High-throughput identification of regulatory elements and functional assays to uncover susceptibility genes for nasopharyngeal carcinoma.

Large-scale genetic association studies have identified multiple susceptibility loci for nasopharyngeal carcinoma (NPC), but the underlying biological mechanisms remain to be explored. To gain insights into the genetic etiology of NPC, we conducted a follow-up study encompassing 6,907 cases and 10,472 controls and identified two additional NPC susceptibility loci, 9q22.33 (rs1867277; OR = 0.74, 95% CI = 0.68-0.81, p = 3.08 × 10-11) and 17q12 (rs226241; OR = 1.42, 95% CI = 1.26-1.60, p = 1.62 × 10-8). The two additional loci, together with two previously reported genome-wide significant loci, 5p15.33 and 9p21.3, were investigated by high-throughput sequencing for chromatin accessibility, histone modification, and promoter capture Hi-C (PCHi-C) profiling. Using luciferase reporter assays and CRISPR interference (CRISPRi) to validate the functional profiling, we identified PHF2 at locus 9q22.33 as a susceptibility gene. PHF2 encodes a histone demethylase and acts as a tumor suppressor. The risk alleles of the functional SNPs reduced the expression of the target gene PHF2 by inhibiting the enhancer activity of its long-range (4.3 Mb) cis-regulatory element, which promoted proliferation of NPC cells. In addition, we identified CDKN2B-AS1 as a susceptibility gene at locus 9p21.3, and the NPC risk allele of the functional SNP rs2069418 promoted the expression of CDKN2B-AS1 by increasing its enhancer activity. The overexpression of CDKN2B-AS1 facilitated proliferation of NPC cells. In summary, we identified functional SNPs and NPC susceptibility genes, which provides additional explanations for the genetic association signals and helps to uncover the underlying genetic etiology of NPC development.

Autoantibody repertoire profiling in tissue and blood identifies colorectal cancer-specific biomarkers.

Autoantibodies (AAbs) in the blood of colorectal cancer (CRC) patients have been evaluated for tumor detection. However, it remains uncertain whether these AAbs are specific to tumor-associated antigens. In this study, we explored the IgG and IgM autoantibody repertoires in both the in situ tissue microenvironment and peripheral blood as potential tumor-specific biomarkers. We applied high-density protein arrays to profile AAbs in the tumor-infiltrating lymphocyte supernatants and corresponding serum from four patients with CRC, as well as in the serum of three noncancer controls. Our findings revealed that there were more reactive IgM AAbs than IgG in both the cell supernatant and corresponding serum, with a difference of approximately 3-5 times. Immunoglobulin G was predominant in the serum, while IgM was more abundant in the cell supernatant. We identified a range of AAbs present in both the supernatant and the corresponding serum, numbering between 432 and 780, with an average of 53.3% shared. Only 4.7% (n = 23) and 0.2% (n = 2) of reactive antigens for IgG and IgM AAbs, respectively, were specific to CRC. Ultimately, we compiled a list of 19 IgG AAb targets as potential tumor-specific AAb candidates. Autoantibodies against one of the top candidates, p15INK4b-related sequence/regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A), were significantly elevated in 53 CRC patients compared to 119 controls (p < 0.0001). The project revealed that tissue-derived IgG AAbs, rather than IgM, are the primary source of tumor-specific AAbs in peripheral blood. It also identified potential tumor-specific AAbs that could be applied for noninvasive screening of CRC.

Inhibition of the rapamycin-insensitive mTORC1 /4E-BP1 axis attenuates TGF-ß1-induced fibrotic response in human Tenon's fibroblasts.

