Closed head injury combined with orbital blowout fracture and displacement of the eyeball into the maxillary sinus in a 14-year-old boy: a case report.

BACKGROUND: Trauma-induced orbital blowout fracture (OBF) with eyeball displacement into the maxillary sinus is rare. CASE PRESENTATION: We present the case of a 14-year-old with a closed head injury, OBF, and displacement of the eyeball into the maxillary sinus following a car accident. A prompt transconjunctival access surgery was performed for eyeball repositioning and orbital reconstruction in a single session, mitigating anaesthesia-related risks associated with multiple surgeries. At the 12-month follow-up, his visual acuity was 20/200. Despite limited eye movement and optic nerve atrophy, overall satisfaction with the ocular appearance was achieved. CONCLUSIONS: This report offers novel insights into the mechanisms of OBF occurrence and the development of postoperative complications.

Co-expressed network analysis based on 289 transcriptome samples reveals methyl jasmonate-mediated gene regulatory mechanism of flavonoid compounds in Dendrobium catenatum.

Flavonoids are momentous bioactive ingredients in orchid plant Dendrobium catenatum (D. catenatum), which are bioactive compounds with great medical and commercial potential. However, the accurate dissection of flavonoids profiling and their accumulation mechanism are largely unknown. In this study, methyl jasmonate (MeJA) treatment was used to investigate the change of flavonoids content and transcripts in two D. catenatum clones (A6 and B1). We identified 40 flavonoids using liquid chromatograph mass spectrometer (LC-MS). By weighted gene co-expressed network analysis (WGCNA) of flavonoids content and transcript expression of MeJA-treated samples, 37 hub genes were identified. Among them, DcCHIL, DcFLS, and DcDFR were highly correlation with two key transcription factors DcWRKY3/4 by correlation analysis of large-scale transcriptome data and above hub genes expression. Furthermore, transient overexpression of DcWRKY3/4 in tobacco leaves significantly increased the content of flavonoids. This study identified flavonoid profiling and built a new approach to mine regulatory mechanism of flavonoids in D. catenatum. These valuable flavonoids and gene resources will be key for understanding and harnessing natural flavonoids products in pharmaceuticals and foods industry of D. catenatum.

HELZ2 promotes K63-linked polyubiquitination of c-Myc to induce retinoblastoma tumorigenesis.

Retinoblastoma is a rare ocular tumor in children that originates in the retina. Several core transcriptional regulators maintain the expansion of retinoblastoma tumors, including c-Myc. Here, we demonstrated that Helicase with zinc finger domain 2 (HELZ2) promoted retinoblastoma tumorigenesis by targeting c-Myc. HELZ2-deficient inhibited retinoblastoma cell proliferation, whereas overexpression of HELZ2 promoted retinoblastoma cell proliferation. In addition, high levels of HELZ2 promoted xenograft retinoblastoma tumorigenesis and inhibited animal survival. Mechanistically, HELZ2 interacted with c-Myc and promoted its K63-linked polyubiquitination. We indicated that HELZ2 promoted the interaction between E3 ubiquitin ligase HUWE1 and c-Myc, and HELZ2-mediated K63-linked polyubiquitination and activation of c-Myc were dependent on HUWE1. Taken together, HELZ2 plays a critical role in the regulation of retinoblastoma tumorigenesis by enhancing the activity of c-Myc.

The zinc-finger protein ZCCHC2 suppresses retinoblastoma tumorigenesis by inhibiting HectH9-mediated K63-linked polyubiquitination and activation of c-Myc.

