Personality Traits and Tinnitus Distress: Results Based on Patients with Tinnitus in China.

Background: Due to the socio-cultural differences between China and other countries, which may affect the development of an individual's personality and behavior, it is necessary to explore the relationship between personality traits and tinnitus distress in the context of China's socio-cultural background. Methods: The Tinnitus Handicap Inventory and the Eysenck Personality Questionnaire Short Scale Chinese version were used to explore the influence of personality traits on tinnitus distress in Chinese patients with tinnitus. Results: The results were not entirely consistent with previous studies from other countries. First, extroversion was significantly higher in patients with bothersome tinnitus, both in acute and chronic conditions. Second, the personality traits that affected the patients with bothersome tinnitus were different in different conditions. Finally, the tridimensional personality structure, high psychoticism / normal extroversion / normal neuroticism, was significantly higher in people with bothersome tinnitus. Furthermore, the difference became more obvious with a prolonged disease course. Conclusions: This study suggested that the relationship between personality traits and tinnitus distress in Chinese patients with tinnitus was not the same as in other countries. "High psychoticism / normal extroversion / normal neuroticism" may be a risk factor for chronic bothersome tinnitus in China.

Deficiency of WTAP in islet beta cells results in beta cell failure and diabetes in mice.

AIMS/HYPOTHESIS: N6-methyladenosine (m6A) mRNA methylation and m6A-related proteins (methyltransferase-like 3 [METTL3], methyltransferase-like 14 [METTL14] and YTH domain containing 1 [YTHDC1]) have been shown to regulate islet beta cell function and the pathogenesis of diabetes. However, whether Wilms' tumour 1-associating protein (WTAP), a key regulator of the m6A RNA methyltransferase complex, regulates islet beta cell failure during pathogenesis of diabetes is largely unknown. The present study aimed to investigate the role of WTAP in the regulation of islet beta cell failure and diabetes. METHODS: Islet beta cell-specific Wtap-knockout and beta cell-specific Mettl3-overexpressing mice were generated for this study. Blood glucose, glucose tolerance, serum insulin, glucose-stimulated insulin secretion (both in vivo and in vitro), insulin levels, glucagon levels and beta cell apoptosis were examined. RNA-seq and MeRIP-seq were performed, and the data were well analysed. RESULTS: WTAP was downregulated in islet beta cells in type 2 diabetes, due to lipotoxicity and chronic inflammation, and islet beta cell-specific deletion of Wtap (Wtap-betaKO) induced beta cell failure and diabetes. Wtap-betaKO mice showed severe hyperglycaemia (above 20 mmol/l [360 mg/dl]) from 8 weeks of age onwards. Mechanistically, WTAP deficiency decreased m6A mRNA modification and reduced the expression of islet beta cell-specific transcription factors and insulin secretion-related genes by reducing METTL3 protein levels. Islet beta cell-specific overexpression of Mettl3 partially reversed the abnormalities observed in Wtap-betaKO mice. CONCLUSIONS/INTERPRETATION: WTAP plays a key role in maintaining beta cell function by regulating m6A mRNA modification depending on METTL3, and the downregulation of WTAP leads to beta cell failure and diabetes. DATA AVAILABILITY: The RNA-seq and MeRIP-seq datasets generated during the current study are available in the Gene Expression Omnibus database repository ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE215156 ; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE215360 ).

Differentiation of true progression from treatment response in high-grade glioma treated with chemoradiation: a comparison study of 3D-APTW and 3D-PcASL imaging and DWI.