Subconjunctival fibrosis is the major cause of failure in both conventional and modern minimally invasive glaucoma surgeries (MIGSs) with subconjunctival filtration. The search for safe and effective anti-fibrotic agents is critical for improving long-term surgical outcomes. In this study, we investigated the effect of inhibiting the rapamycin-insensitive mTORC1/4E-BP1 axis on the transforming growth factor-beta 1(TGF-ß1)-induced fibrotic responses in human Tenon's fibroblasts (HTFs), as well as in a rat model of glaucoma filtration surgery (GFS). Primary cultured HTFs were treated with 3 ng/mL TGF-ß1 for 24 h, followed by treatment with 10 µM CZ415 for additional 24 h. Rapamycin (10 µM) was utilized as a control for mTORC1/4E-BP1 signaling insensitivity. The expression levels of fibrosis-associated molecules were measured using quantitative real-time PCR, Western blotting, and immunofluorescence analysis. Cell migration was assessed through the scratch wound assay. Additionally, a rat model of GFS was employed to evaluate the anti-fibrotic effect of CZ415 in vivo. Our findings indicated that both rapamycin and CZ415 treatment significantly reduced the TGF-ß1-induced cell proliferation, migration, and the expression of pro-fibrotic factors in HTFs. CZ415 also more effectively inhibited TGF-ß1-mediated collagen synthesis in HTFs compared to rapamycin. Activation of mTORC1/4E-BP signaling following TGF-ß1 exposure was highly suppressed by CZ415 but was only modestly inhibited by rapamycin. Furthermore, CZ415 was found to decrease subconjunctival collagen deposition in rats post GFS. Our results suggest that rapamycin-insensitive mTORC1/4E-BP1 signaling plays a critical role in TGF-ß1-driven collagen synthesis in HTFs. This study demonstrated that inhibition of the mTORC1/4E-BP1 axis offers superior anti-fibrotic efficacy compared to rapamycin and represents a promising target for improving the success rate of both traditional and modern GFSs.

Clinical and genome-wide association analysis of chemoradiation-induced hearing loss in nasopharyngeal carcinoma.

Chemoradiation-induced hearing loss (CRIHL) is one of the most devasting side effects for nasopharyngeal carcinoma (NPC) patients, which seriously affects survivors' long-term quality of life. However, few studies have comprehensively characterized the risk factors for CRIHL. In this study, we found that age at diagnosis, tumor stage, and concurrent cisplatin dose were positively associated with chemoradiation-induced hearing loss. We performed a genome-wide association study (GWAS) in 777 NPC patients and identified rs1050851 (within the exon 2 of NFKBIA), a variant with a high deleteriousness score, to be significantly associated with hearing loss risk (HR = 5.46, 95% CI 2.93-10.18, P = 9.51 × 10-08). The risk genotype of rs1050851 was associated with higher NFKBIA expression, which was correlated with lower cellular tolerance to cisplatin. According to permutation-based enrichment analysis, the variants mapping to 149 hereditary deafness genes were significantly enriched among GWAS top signals, which indicated the genetic similarity between hereditary deafness and CRIHL. Pathway analysis suggested that synaptic signaling was involved in the development of CRIHL. Additionally, the risk score integrating genetic and clinical factors can predict the risk of hearing loss with a relatively good performance in the test set. Collectively, this study shed new light on the etiology of chemoradiation-induced hearing loss, which facilitates high-risk individuals' identification for personalized prevention and treatment.

Genomic Landscapes of Epstein-Barr Virus in Pulmonary Lymphoepithelioma-Like Carcinoma.

