralis spectral-domain optical coherence tomography (SD-OCT). Methods Cross-sectional observational analysis study. High-resolution macular volume scans (30° * 25°) were obtained for 133 type 2 diabetes mellitus (T2DM) patients with no DR, 42 T2DM patients with mild DR and 115 healthy controls. The mean thickness was measured in all 9 Early Treatment Diabetic Retinopathy Study (ETDRS) sectors for 8 separate layers, inner retinal layer (IRL), outer retinal layer (ORL) and total retina (TR), after automated segmentation. The ETDRS grid consisted of three concentric circles of 1-, 3-, and 6-mm diameter. The superior, inferior, temporal, and nasal sectors of the 3- and 6-mm circles were respectively designated as S3, I3, T3, and N3 and S6, I6, T6, and N6. Linear regression analyses were conducted to evaluate the associations between the intra-retinal layer thicknesses, age, diabetes duration, fasting blood glucose and HbA1c. Results The mean age and duration of T2DM were 61.1 and 13.7 years, respectively. Although no significant differences in the average TR and ORL volumes were observed among the groups, significant differences were found in the volume and sectorial thicknesses of the inner plexiform layer (IPL), outer plexiform layer (OPL) and IRL among the groups. In particular, the thicknesses of the IPL (S3, T3, S6, I6 and T6 sectors) and the IRL (S6 sector) were decreased in the no-DR group compared with the controls (P < 0.05). The thickness of the OPL (S3, N3, S6 and N6 sectors) was thinner in the no-DR group than in mild DR (P < 0.05). The average IPL thickness was significantly negatively correlated with age and the duration of diabetes. Conclusion The assessment of the intra-retinal layer thickness showed a significant decrease in the IPL and IRL thicknesses in Chinese adults with T2DM, even in the absence of visible microvascular signs of DR.

The present study aimed to investigate the mechanism underlying the effects of minocycline on diabetic retinopathy‑associated cellular apoptosis. A total of 40 Sprague Dawley (SD) rats were used as a diabetic retinopathy model following injection with streptozotocin. Among the 34 rats in which the diabetes model was successfully established, 24 rats were divided into two experimental groups: I and II (T1 and T2, respectively), and orally administered with various doses of minocycline. The remaining 10 rats served as the diabetic retinopathy control group. An additional group of 10 healthy SD rats with comparable weight served as normal controls. The rats in T1 and T2 groups were treated daily for eight consecutive weeks with minocycline at a dose of 2.5 mg/kg and 5 mg/kg, respectively. The mRNA expression levels of poly (ADP‑ribose) polymerase‑1 (PARP‑1) were subsequently measured by reverse transcription‑quantitative polymerase chain reaction, and the protein expression levels of poly‑ADP‑ribose were measured by western blot analysis and immunohistochemistry. Retinal morphology was observed following hematoxylin and eosin staining, and retinal cell apoptosis was measured by terminal deoxynucleotidyl transferase dUTP nick end labeling and caspase‑3 activity assays. The amplitudes of the electroretinogram (ERG) b‑wave and oscillary potentials (OPs) were measured using visual electrophysiology, and compared among the four groups. The results of the present study demonstrated that in the diabetic rats, retinal PARP‑1 gene expression was markedly upregulated, the number of apoptotic cells and the activity levels of caspase‑3 were increased, and the amplitude of the ERG b‑wave and the OPs were markedly lower as compared with the normal rats. Following treatment with minocycline, the abnormal expression of PARP‑1 in the retina was inhibited, and cellular apoptosis was decreased. In conclusion, the results of the present study suggest that PARP‑1 is involved in the development of diabetic retinopathy, and minocycline is able to inhibit PARP‑1 expression and decrease cellular apoptosis, suggesting that minocycline may prove to be a promising drug for the treatment of diabetic retinopathy.

A double layer CeO2/Nb2O5 thin film by magnetron sputtering was prepared. The property and microstructure of the thin film were carefully characterized by x-ray photoelectron spectroscopy (XPS), transmission electron microscopy, and high resolution transmission electron microscopy. XPS measurement clearly demonstrated that the Nb2O5 layer underlying CeO2 as a electrical-conductive layer could greatly improve the reduction ability of CeO2 thin film compared with that of a single layer CeO2 thin film. Fitting to the XPS experimental data and deconvoluting the spectra showed the increase of Ce3+ concentration in the double layer CeO2/Nb2O5 thin film. The microstructure of the double layer thin film was composed of three distinguishable layers, which are a polycrystalline CeO2 layer, an amorphous Nb2O5 layer, and an intermediate amorphous layer with regard to the silicon substrate. The interface between CeO2 and Nb2O5 was rough and indistinct. A detailed analysis was given from the viewpoint of interdiffusion...