PURPOSE: To assess and compare the diagnostic performance of 3D amide proton-transfer-weighted (3D-APTW) imaging, 3D pseudocontinuous arterial spin-labeling (3D-PcASL) imaging, and diffusion-weighted imaging in distinguishing true progression (TP) from treatment response (TR) in posttreatment malignant glioma patients. MATERIALS AND METHODS: Forty-eight patients with suspected tumor recurrence were prospectively enrolled. Histological or longitudinal routine MRI follow-up over six months was assessed to confirm lesion type. The apparent diffusion coefficient (ADC), relative APTWmax (rAPTW), and relative CBFmax values (rCBF) were measured in lesions with enhancing regions on post-gadolinium T1 -weighted MRI. MRI parameters between the TP and TR groups were compared using Student's t tests. In addition, a receiver operating characteristic (ROC) curve was constructed, and the area under the ROC curve (AUC) was calculated to assess the differentiation diagnostic performance of each parameter. RESULTS: The TP group showed a significantly higher rAPTW and rCBF than the TR group; the AUCs of rAPTW and rCBF to distinguish between TP and TR were 0.911 (with sensitivity of 90.3% and specificity of 82.4%) and 0.852 (with sensitivity of 80.6% and specificity of 82.4%), respectively. By adding the rAPTW values to rCBF values, the diagnostic ability was improved from 0.852 to 0.951. ADC showed no significant differences between the TP and TR groups, with an AUC lower than 0.70. CONCLUSION: Both 3D-PcASL and 3D-APTW imaging could distinguish TP from TR, and 3D-APTW had a better diagnostic performance. Combining the rAPTW values and rCBF values achieved a better diagnostic performance.

A CTCF-Binding Element and Histone Deacetylation Cooperatively Maintain Chromatin Loops, Linking to Long-Range Gene Regulation in Cancer Genomes.

BACKGROUND: Genes spanning long chromosomal domains are coordinately regulated in human genome, which contribute to global gene dysregulation and carcinogenesis in cancer. It has been noticed that epigenetic modification and chromatin architecture may participate in the regulation process. However, the regulation patterns and functional elements of long-range gene regulation are unclear. METHODS: Based on the clinical transcriptome data from different tumor sets, a novel expressional correlation analysis pipeline was performed to classify the co-regulated regions and subsets of intercorrelated regions. The GLAM2 program was used to predict conserved DNA elements that enriched in regions. Two conserved elements were selected to delete in Ishikawa and HeLa cells by CRISPR-Cas9. SAHA treatment and HDAC knockdown were used to change the histone acetylation status. Using qPCR, MTT, and scratch healing assay, we evaluate the effect on gene expression and cancer cell phenotype. By DNA pull-down and ChIP, the element-binding proteins were testified. 3C and 3D-FISH were performed to depict the alteration in chromatin architecture. RESULTS: In multiple cancer genomes, we classified subsets of coordinately regulated regions (sub-CRRs) that possibly shared the same regulatory mechanisms and exhibited similar expression patterns. A new conserved DNA element (CRE30) was enriched in sub-CRRs and associated with cancer patient survival. CRE30 could restrict gene regulation in sub-CRRs and affect cancer cell phenotypes. DNA pull-down showed that multiple proteins including CTCF were recruited on the CRE30 locus, and ChIP assay confirmed the CTCF-binding signals. Subsequent results uncovered that as an essential element, CRE30 maintained chromatin loops and mediated a compact chromatin architecture. Moreover, we found that blocking global histone deacetylation induced chromatin loop disruption and CTCF dropping in the region containing CRE30, linked to promoted gene regulation. Additionally, similar effects were observed with CRE30 deletion in another locus of chromosome 8. CONCLUSIONS: Our research clarified a new functional element that recruits CTCF and collaborates with histone deacetylation to maintain high-order chromatin organizations, linking to long-range gene regulation in cancer genomes. The findings highlight a close relationship among conserved DNA element, epigenetic modification, and chromatin architecture in long-range gene regulation process.

Detection and Treatment of Persistent Mullerian Duct Syndrome With Transverse Testicular Ectopia.

The coexistence of persistent Mullerian duct syndrome (PMDS) with transverse testicular ectopia (TTE) is extremely rare. Due to a lack of distinctive clinical features in the early stages, PMDS coexists with TTE is usuallydiagnosed when patients are examined for other diseases,including cryptorchidism and inguinal hernia. We present a case of a 51-year-old man who presented with a recurrent left indirect inguinal hernia for 2 years and right congenital cryptorchidism. The patient was diagnosed as PMDS with TTE by preoperative magnetic resonance imaging and underwent laparoscopic resection of the right transverse ectopic testis and Mullerian duct residues.