Epstein-Barr virus (EBV) infection is associated with multiple malignancies, including pulmonary lymphoepithelioma-like carcinoma (pLELC), a particular subtype of primary lung cancer. However, the genomic characteristics of EBV related to pLELC remain unclear. Here, we obtained the whole-genome data set of EBV isolated from 78 pLELC patients and 37 healthy controls using EBV-captured sequencing. Compared with the reference genome (NC_007605), a total of 3,995 variations were detected across pLELC-derived EBV sequences, with the mutational hot spots located in latent genes. Combined with 180 published EBV sequences derived from healthy people in Southern China, we performed a genome-wide association study and identified 32 variations significantly related to pLELC (P < 2.56 × 10-05, Bonferroni correction), with the top signal of single nucleotide polymorphism (SNP) coordinate T7327C (OR = 1.22, P = 2.39 × 10-15) locating in the origin of plasmid replication (OriP). The results of population structure analysis of EBV isolates in East Asian showed the EBV strains derived from pLELC were more similar to those from nasopharyngeal carcinoma (NPC) than other EBV-associated diseases. In addition, typical latency type-II infection were recognized for EBV of pLELC at both transcription and methylation levels. Taken together, we defined the global view of EBV genomic profiles in pLELC patients for the first time, providing new insights to deepening our understanding of this rare EBV-associated primary lung carcinoma. IMPORTANCE Pulmonary lymphoepithelioma-like carcinoma (pLELC) is a rare, distinctive subtype of primary lung cancer closely associated with Epstein-Barr virus (EBV) infection. Here, we gave the first overview of pLELC-derived EBV at the level of genome, methylation and transcription. We obtained the EBV sequences data set from 78 primary pLELC patients, and revealed the sequences diversity across EBV genome and detected variability in known immune epitopes. Genome-wide association analysis combining 217 healthy controls identifies significant variations related to the risk of pLELC. Meanwhile, we characterized the integration landscapes of EBV at the genome-wide level. These results provided new insight for understanding EBV's role in pLELC tumorigenesis.

Peptidome-wide association analysis of Epstein-Barr virus identifies epitope repertoires associated with nasopharyngeal carcinoma.

Human leukocyte antigen (HLA) molecules are essential for presenting Epstein-Barr virus (EBV) antigens and are closely related to nasopharyngeal carcinoma (NPC). This study aims to systematically investigate the association between HLA-bound EBV peptides and NPC risk through in silico HLA-peptide binding prediction. A total of 455 NPC patients and 463 healthy individuals in NPC endemic areas were recruited, and HLA-target sequencing was performed. HLA-peptide binding prediction for EBV, followed by peptidome-wide logistic regression and motif analysis, was applied. Binding affinity changes for EBV peptides carrying high-risk mutations were analyzed. We found that NPC-associated EBV peptides were significantly enriched in immunogenic proteins and core linkage disequilibrium (LD) proteins related to evolution, especially those binding HLA-A alleles (p = 3.10 × 10-4 for immunogenic proteins and p = 8.10 × 10-5 for core LD proteins related to evolution). These peptides were clustered and showed binding motifs of HLA supertypes, among which supertype A02 presented an NPC-risk effect (padj = 3.77 × 10-4 ) and supertype A03 presented an NPC-protective effect (padj = 4.89 × 10-4 ). Moreover, a decreased binding affinity toward risk HLA supertype A02 was observed for the peptide carrying the NPC-risk mutation BNRF1 V1222I (p = 0.0078), and an increased binding affinity toward protective HLA supertype A03 was observed for the peptide carrying the NPC-risk mutation BALF2 I613V (p = 0.022). This study revealed the distinct preference of EBV peptides for binding HLA supertypes, which may contribute to shaping EBV population structure and be involved in NPC development.

The interaction and mediation effects between the host genetic factors and Epstein-Barr virus VCA-IgA in the risk of nasopharyngeal carcinoma.