This paper reports on the radiation damage of gamma aluminum oxynitride (γ-AlON) transparent ceramic, which remarkably degrades UV–vis transparency and hence limits its applications in optoelectronic devices. The radiation-induced optical absorption of the as-sintered γ-AlON consists of at least two subbands: one is in the UV region with a peak at 270 nm and the other optical absorption band centers at 550 nm, covering the whole visible light spectrum, which makes the sample colored. Interestingly, all the radiation-induced color centers can be completely 'bleached' by low temperature annealing. In the thermoluminescence curve, we observed a broad luminescence in the range of 25–300 °C with the peak at 120 °C. Furthermore, the x-ray excited luminescence spectra revealed that there exist multiple emission centers in the γ-AlON. Based on this experimental fact, the radiation damage and luminescent mechanisms were studied. These optical properties of the γ-AlON are considered to be related to defect states. In the as-sintered γ-AlON, charge balancing is realized by the co-existence of and , and the predominant defect form is , which is optically inactive and no optical absorption occurs. However, isolated and can be formed by irradiation and it is these that are responsible for the radiation damage of γ-AlON transparent ceramic. In the end, the UV absorption and visible-light absorption in the irradiated sample were ascribed to VAl-related and ON-related intrinsic defects, respectively.

To determine the incidence of vitreoretinal pathologic conditions in myopic eyes after laser in situ keratomileusis.Vitreoretinal pathologic conditions of 1981 consecutive eyes (995 patients) having undergone laser-assisted in situ keratomileusis for the correction of myopia were studied. Preoperative and postoperative basic examinations included visual acuity, manifest and cycloplegic refraction, slit-lamp microscope examination, applanation tonometry and a fundus examination after pupil dilatation by indirect ophthalmoscopy and biomicroscopy with spherical lens of + 90 diopters. Before laser in situ keratomileusis, preventive treatment was carried out for predisposing lesion of retinal detachment in 8 eyes: 6 eyes for lattice degeneration and 2 eyes for atrophic holes. Postoperative examinations were conducted at 1, 3 and 12 months and once a year thereafter. All eyes were followed up for/= 12 months.Eyes were followed for a mean of (18.40 +/- 4.50) months (range 12 - 28) after the surgery. Sixteen eyes of 13 patients (0.81%) developed vitreoretinopathy after LASIK, including 6 eyes with lattice degeneration (0.30%) in which one of them had previous laser treatment, 2 with posterior vitreous detachment (0.10%), 2 with macular hemorrhage (0.10%), 4 with rhegmatogenous retinal detachment (0.20%), and 2 with retinal tear without retinal detachment (0.10%) in which one of them had previous laser treatment for lattice degeneration. Five patients were males (5 eyes involved). Others were females. Mean age of the group with vitreoretinal pathologic conditions was 31.80 +/- 5.85 years (range 22 to 43). The interval between refractive surgery and development of vitreoretinal complication was (10.38 +/- 6.20) months (range 1 to 24). The eyes that developed vitreoretinopathy had myopia -4.75 to -15.00 diopters (mean -9.45 +/- 2.61 D) before LASIK. The comparison of incidences of vitreoretinopathy after LASIK between the group of/= -6.00 D and-6.00 D before surgery showed significant difference (P0.01, chi(2) = 60.78). The comparison of incidences of vitreoretinopathy after LASIK had also significant difference (P0.01, chi(2) = 138.64) between the eyes with pre-LASIK lattice degeneration and dry hole and eyes without such lesions. The cases of lattice degeneration and retinal tear were treated with laser retinopexy. All cases of rhegmatogenous retinal detachment were managed with cryoretinopexy and scleral buckling. Retinal reattachment was attained in all eyes and good visual acuities were recovered.No direct cause-effect relationship between LASIK and vitreoretinopathy can be proven from this study. Although the incidence of vitreoretinal pathologic conditions in myopic eyes after laser in situ keratomileusis is low, it is necessary to strictly filter candidates. Preoperatively and postoperatively, pay attention to the lattice degeneration and other retina lesions, and long-term follow-up is important.

To evaluate efficacy of photo therapeutic keratectomy (PTK) on corneal epithelial growth under the lamellar flap after excimer laser in situ keratomileusis (LASIK).In the 6 eyes with epithelial in-growth, the corneal cap was lifted, and the in-growing epithelium was removed from the interface. Five to 10 pulses of PTK being 7 mm in diameter were placed over the undersurface of the flap and the stromal bed, irrigation between the interface and replacing corneal flap were performed, and 50 to 75 pulses PTK being 3 mm in diameter were utilized to smooth the flap edge. The follow-up period ranged from 5 to 12 months.In the follow-up, no epithelial implantation reoccurred in these 6 eyes. The uncorrected visual acuity achieved their best preoperative corrected visual acuity.The results indicate that PTK can prevent recurrent epithelial in-growth after LASIK.

To evaluate the long-term results of laser in situ keratomileusis (LASIK) for the correction of myopia.A total of 1 285 eyes with preoperative refraction of -1.50 - -25.00 diopters were treated with LASIK. Based on the preoperative refraction, the patients were divided into 3 groups (-1.50 - -6.00 D, -6.12 - -12.00 D, -12.12 - -25.00 D). The mean follow-up was 26.7 months and the results were concluded and analyzed.At two years, respectively 93.4%, 86.7% and 65.5% in the above three groups were within +/- 1.00 D, 84.4%, 79.7%, 42.1% were within +/- 0.50 D; the uncorrected visual acuity was/= 0.5 in 99.6%, 93.8% and 62.6% of the patients, and 90.4%, 68.6%, and 27.2% had vision of/= 1.0. Thirty-nine eyes with regression or under correction, and 2 eyes with epithelial ingrowth had been retreated with LASIK.LASIK is effective and safe for the correction of mild, moderate, high and super-high myopia. The results of follow-up for two years are stable.