Retinoblastoma (RB) is the most common intraocular malignancy. The tumor propagation of RB is maintained by several core transcriptional regulators, including c-Myc. Strictly regulated posttranslational modifications control the c-Myc protein. However, the posttranslational regulatory mechanisms for c-Myc in retinoblastoma remain largely unclear. Here, we identified the zinc-finger protein ZCCHC2 as a critical negative regulator of c-Myc-associated tumorigenesis. Knockout of ZCCHC2 promoted retinoblastoma cell proliferation, whereas ZCCHC2 overexpression had the opposite effect. Meanwhile, the level of ZCCHC2 was positively correlated with retinoblastoma tumorigenesis and animal survival in vivo. Mechanistically, ZCCHC2 was associated with c-Myc and negatively regulated the K63-linked polyubiquitination of c-Myc. We demonstrated that ZCCHC2 inhibits the interaction of the E3 ubiquitin ligase HectH9 with c-Myc and that ZCCHC2 inhibits HectH9-mediated K63-linked polyubiquitination and activation of c-Myc. Altogether, these data suggest that ZCCHC2 plays a role in the regulation of RB tumorigenesis through the inhibition activity of c-Myc.

A Dual Role of ATM in Ischemic Preconditioning and Ischemic Injury.

The ataxia-telangiectasia mutated (ATM) protein is regarded as the linchpin of cellular defenses to stress. Deletion of ATM results in strong oxidative stress and degenerative diseases in the nervous system. However, the role of ATM in neuronal ischemic preconditioning and lethal ischemic injury is still largely unknown. In this study, mice cortical neurons preconditioned with sublethal exposure to oxygen glucose deprivation (OGD) exhibited ATM/glucose-6-phosphate dehydrogenase pathway activation. Additionally, pharmacological inhibition of ATM prior to the preconditioning reversed neuroprotection provided by preconditioning in vitro and in vivo. Meanwhile, we found that ATM/P53 pro-apoptosis pathway was driven by lethal OGD injury, and pharmacological inhibition of ATM during fatal oxygen-glucose deprivation/reperfusion injury promoted neuronal survival. More importantly, inhibition of ATM activity after cerebral ischemia protected against cerebral ischemic-reperfusion damage in mice. In conclusion, our data show the dual role of ATM in neuronal ischemic preconditioning and lethal ischemic injury, involving in the protection of ischemic preconditioning, but promoting neuronal death in lethal ischemic injury. Thus, the present study provides new opportunity for the treatment of ischemic stroke.

C-MET-dependent signal transduction mediates retinoblastoma growth by regulating PKM2 nuclear translocation.

Mesenchymal epithelial transition (C-MET) factor overexpression has been found in many types of cancer and has served as an important molecular target for therapeutic intervention. However, the role of C-MET in retinoblastoma remains largely unclear. The present study aimed to investigate the potential role and mechanism of C-MET in Y79 retinoblastoma cells. We found that C-MET was highly expressed in Y79 retinoblastoma cells, and, in addition, the levels of C-MET were positively correlated with cell proliferation and retinoblastoma growth. Inhibition of C-MET suppressed Y79 retinoblastoma cell proliferation and tumour growth. Mechanistically, we showed that HGF-induced C-MET-dependent signal transduction resulted in ERK 1/2 phosphorylation, which subsequently promoted the nuclear translocation of PKM2. Nuclear PKM2 further interacted with histone H3 and contributed to C-MET-dependent cyclin D1 and c-Myc expression and cell proliferation. These findings highlight the role of C-MET in Y79 retinoblastoma cells and reveal a C-MET-dependent signal transduction mechanism. C-MET may be a potential therapeutic target for retinoblastoma. SIGNIFICANCE OF THE STUDY: We demonstrated a new target of retinoblastoma, C-MET. C-MET-dependent signal transduction promotes Y79 retinoblastoma cell proliferation and tumour growth through ERK 1/2/PKM2/histone H3 signalling pathway. C-MET may be a potential target for retinoblastoma therapy.

Evaluation of Autologous Blood in Pterygium Surgery With Conjunctival Autograft.