Genome-Wide DNA Methylation Analysis Reveals Epigenetic Pattern of SH2B1 in Chinese Monozygotic Twins Discordant for Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Aberrant DNA methylation has been observed in ASD but the mechanisms remain largely unknown. Here, we employed discordant monozygotic twins to investigate the contribution of DNA methylation to ASD etiology. Genome-wide DNA methylation analysis was performed using samples obtained from five pairs of ASD-discordant monozygotic twins, which revealed a total of 2,397 differentially methylated genes. Further, such gene list was annotated with Kyoto Encyclopedia of Genes and Genomes and demonstrated predominant activation of neurotrophin signaling pathway in ASD-discordant monozygotic twins. The methylation of SH2B1 gene was further confirmed in the ASD-discordant, ASD-concordant monozygotic twins, and a set of 30 pairs of sporadic case-control by bisulfite-pyrosequencing. The results showed that there was a greater DNA methylation difference in ASD-discordant monozygotic twins than ASD-concordant monozygotic twins. Further, verification of the Chr.16:28856743 of SH2B1 showed significant differences in DNA methylation between case and control. These results suggest abnormal methylation of SH2B1 is associated with ASD etiology. Our data suggest that it might be worthwhile to further explore the functions of SH2B1 and related genes of neurotrophin signaling pathway in ASD.

Discovery of potential urine-accessible metabolite biomarkers associated with muscle disease and corticosteroid response in the mdx mouse model for Duchenne.

Urine is increasingly being considered as a source of biomarker development in Duchenne Muscular Dystrophy (DMD), a severe, life-limiting disorder that affects approximately 1 in 4500 boys. In this study, we considered the mdx mice-a murine model of DMD-to discover biomarkers of disease, as well as pharmacodynamic biomarkers responsive to prednisolone, a corticosteroid commonly used to treat DMD. Longitudinal urine samples were analyzed from male age-matched mdx and wild-type mice randomized to prednisolone or vehicle control via liquid chromatography tandem mass spectrometry. A large number of metabolites (869 out of 6,334) were found to be significantly different between mdx and wild-type mice at baseline (Bonferroni-adjusted p-value < 0.05), thus being associated with disease status. These included a metabolite with m/z = 357 and creatine, which were also reported in a previous human study looking at serum. Novel observations in this study included peaks identified as biliverdin and hypusine. These four metabolites were significantly higher at baseline in the urine of mdx mice compared to wild-type, and significantly changed their levels over time after baseline. Creatine and biliverdin levels were also different between treated and control groups, but for creatine this may have been driven by an imbalance at baseline. In conclusion, our study reports a number of biomarkers, both known and novel, which may be related to either the mechanisms of muscle injury in DMD or prednisolone treatment.

Metabolomic Analysis of Liver Tissues for Characterization of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) causes more than half a million annual deaths worldwide. Understanding the mechanisms contributing to HCC development is highly desirable for improved surveillance, diagnosis, and treatment. Liver tissue metabolomics has the potential to reflect the physiological changes behind HCC development. Also, it allows identification of biomarker candidates for future evaluation in biofluids and investigation of racial disparities in HCC. Tumor and nontumor tissues from 40 patients were analyzed by both gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) platforms to increase the metabolome coverage. The levels of the metabolites extracted from solid liver tissue of the HCC area and adjacent non-HCC area were compared. Among the analytes detected by GC-MS and LC-MS with significant alterations, 18 were selected based on biological relevance and confirmed metabolite identification. These metabolites belong to TCA cycle, glycolysis, purines, and lipid metabolism and have been previously reported in liver metabolomic studies where high correlation with HCC progression is implied. We demonstrated that metabolites related to HCC pathogenesis can be identified through liver tissue metabolomic analysis. Additionally, this study has enabled us to identify race-specific metabolites associated with HCC.

Lobaplatin-based regimens outperform cisplatin for metastatic breast cancer after anthracyclines and taxanes treatment.