Previous studies have demonstrated strong associations between host genetic factors and Epstein-Barr virus (EBV) VCA-IgA with the risk of nasopharyngeal carcinoma (NPC). However, the specific interplay between host genetics and EBV VCA-IgA on NPC risk is not well understood. In this two-stage case-control study (N = 4804), we utilized interaction and mediation analysis to investigate the interplay between host genetics (genome-wide association study-derived polygenic risk score [PRS]) and EBV VCA-IgA antibody level in the NPC risk. We employed a four-way decomposition analysis to assess the extent to which the genetic effect on NPC risk is mediated by or interacts with EBV VCA-IgA. We consistently found a significant interaction between the PRS and EBV VCA-IgA on NPC risk (discovery population: synergy index [SI] = 2.39, 95% confidence interval [CI] = 1.85-3.10; replication population: SI = 3.10, 95% CI = 2.17-4.44; all pinteraction < 0.001). Moreover, the genetic variants included in the PRS demonstrated similar interactions with EBV VCA-IgA antibody. We also observed an obvious dose-response relationship between the PRS and EBV VCA-IgA antibody on NPC risk (all ptrend < 0.001). Furthermore, our decomposition analysis revealed that a substantial proportion (approximately 90%) of the genetic effects on NPC risk could be attributed to host genetic-EBV interaction, while the risk effects mediated by EBV VCA-IgA antibody were weak and statistically insignificant. Our study provides compelling evidence for an interaction between host genetics and EBV VCA-IgA antibody in the development of NPC. These findings emphasize the importance of implementing measures to control EBV infection as a crucial strategy for effectively preventing NPC, particularly in individuals at high genetic risk.

The Patterns of Visual Field Defects in Primary Angle-Closure Glaucoma Compared to High-Tension Glaucoma and Normal-Tension Glaucoma.

INTRODUCTION: The aim of this study was to compare the patterns of visual field (VF) defects in primary angle-closure glaucoma (PACG) to control groups of eyes with high-tension glaucoma (HTG) and normal-tension glaucoma (NTG). METHODS: Forty-eight eyes with PACG were enrolled, and control eyes with HTG and NTG matched for age, sex, and mean deviation of VF defect were selected. VF tests were performed using the 24-2 program of the Humphrey field analyzer. VF defects were classified into six patterns with the Ocular Hypertension Treatment Study classification system and were categorized into three stages (early, moderate, and advanced). Each hemifield was divided into five regions according to the Glaucoma Hemifield Test (GHT). The mean total deviation (TD) of each GHT region was calculated. RESULTS: Compared with HTG and NTG groups, the partial arcuate VF defects were more common in the PACG group. In the PACG group, the nasal GHT region in the inferior hemifield had the worst mean TD (-8.48 ± 8.62 dB), followed by the arcuate 1 (-7.81 ± 7.91 dB), arcuate 2 (-7.46 ± 7.43 dB), paracentral (-7.19 ± 7.98 dB), and central (-5.14 ± 6.24 dB) regions; the mean TD of the central region was significantly better than those for all other regions (all p < 0.05). A similar trend was observed in the superior hemifield in the PACG group but not the VF hemifields of the HTG and NTG groups. CONCLUSION: Patterns of VF defect in PACG patients differ from those with HTG and NTG. This discrepancy might be due to the differences in the pathogenic mechanisms of glaucomatous optic neuropathy.

Genomic landscape of Epstein-Barr virus in familial nasopharyngeal carcinoma.

To better understand the genomic characteristics of Epstein-Barr virus (EBV) in familial nasopharyngeal carcinoma (NPC), we sequenced the EBV genomes by whole-genome capture in 38 unrelated patients with NPC family history in first-degree relatives and 47 healthy controls, including 13 with family history and 34 without. Compared with type 1 reference genome, mutation hotspots were observed in the latent gene regions of EBV in familial NPC cases. Population structure analysis showed that one cluster has a higher frequency in familial cases than in controls (OR=5.33, 95 % CI 2.50-11.33, P=1.42×10-5), and similar population structure composition was observed among familial and sporadic NPC cases in high-endemic areas. By genome-wide association analysis, four variants were found to be significantly associated with familial NPC. Consistent results were observed in the meta-analysis integrating two published case-control EBV sequencing studies in NPC high-endemic areas. High-risk haplotypes of EBV composed of 34 variants were associated with familial NPC risk (OR=13.85, 95 % CI 4.13-46.44, P=2.06×10-5), and higher frequency was observed in healthy blood-relative controls with NPC family history (9/13, 69.23 %) than those without family history (16/34, 47.06%). This study suggested the potential contribution of EBV high-risk subtypes to familial aggregation of NPC.