PURPOSE: Autologous blood has been used exploratively with conjunctival autograft in pterygium surgery. However, it is controversial whether autologous blood performed better than other fixation methods, including fibrin glue and sutures. This meta-analysis was conducted to evaluate the effectiveness of using autologous blood in pterygium surgery with conjunctival autograft. METHODS: The study was conducted according to the PRISMA guidelines. The MEDLINE, Cochrane library, and Embase databases were systematically searched from their establishment until April 1, 2018. Randomized controlled trials comparing autologous blood with fibrin glue/suture in pterygium surgery with conjunctival autograft were included. The methodological quality of the included studies was assessed using the Cochrane risk of bias tool. Outcome measurements were recurrence, graft displacement, graft retraction, and surgical duration. Review Manager 5.3 (Cochrane Community, Cochrane Collaboration, London, UK) was used to perform the statistical analysis. When I < 50%, statistical heterogeneity was considered acceptable, and a fixed-effects model was adopted; alternatively, the random-effects model was used. RESULTS: Seven randomized controlled trials including 516 patients were finally included in the meta-analysis. Four studies with 379 patients compared autologous blood and fibrin glue. Autologous blood was inferior to fibrin glue with respect to surgical duration, graft retraction, and graft displacement. However, there was no statistical difference between the 2 groups in terms of the recurrence rate. Four studies with 152 patients compared autologous blood and traditional suturing. Autologous blood was superior to sutures in terms of surgical duration and inferior to sutures in terms of graft retraction. No difference was detected in terms of graft displacement and recurrence rate. CONCLUSIONS: In conclusion, autologous blood is an appropriate method for graft fixation in pterygium surgery. Current research suggests that autologous blood derivatives may be a promising approach after pterygium excision. However, this requires further confirmation.

Decitabine-Induced Changes in Human Myelodysplastic Syndrome Cell Line SKM-1 Are Mediated by FOXO3A Activation.

The epigenetic silencing of tumor suppressor genes in myelodysplastic syndromes (MDS) can potentially confer a growth advantage to individual cellular clones. Currently, the recommended treatment for patients with high-risk MDS is the methylation agent decitabine (DAC), a drug that can induce the reexpression of silenced tumor suppressor genes. We investigated the effects of DAC treatment on the myeloid MDS cell line SKM-1 and investigated the role of FOXO3A, a potentially tumor-suppressive transcription factor, by silencing its expression prior to DAC treatment. We found that FOXO3A exists in an inactive, hyperphosphorylated form in SKM-1 cells, but that DAC both induces FOXO3A expression and reactivates the protein by reducing its phosphorylation level. Furthermore, we show that this FOXO3A activation is responsible for the DAC-induced differentiation of SKM-1 cells into monocytes, as well as for SKM-1 cell cycle arrest, apoptosis, and autophagy. Collectively, these results suggest that FOXO3A reactivation may contribute to the therapeutic effects of DAC in MDS.

Anti-fibrotic, anti-VEGF or radiotherapy treatments as adjuvants for pterygium excision: a systematic review and network meta-analysis.

BACKGROUND: Anti-fibrotic, anti-VEGF (vascular endothelial growth factor) medications, or radiotherapy, as adjuvant for pterygium surgical procedure, has been suggested for reducing recurrence, but difficulties may be experienced in deciding which treatment to use. The purpose of this study was to compare the efficacies of these different adjuvants for preventing recurrence following pterygium surgery. METHODS: We conducted a systematic review to identify randomized controlled trials of patients with primary or recurrent pterygium who received anti-fibrotic, anti-VEGF medication, or radiotherapy as adjuvants in combination with surgical procedure. The surgical procedure contained bare sclera technique or petrygium excision combination with tissue grafting. The primary outcome of this study was recurrence. Direct-comparison and Bayesian network meta-analyses were performed to assess direct and indirect evidence of efficacy. RESULTS: We obtained data from 34 randomized controlled trials, representing a total of 2483 patients. Adjuvants included bevacizumab, 5-FU (5-fluorouracil), MMC (mitomycin C), and ß-RT (beta-radiotherapy). Compared with placebo, we found distinguishable improvement in recurrence with bevacizumab (odds ratio [OR] 0.38, 95% confidence interval [CI] 0.18-0.80), MMC (0.12, 95% CI 0.06-0.21), and ß-RT (0.17, 95% CI 0.04-0.69), but not with 5-FU (0.41, 95% CI 0.12-1.39). MMC significantly reduced recurrence when compared to bevacizumab (0.31, 95% CI 0.13-0.77) and 5-FU (0.28, 95% CI 0.08-0.99). The probability of having the most recurrences after excision was lowest for MMC, followed by bevacizumab and ß-RT. Similar results were found in subgroup analyses, including for primary pterygium, and the patients receiving bare sclera technique or conjunctival autograft. CONCLUSIONS: Adjuvants such as MMC, bevacizumab, and ß-RT could effectively prevent recurrence following pterygium excision. However, their efficacy and acceptability require further clarification in future randomized controlled trials.