The goal of this study was to assess the antitumor efficacy and safety of lobaplatin-based regimens as the second line of treatment in patients with metastatic breast cancer (MBC) resistant to anthracyclines and taxanes, compared with that of cisplatin-based regimens. During August 2012 to April 2015, 87 patients who received lobaplatin-based regimens or cisplatin-based regimens were included. Medical records of the patients noted that lobaplatin (30 mg/m2) or cisplatin (25 mg/m2), combined with another chemotherapeutic agent such as Gemcitabine (1000 mg/m2) or Vinorelbine (25 mg/m2), was intravenously given to the patients on a basis of twenty-one days as one treatment cycle. All the patients were followed until August 2017. The endpoint of this study was progression-free survival (PFS), overall survival (OS), and estimated objective response rate (RR). Safety and drug tolerability data were also obtained. Lobaplatin-based regimens prolonged PFS compared to cisplatin-based regimens (median 13.2 vs 4.7 months, hazard ratio = 0.37, 95% confidence intervals: 0.21-0.67, P = .0007), while OS was not significantly different between the two groups (hazard ratio = 0.72, 95% confidence intervals: 0.40-1.30, P = .2767), as was objective RR (37.8% vs 33.4%, x2 = 0.19, P = .6653). Nausea/vomiting and renal injury were more frequent with cisplatin-based regimens. Our results show that lobaplatin-based regimens are superior to cisplatin in terms of efficacy and are better tolerated.

INDEED: R package for network based differential expression analysis.

With recent advancement of omics technologies, fueled by decreased cost and increased number of available datasets, computational methods for differential expression analysis are sought to identify disease-associated biomolecules. Conventional differential expression analysis methods (e.g. student's t-test, ANOVA) focus on assessing mean and variance of biomolecules in each biological group. On the other hand, network-based approaches take into account the interactions between biomolecules in choosing differentially expressed ones. These interactions are typically evaluated by correlation methods that tend to generate over-complicated networks due to many seemingly indirect associations. In this paper, we introduce a new R/Bioconductor package INDEED that allows users to construct a sparse network based on partial correlation, and to identify biomolecules that have significant changes both at individual expression and pairwise interaction levels. We applied INDEED for analysis of two omic datasets acquired in a cancer biomarker discovery study to help rank disease-associated biomolecules. We believe biomolecules selected by INDEED lead to improved sensitivity and specificity in detecting disease status compared to those selected by conventional statistical methods. Also, INDEED's framework is amenable to further expansion to integrate networks from multi-omic studies, thereby allowing selection of reliable disease-associated biomolecules or disease biomarkers.

Tracking Functional Tumor Cell Subpopulations of Malignant Glioma by Phasor Fluorescence Lifetime Imaging Microscopy of NADH.

Intra-tumoral heterogeneity is associated with therapeutic resistance of cancer and there exists a need to non-invasively identify functional tumor subpopulations responsible for tumor recurrence. Reduced nicotinamide adenine dinucleotide (NADH) is a metabolic coenzyme essential in cellular respiration. Fluorescence lifetime imaging microscopy (FLIM) of NADH has been demonstrated to be a powerful label-free indicator for inferring metabolic states of living cells. Using FLIM, we identified a significant shift towards longer NADH fluorescence lifetimes, suggesting an increase in the fraction of protein-bound NADH, in the invasive stem-like tumor-initiating cell (STIC) subpopulation relative to the tumor mass-forming cell (TMC) subpopulation of malignant gliomas. By applying our previously studied model to transition glioma from a majority of STIC to a majority of TMC in serum-adherent culture conditions following serial passages, we compared changes in NADH states, cellular respirations (oxidative phosphorylation and glycolysis), EGFR expression, and cell-growth speed over passages. We identified a significant positive correlation between free-NADH fraction and cell growth, which was related to an increase of TMC fraction. In comparison, the increase of EGFR and cellular respirations preceded all these changes. In conclusion, FLIM of NADH provides a non-invasive method to monitor the dynamics of tumor heterogeneity before and after treatment.

Related Factors of Asymmetrical Vein Sign in Acute Middle Cerebral Artery Stroke and Correlation with Clinical Outcome.