Mental health and self-management in glaucoma patients during the COVID-19 pandemic: a cross-sectional study in China.

PURPOSE: To investigate mental health and self-management in glaucoma patients during the COVID-19 pandemic in China and to describe the correlation between anxiety, depression, glaucoma, and self-management. METHODS: This cross-sectional study included glaucoma patients who enrolled in the case management platform and completed an online survey. The survey included the Generalized Anxiety Disorder (GAD-7), Patient Health Questionnaire (PHQ-9), and Glaucoma Self-Management Questionnaire (GSMQ). RESULTS: Among 109 glaucoma patients enrolled in this study, the proportions of patients suffering from depression and anxiety during the COVID-19 pandemic were 26.6% and 20.2%, respectively. A statistical association was found between depression and self-management behaviour in these glaucoma patients (r = -0.247, P = 0.010). The self-management scores in patients less than 35 years were lower than those in patients aged 35-60 years (P = 0.046). The scores of body function promotion in men were lower than those in women (P = 0.048). Patients with primary school education and below had lower scores in the medical management of disease than those with either middle school education (P = 0.032) or community college education or higher (P = 0.022). CONCLUSION: A high proportion of anxiety and depression was found in glaucoma patients during the COVID-19 pandemic. Better self-management behaviour was associated with stronger mental health regulation. It is important to help glaucoma patients improve their self-management behaviours, especially for young men with low educational levels.

Detecting eyes with high risk of angle closure among apparently normal eyes by anterior segment OCT: a health examination center-based model.

BACKGROUND: The main barriers keeping individuals with high-risk of angle closure from seeking eye-care service are the absence of both disease awareness and convenient and low-cost access to the ocular health care system. Present study described the efficacy of a health examination center-based screening model designed to detect eyes with high risk of angle closure (HRAC) among healthy individuals using anterior segment optical coherence tomography (AS-OCT). METHODS: From March 1 to April 30, 2017, consecutive individuals aged ≥ 40 years undergoing routine physical examinations at a health examination center were invited to enroll. Presenting visual acuity (PVA), intraocular pressure (IOP) measurement, non-mydriatic fundus photography and AS-OCT were performed by three trained nurses. Participants with PVA < 6/12 in the better-seeing eye, IOP ≥ 24 mmHg, or abnormal fundus photography in either eye were referred to the outpatient clinic, but not included in the analysis. Eyes with HRAC were defined as having trabecular-iris angle < 12 degrees in ≥ 3 quadrants. Configuration of the iris was classified into flat, bowing, bombe, thick peripheral iris and mixed mechanism. RESULTS: Altogether, 991 participants (77.3%) with readable OCT images (mean age 55.5 ± 9.0 years; 58.4% men) were included. HRAC was diagnosed in 78 eyes (7.9%, 61.3 ± 8.2 years, 41.0% men). The prevalence of HRAC increased with age (p < 0.001) and was much higher among women (11.2%) than men (5.5%) (p = 0.001). The mixed mechanism iris configuration was most common among eyes with HRAC (37/78, 47.4%). CONCLUSION: HRAC is prevalent among asymptomatic Chinese adults undergoing routine health screening. Health examination center-based eye screening with AS-OCT administered by non-specialists may be a good model to screen narrow angles in the population at large.

A Novel and Reversible Experimental Primate Ocular Hypertension Model: Blocking Schlemm's Canal.