Sequence2Vec: a novel embedding approach for modeling transcription factor binding affinity landscape.

MOTIVATION: An accurate characterization of transcription factor (TF)-DNA affinity landscape is crucial to a quantitative understanding of the molecular mechanisms underpinning endogenous gene regulation. While recent advances in biotechnology have brought the opportunity for building binding affinity prediction methods, the accurate characterization of TF-DNA binding affinity landscape still remains a challenging problem. RESULTS: Here we propose a novel sequence embedding approach for modeling the transcription factor binding affinity landscape. Our method represents DNA binding sequences as a hidden Markov model which captures both position specific information and long-range dependency in the sequence. A cornerstone of our method is a novel message passing-like embedding algorithm, called Sequence2Vec, which maps these hidden Markov models into a common nonlinear feature space and uses these embedded features to build a predictive model. Our method is a novel combination of the strength of probabilistic graphical models, feature space embedding and deep learning. We conducted comprehensive experiments on over 90 large-scale TF-DNA datasets which were measured by different high-throughput experimental technologies. Sequence2Vec outperforms alternative machine learning methods as well as the state-of-the-art binding affinity prediction methods. AVAILABILITY AND IMPLEMENTATION: Our program is freely available at https://github.com/ramzan1990/sequence2vec. CONTACT: xin.gao@kaust.edu.sa or lsong@cc.gatech.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

An improved surgical method to correct conjunctivochalasis: conjunctival semiperitomy based on corneal limbus with subconjunctival cauterization.

OBJECTIVE: To introduce an improved surgical method to correct conjunctivochalasis. DESIGN: Retrospective study. PARTICIPANTS: We studied 28 eyes in 28 patients. METHODS: First, conjunctival semiperitomy based on the corneal limbus was performed. Next, the subconjunctival tissues received 2 lines (12 to 18 spots) of gentle cauterization using a cautery to adhere the conjunctiva to underlying sclera. The grade of conjunctivochalasis, Schirmer test (St), and tear breakup time (BUT) were recorded under a slit-lamp, and the severity of patients' symptoms were assessed by using the Ocular Surface Disease Index (OSDI) questionnaires. The values before surgery and 3 months after surgery were collected and then compared. RESULTS: The conjunctivochalasis gradings were as follows: preoperatively, there were 0 eyes in grade 0 and grade 1; 13 (46.43%) eyes in grade 2; and 15 (53.57%) eyes in grade 3. Postoperatively, there were 26 (92.86%) eyes in grade 0; 2 (7.14%) eyes in grade 1; and 0 eyes in grades 2 and 3. Preoperatively, the St, BUT, and OSDI were 8.49 ± 4.42 mm, 7.74 ± 2.72 seconds, and 40.64 ± 10.30, respectively; postoperatively, they were 13.22 ± 4.26 mm, 12.06 ± 2.48 seconds, and 10.50 ± 3.87, respectively. There was a significant difference (p < 0.05) between pre- and postoperative patients in conjunctivochalasis grade, St, BUT and OSDI. CONCLUSIONS: Conjunctival semiperitomy combined with gentle subconjunctival cauterization is a better therapy for conjunctivochalasis because it both resects the redundant conjunctiva and reestablishes the anatomic tight adhesion between the conjunctiva and the underlying sclera along the corneal limbus.

Identification of two mutations of the RHO gene in two Chinese families with retinitis pigmentosa: correlation between genotype and phenotype.