OBJECTIVE: The aim of our study was to analyze the related factors of asymmetrical cortical vein sign (ACVS) and asymmetrical medullary vein sign (AMVS) on susceptibility-weighted imaging (SWI) in patients with acute middle cerebral artery (MCA) stroke and whether their presence can be used as an independent predictor for clinical outcome. METHODS: According to the presence of ACVS and AMVS on SWI, 124 patients with acute MCA stroke within 3 days were divided into several different groups. In addition, those patients were also divided into good and poor outcome group by using the modified Rankin Scale at 3 months after stroke. We investigated respectively the differences in magnetic resonance imaging findings and the clinical data among those different groups. RESULTS: The ACVS was demonstrated in 90 of 124 patients. Of the 90 patients, 47 were accompanied with the AMVS. The rest of 34 patients showed no ACVS and AMVS. The infarct size and MCA status showed significant differences among the ACVS+, AMVS+ group; ACVS+, AMVS- group; and ACVS-, AMVS- group (all P < .001). Moreover, the ACVS, AMVS, and MCA occlusion were more common in the poor outcome group (all P< .001). In the multivariate logistic regression, AMVS (P = .027; odds ratio, 2.37; 95% confidence interval, 1.23-8.73) was associated with poor outcome. CONCLUSIONS: The ACVS and AMVS were correlated to the status of MCA steno-occlusion and infarct size, whereas the AMVS was proved to be independently related to the stroke severity and poor outcome rather than the ACVS.

Association of lower serum Brain-derived neurotrophic factor levels with larger infarct volumes in acute ischemic stroke.

OBJECTIVE: Brain-derived neurotrophic factor (BDNF) plays a potential role in stroke recovery, as it promotes plasticity. The aim of this study is to investigate the association between infarct volume using DWI and BDNF at admission in patients with acute ischemic stroke (AIS). METHODS: The study population comprised consecutive patients with an AIS diagnosis who had been referred to our hospital between January 2015 and June 2016. The severity of stroke was evaluated by the National Institutes of Health Stroke Scale (NIHSS) at admission. Infarct volumes indicated by DWI were measured with MIPAV software. The relationship between median DWI infarct volume and serum BDNF level quartiles was evaluated using a semiparametric approach with univariate and multivariate quartile regression analysis. RESULTS: In this study, 270 patients were included and met the study criteria. The median DWI infarct volumes for the serum BDNF level quartiles (lowest to highest) were 10.56, 5.13, 3.75 and 2.43ml. Nonparametric Spearman rank correlation revealed a statistically significant negative correlation between serum BDNF level and DWI infarct volume (r=-0.363; P<0.001). The median DWI infarct volume in the lowest BDNF quartile was significantly larger than those in the upper 3 quartiles (P<0.001). Further, median adjusted DWI infarct volumes (IQR) for each of the BDNF level quartiles were 7.77, 4.56, 3.75, and 2.43ml from lowest to highest quartiles. CONCLUSIONS: Larger stroke infarct volumes using DWI are associated with lower levels of BDNF at admission. Further investigations are suggested to elucidate the role of BDNF as part of a potential neuroprotective strategy.

Weaponizing human EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) for 21st century cancer therapeutics.

De-regulated EFEMP1 gene expression in solid tumors has been widely reported with conflicting roles. We dissected EFEMP1 to identify domains responsible for its cell context-dependent dual functions, with the goal being to construct an EFEMP1-derived tumor-suppressor protein (ETSP) that lacked tumor-promoting function. Exon/intron boundaries of EFEMP1 were used as boundaries of functional modules in constructing EFEMP1 variants, with removal of various module(s), and/or mutating an amino acid residue to convert a weak integrin binding-site into a strong one. A series of in vitro assays on cancerous features, and subcutaneous and intracranial xenograft-formation assays, were carried out for effects from overexpression of wild-type and variant forms of EFEMP1 in two glioma subpopulations characterized as tumor mass-forming cells (TMCs) or stem-like tumor initiating cells (STICs), where EFEMP1 showed cellcontext- dependent dual functions. One of the EFEMP1 variants was identified as the sought-after ETSP, which had a stronger tumor-suppression function in TMCs by targeting EGFR and angiogenesis, and a new tumor-suppression function in STICs by targeting NOTCH signaling and MMP2-mediated cell invasion. Therefore, ETSP may form the basis for further important research to develop a novel cancer therapy to treat many types of cancer by its tumor suppressor effect in the extracellular matrix compartment.