INTRODUCTION: The purpose of this study was to establish a novel and reversible experimental ocular hypertension primate model by blocking Schlemm's canal. METHODS: A model was induced in adult cynomolgus monkeys (n=4) by blocking Schlemm's canal with an inserted microcatheter (200 µm diameter); it was removed 6 weeks later from one monkey to reverse the elevated intraocular hypertension. All animals were monitored for 11 months; weekly measurements of intraocular pressure and biweekly examinations with spectral domain optical coherence tomography and disc photography were performed. Histopathology of the eye and retinal ganglion cell counts were completed at the end of the study. RESULTS: The intraocular pressure of the blocked eyes was significantly higher than that of the contralateral eyes at 1 month after the blockage (P <0.001); the mean intraocular pressure was similar to the contralateral eye from 1 week to 11 months after the microcatheter was removed in monkey A (P=0.170). The mean intraocular pressure of the blocked eyes of the remaining monkeys was significantly higher than that of the contralateral eyes throughout the follow-up period (P <0.001). The fundus imaging showed decreases in the retinal nerve fibre layer thickness, and localised defects were observed in two blocked eyes. A histological examination demonstrated that the number of retinal ganglion cells in blocked eyes of monkeys A, B, and C was significantly decreased compared with the control. CONCLUSION: Schlemm's canal blockage alone in the monkey model produces sustained elevation of intraocular pressure, which present a novel animal model for studying the pathogenesis of glaucoma.

Identification of peripheral anterior synechia with anterior segment optical coherence tomography.

PURPOSE: To generate a model that evaluates the presence and extent of peripheral anterior synechia (PAS) based on anterior segment optical coherence tomography (AS-OCT). METHODS: The extent of PAS involvement in the eyes of patients with angle closure was assessed by indentation gonioscopy, and the part of non-PAS and PAS were assigned into two groups (NPAS and PAS). Anterior chamber angles were then imaged by AS-OCT with light-emitting diode (LED) irradiation directly into the pupils, leading to pupillary constriction and increasing anterior chamber angle width. Parameters including the angle opening distance at 750 µm anterior to the scleral spur (AOD750) and trabecular-iris space area at 750 µm anterior to the scleral spur (TISA750) were then obtained. The differences before and after LED irradiation of AOD750 and TISA750 were calculated and used to generate a PAS model based on binary logistic regression. Validation data were then tested. RESULTS: A total of 258 AS-OCT images in 14 eyes were assigned to the modeling data, and 120 were assigned to the validation data. There were no differences in AOD750 and TISA750 in the dark between NPAS and PAS (PAOD750 = 0.258, PTISA750 = 0.486), whereas after LED light exposure, TISA750light was larger in NPAS than in PAS (P = 0.047). The light-dark differences of both parameters showed significant differences between the two groups (PAOD750dif = 0.019, PTISA750dif < 0.001). The area under the curve of the model performance was 0.841, and the overall correct rate was 80.8% based on the validation data. CONCLUSIONS: The present study demonstrates that the AS-OCT-based PAS model could be useful in the identifying of the presence of synechial angle closure and evaluating the extent of PAS in a single eye.

Genome-wide association study identifies genetic susceptibility loci and pathways of radiation-induced acute oral mucositis.

BACKGROUND: Radiation-induced oral mucositis (OM) is one of the most common acute complications for head and neck cancer. Severe OM is associated with radiation treatment breaks, which harms successful tumor management. Radiogenomics studies have indicated that genetic variants are associated with adverse effects of radiotherapy. METHODS: A large-scale genome-wide scan was performed in 1467 nasopharyngeal carcinoma patients, including 753 treated with 2D-CRT from Genetic Architecture of the Radiotherapy Toxicity and Prognosis (GARTP) cohort and 714 treated with IMRT (192 from the GARTP and 522 newly recruited). Subgroup analysis by radiotherapy technique was further performed in the top associations. We also performed physical and regulatory mapping of the risk loci and gene set enrichment analysis of the candidate target genes. RESULTS: We identified 50 associated genomic loci and 64 genes via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping and gene-based analysis, and 36 of these loci were replicated in subgroup analysis. Interestingly, one of the top loci located in TNKS, a gene relevant to radiation toxicity, was associated with increased OM risk with OR = 3.72 of the lead SNP rs117157809 (95% CI 2.10-6.57; P = 6.33 × 10-6). Gene set analyses showed that the 64 candidate target genes were enriched in the biological processes of regulating telomere capping and maintenance and telomerase activity (Top P = 7.73 × 10-7). CONCLUSIONS: These results enhance the biological understanding of radiotherapy toxicity. The association signals enriched in telomere function regulation implicate the potential underlying mechanism and warrant further functional investigation and potential individual radiotherapy applications.