PURPOSE: To describe the clinical and genetic findings in two Chinese families with retinitis pigmentosa (RP). METHODS: Two unrelated families were examined clinically. After informed consent was obtained, genomic DNA was extracted from the venous blood of all participants. Genotyping and haplotyping analysis was performed on the known genetic loci for autosomal dominant retinitis pigmentosa (adRP) with a panel of polymorphic markers in the two families, and then mutation screening of all coding exons of the RHO gene was performed by direct sequencing of PCR-amplified DNA fragments. Whenever substitutions were identified in a patient, restriction fragment length polymorphism analysis was performed on all available family members and on 100 normal controls. RESULTS: Clinical examination and pedigree analysis revealed two four-generation families (83 and 112) with adRP. A significant two-point linkage odd disequilibrium (LOD) score was generated at marker D3S1292 (Zmax=1.90, θ=0) for family 83 and (Zmax=2.77, θ=0) for family 112, respectively, and further linkage and haplotype studies confined the disease locus to 3q21-22 where the RHO gene is located. Mutation screening of the RHO gene in the two families revealed a G→C transversion at position 505 (p.A169P) of the cDNA sequence in family 83 and a C→A transversion at position 1040 (p.P347Q) of the cDNA in family 112. The novel p.A169P and recurrent p.P347Q mutations cosegregated with the phenotypes of the two families. Secondary structure prediction suggested that the mutant rhodopsin 169P led to significant secondary structure changes between residues 165 and 169, which may interfere with the correct folding of the transmembrane domain. CONCLUSIONS: Two mutations of the RHO gene were identified in two Chinese families with adRP. Our findings further suggest codon 347 is the mutation hotspot of the RHO.

Seven novel mutations in the long isoform of the USH2A gene in Chinese families with nonsyndromic retinitis pigmentosa and Usher syndrome Type II.

PURPOSE: To describe the clinical and genetic findings in one Chinese family with autosomal recessive retinitis pigmentosa (arRP) and in three unrelated Chinese families with Usher syndrome type II (USH2). METHODS: One family (FR1) with arRP and three unrelated families (F6, F7, and F8) with Usher syndrome (USH), including eight affected members and seven unaffected family individuals were examined clinically. The study included 100 normal Chinese individuals as normal controls. After obtaining informed consent, peripheral blood samples from all participants were collected and genomic DNA was extracted. Genotyping and haplotyping analyses were performed on the known genetic loci for arRP with a panel of polymorphic markers in family FR1. In all four families, the coding region (exons 2-72), including the intron-exon boundary of the USH2A (Usher syndrome type -2A protein) gene, was screened by PCR and direct DNA sequencing. Whenever substitutions were identified in a patient, a restriction fragment length polymorphism (RFLP) analysis, single strand conformation polymorphism (SSCP) analysis, or high resolution melt curve analysis (HRM) was performed on all available family members and on the 100 normal controls. RESULTS: The affected individuals presented with typical fundus features of retinitis pigmentosa (RP), including narrowing of the vessels, bone-spicule pigmentation, and waxy optic discs. The electroretinogram (ERG) wave amplitudes of the available probands were undetectable. Audiometric tests in the affected individuals in family FR1 were normal, while indicating moderate to severe sensorineural hearing impairment in the affected individuals in families F6, F7, and F8. Vestibular function was normal in all patients from all four families. The disease-causing gene in family FR1 was mapped to the USH2A locus on chromosome 1q41. Seven novel mutations (two missenses, one 7-bp deletion, two small deletions, and two nonsenses) were detected in the four families after sequencing analysis of USH2A. CONCLUSIONS: The results further support that mutations of USH2A are also responsible for non-syndromic RP. The mutation spectrum among Chinese patients might differ from that among European Caucasians.

Large novel deletions detected in Chinese families with aniridia: correlation between genotype and phenotype.