Diurnal fluctuations of macular vessel density in patients with primary open-angle glaucoma and healthy subjects.

PURPOSE: To investigate the diurnal fluctuations of macular vessel density (VD) in primary open-angle glaucoma (POAG) and healthy subjects using optical coherence tomography angiography. METHODS: A total of 22 POAG eyes and 15 healthy eyes were included in this study. Macular VD, intraocular pressure, and blood pressure were repeatedly measured from 8 AM to 8 PM at a 2-h interval on a single day. MAIN OUTCOME MEASURES: the macular VD measurements, their diurnal fluctuations, including the difference between their maximal and minimal value (max-min) and their coefficient of variation (CV) in superficial capillary plexus (SCP) and deep capillary plexus (DCP). The mixed-effects model was performed to compare the fluctuations between groups. RESULTS: After adjusted age, the diurnal fluctuations of macular VD in SCP and DCP were significantly higher in POAG eyes compared with healthy subjects (max-min: 6.65 ± 3.54%, 3.92 ± 3.63%, respectively; p = 0.037 and CV: 0.06 ± 0.03, 0.04 ± 0.03, respectively; p = 0.003). The fovea VD in DCP of POAG eyes was higher than in healthy subjects (31.52 ± 4.68% and 25.71 ± 3.70%, p = 0.009). However, there was no significant difference between the fovea VD in SCP in two groups (20.97 ± 4.75% and 19.29 ± 4.35%, p = 0.670). The diurnal macular superficial VD measured in most of the participants was lower in the morning. CONCLUSIONS: Whether it is a max-min or a CV assessment method, the POAG eyes had more significant diurnal fluctuations of macular VD than healthy controls, suggesting impaired vascular autoregulation in POAG eyes.

Genomic Characterization of Esophageal Squamous Cell Carcinoma Reveals Critical Genes Underlying Tumorigenesis and Poor Prognosis.

The genetic mechanisms underlying the poor prognosis of esophageal squamous cell carcinoma (ESCC) are not well understood. Here, we report somatic mutations found in ESCC from sequencing 10 whole-genome and 57 whole-exome matched tumor-normal sample pairs. Among the identified genes, we characterized mutations in VANGL1 and showed that they accelerated cell growth in vitro. We also found that five other genes, including three coding genes (SHANK2, MYBL2, FADD) and two non-coding genes (miR-4707-5p, PCAT1), were involved in somatic copy-number alterations (SCNAs) or structural variants (SVs). A survival analysis based on the expression profiles of 321 individuals with ESCC indicated that these genes were significantly associated with poorer survival. Subsequently, we performed functional studies, which showed that miR-4707-5p and MYBL2 promoted proliferation and metastasis. Together, our results shed light on somatic mutations and genomic events that contribute to ESCC tumorigenesis and prognosis and might suggest therapeutic targets.

Integrating opportunistic glaucoma screening into general health examinations in China: A pilot study.