PURPOSE: To describe the clinical and genetic findings in two Chinese families with aniridia and other ocular abnormalities. METHODS: Two unrelated families were examined clinically. After informed consent was obtained, genomic DNA was extracted from the venous blood of all participants. Mutation screening of all exons of the PAX6 (paired box gene 6) gene was performed by direct sequencing of PCR-amplified DNA fragments. Multiplex ligation-dependent probe amplification (MLPA) was performed to detect large deletions. Linkage analysis was used to validate the large deletions revealed by MLPA in all available family members. RESULTS: Clinical examination and pedigree analysis revealed one four-generation family (85) and one three- generation family (86) with total aniridia, congenital cataracts, foveal hypoplasia, and glaucoma. No mutation in PAX6 was identified after PCR-sequencing. Through MLPA analysis, a large deletion including the whole PAX6 gene, DKFZp686k1684 (hypothetical LOC440034), and the RCN1 (reticulocalbin 1) gene was detected in family 85; a 3' deletion to the PAX6 gene including the ELP4 (elongator complex protein 4) and the DCDC1 (doublecortin domain containing 1) gene was identified in family 86.The two large deletions were confirmed with linkage analysis and the "loss of heterozygous" in the different PAX6 regions were co-segregated with the phenotype of the two families, respectively. CONCLUSIONS: Patients with the PAX6 contiguous gene deletion, including the RCN1 gene, presented more severe vision impairments than those carrying the PAX6 3' deletion. Large deletions may account for several Chinese families and sporadic cases with aniridia and screening for these kinds of alterations should be included in aniridia patients' analyses.

Identification of five novel mutations in the long isoform of the USH2A gene in Chinese families with Usher syndrome type II.

PURPOSE: Usher syndrome type II (USH2) is the most common form of Usher syndrome, an autosomal recessive disorder characterized by moderate to severe hearing loss, postpuberal onset of retinitis pigmentosa (RP), and normal vestibular function. Mutations in the USH2A gene have been shown to be responsible for most cases of USH2. To further elucidate the role of USH2A in USH2, mutation screening was undertaken in three Chinese families with USH2. METHODS: Three unrelated Chinese families, consisting of six patients and 10 unaffected relatives, were examined clinically, and 100 normal Chinese individuals served as controls. Genomic DNA was extracted from the venous blood of all participants. The coding region (exons 2-72), including the intron-exon boundary of USH2A, was amplified by polymerase chain reaction (PCR). The PCR products amplified from the three probands were analyzed using direct sequencing to screen sequence variants. Whenever substitutions were identified in a patient, restriction fragment length polymorphism analysis, or single strand conformation polymorphism analysis was performed on all available family members and the control group. RESULTS: Fundus examination revealed typical fundus features of RP, including narrowing of the vessels, bone-speckle pigmentation, and waxy optic discs. The ERG wave amplitudes of three probands were undetectable. Audiometric tests indicated moderate to severe sensorineural hearing impairment. Vestibular function was normal. Five novel mutations (one small insertion, one small deletion, one nonsense, one missense, and one splice site) were detected in three families after sequence analysis of USH2A. Of the five mutations, four were located in exons 22-72, specific to the long isoform of USH2A. CONCLUSIONS: The mutations found in our study broaden the spectrum of USH2A mutations. Our results further indicate that the long isoform of USH2A may harbor even more mutations of the USH2A gene.

Late-onset bilateral lens dislocation and glaucoma associated with a novel mutation in FBN1.

PURPOSE: To describe the clinical and genetic findings in one Chinese family with late-onset bilateral lens dislocation and secondary glaucoma. METHODS: One family including three affected members and 16 unaffected family members was examined clinically. After informed consent was obtained, genomic DNA was extracted from venous blood of all participants. Linkage analysis was performed with two microsatellite markers around the fibrillin-1 (FBN1) gene (D15S992 and D15S126). Mutation screening was performed using direct DNA sequence analysis and single strand conformation polymorphism (SSCP). RESULTS: Clinical examination and pedigree analysis revealed that four members in three generations were affected by late-onset lens dislocation and secondary glaucoma but had no signs of cardiovascular abnormality or abnormal skeletal features. By genotyping, the family showed the linkage to FBN1 on 15q21.1. After mutation screening analysis on 65 exons of FBN1, a novel heterozygous missense mutation, c.2860C>T (R954C), was detected. This mutation cosegregated with the disease phenotype in the family and was not found in 100 normal controls. CONCLUSIONS: Late-onset isolated ectopia lentis with secondary glaucoma is consistent with a novel mutation in FBN1. Our finding expands the spectrum of FBN1 mutations and is useful for further genetic consultation and genetic diagnosis.