IMPORTANCE: Under-detection and late diagnosis are major causes of glaucoma-related visual impairment. Cost-effective opportunistic glaucoma screening is of great interest in the early identification and prevention of glaucoma. BACKGROUND: To describe the results of a health examination centre-based opportunistic glaucoma screening and referral model. DESIGN: This single centre cross-sectional study was conducted in a health examination centre affiliated to a tertiary hospital in Shenyang, northeastern China. PARTICIPANTS: From 21 March to 30 September 2016, 14 367 individuals aged ≥ 30 years undergoing routine physical examinations were invited for this glaucoma screening. METHODS: Presenting visual acuity, non-contact pneumotonometry and non-mydriatic fundus photography were evaluated. Fundus photographs were classified as non-glaucoma, possible, probable and definitive glaucoma. Participants with probable and definite glaucomatous discs or intraocular pressure ≥ 24 mmHg were referred for definitive examinations. MAIN OUTCOME MEASURES: Detection rate of glaucoma suspects and ocular hypertension (OHT). Cost to identify a single case with suspected and diagnosed glaucoma was also calculated. RESULTS: Altogether, 277 glaucoma suspects and 327 ocular hypertension suspects were identified. Among 190 participants with probable/definite glaucomatous discs, 93 (48.9%) accepted further examination. Among these, 78 were diagnosed as glaucoma, seven as suspects and eight were excluded. Only 98 ocular hypertension suspects (30.0%) accepted further examinations: eight had primary angle closure and 23 had confirmed ocular hypertension. The cost to identify a single glaucoma suspect and definite glaucoma case were US$135 and US$857, respectively. CONCLUSIONS AND RELEVANCE: This novel screening model provides opportunities to improve glaucoma detection at low cost. Interventions to improve follow-up are needed.

Tumor Cell Content and RNA Integrity of Surgical Tissues from Different Types of Tumors and Its Correlation with Ex Vivo and In Vivo Ischemia.

BACKGROUND: Tissues from tumor patients are important resources for promoting cancer research, and therefore many biobanks have been established to collect tumor tissues; however, the quality of tumor tissues after surgical resection has not been well documented. METHODS: A total of 896 cases of tissues from 12 types of tumors were chosen for this study. First, histopathological examination was conducted to evaluate the tumor cell content; second, microchip electrophoresis was used to determine the RNA integrity number (RIN) in 466 cases of tissues with a tumor cell content ≥ 75%; and, finally, a correlation test was used to analyze the effect of ischemia on RNA integrity in 384 cases of tissues with a recorded ischemia time. RESULTS: Tumor tissues from 12 different organs had different tumor cell contents and RNA integrity. The liver had the highest percentage (69.7%) of tissue samples with a tumor cell content ≥ 75%, and the highest percentage (96%) of samples with an RIN ≥ 7. RNA integrity was not correlated with limited ex vivo ischemia time (5-60 min) in any of the 12 types of tumors. In contrast, a significant correlation with in vivo ischemia time was observed in several types of tumors. CONCLUSIONS: Not every sample of excised tumor tissue has a sufficient amount of tumor cells and enough RNA integrity. In vivo ischemia has a more significant influence on RNA integrity, and tumor tissues have different tolerances to pre-analytical variables. Those conducting translational research should pay attention to pre-analytical variables when collecting and utilizing tumor tissues.

SHMT1 C1420T polymorphism contributes to the risk of non-Hodgkin lymphoma: evidence from 7309 patients.

BACKGROUND: Serine hydroxymethyltransferase 1 (SHMT1) is a key enzyme in the folate metabolic pathway that plays an important role in biosynthesis by providing one carbon unit. SHMT1 C1420T may lead to the abnormal biosynthesis involved in DNA synthesis and methylation, and it may eventually increase cancer susceptibility. Many epidemiologic studies have explored the association between C1420T polymorphism and the risk of non-Hodgkin lymphoma (NHL), but the results have been contradictory. Therefore, we performed this meta-analysis to evaluate the relationship. METHODS: The meta-analyses were conducted to evaluate the effect of SHMT1 C1420T polymorphism on NHL risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to measure the strength of the association. RESULTS: Eight studies encompassing 3232 cases and 4077 controls were included. A statistically significant association was found between SHMT1 C1420T polymorphism and NHL risk under the allelic comparison (T vs. C: OR = 1.09, 95% CI 1.01-1.17); a borderline association was found between SHMT1 C1420T polymorphism and NHL risk under the homozygote model (TT vs. CC: OR = 1.18, 95% CI 1.00-1.39) and the dominant model (CT+TT vs. CC: OR = 1.10, 95% CI 1.00-1.21). CONCLUSION: SHMT1 C1420T polymorphism may be associated with NHL risk, which needs to be validated in large, prospective studies.