Klotho gene silencing promotes pathology in the mdx mouse model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a lethal muscle disease involving progressive loss of muscle regenerative capacity and increased fibrosis. We tested whether epigenetic silencing of the klotho gene occurs in the mdx mouse model of DMD and whether klotho silencing is an important feature of the disease. Our findings show that klotho undergoes muscle-specific silencing at the acute onset of mdx pathology. Klotho experiences increased methylation of CpG sites in its promoter region, which is associated with gene silencing, and increases in a repressive histone mark, H3K9me2. Expression of a klotho transgene in mdx mice restored their longevity, reduced muscle wasting, improved function and greatly increased the pool of muscle-resident stem cells required for regeneration. Reductions of fibrosis in late, progressive stages of the mdx pathology achieved by transgene expression were paralleled by reduced expression of Wnt target genes (axin-2), transforming growth factor-beta (TGF-ß1) and collagens types 1 and 3, indicating that Klotho inhibition of the profibrotic Wnt/TGFß axis underlies its anti-fibrotic effect in aging, dystrophic muscle. Thus, epigenetic silencing of klotho during muscular dystrophy contributes substantially to lost regenerative capacity and increased fibrosis of dystrophic muscle during late progressive stages of the disease.

Protective effect of Sheng-Nao-Kang decoction on focal cerebral ischemia-reperfusion injury in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Sheng-Nao-Kang decoction (SNK), a modified traditional Chinese medicine (TCM), has been used clinically for the treatment of acute and chronic cerebrovascular related diseases. To evaluate the protective effect of SNK on focal cerebral ischemia-reperfusion (I/R) injury in rats and investigate the underlying mechanisms. MATERIALS AND METHODS: Focal cerebral I/R injury in rats was induced by middle cerebral artery occlusion (MCAO) for 2h followed by reperfusion for 24h. Adult male Sprague-Dawley (SD) rats were randomly divided into six kinds of groups: Sham group; I/R group; SNK-treated groups at doses of 0.7 g/kg, 1.4 g/kg and 2.8 g/kg; and nimodipine (NMP)-treated group. The recoveries of neurological function in rats were estimated by neurological defect scoring and 2,3,5-triphenyltetrazolium chloride (TTC) staining after 24h reperfusion. Various biochemical indexes in serum were assayed by colorimetry, including malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), inducible nitric oxide synthase (iNOS) and total nitric oxide synthase (TNOS). Histological structures of the brain in rats were observed by hematoxylin and eosin (H&E) staining. Immunohistochemistry was performed to detect the caspase-3 protein content in rats. RESULTS: SNK administration significantly reduced the neurological defect scores and lessened the cerebral infarction volume. The treatment of SNK lowered MDA content, up-regulated SOD and GSH-Px levels, down-regulated iNOS and TNOS levels in serum. Furthermore, histological examination indicated that dense neuropil and largely surviving neurons were seen in SNK-treated rats. SNK administration restrained the expression of caspase-3 positive protein significantly. CONCLUSION: The results suggest that SNK demonstrates a strong and ameliorative effect on cerebral I/R damage in rats. The protective mechanisms of SNK are associated with its properties of anti-apoptosis and anti-oxidation as well as regulation of iNOS and TNOS.

Tumor-specific chromosome mis-segregation controls cancer plasticity by maintaining tumor heterogeneity.

Aneuploidy with chromosome instability is a cancer hallmark. We studied chromosome 7 (Chr7) copy number variation (CNV) in gliomas and in primary cultures derived from them. We found tumor heterogeneity with cells having Chr7-CNV commonly occurs in gliomas, with a higher percentage of cells in high-grade gliomas carrying more than 2 copies of Chr7, as compared to low-grade gliomas. Interestingly, all Chr7-aneuploid cell types in the parental culture of established glioma cell lines reappeared in single-cell-derived subcultures. We then characterized the biology of three syngeneic glioma cultures dominated by different Chr7-aneuploid cell types. We found phenotypic divergence for cells following Chr7 mis-segregation, which benefited overall tumor growth in vitro and in vivo. Mathematical modeling suggested the involvement of chromosome instability and interactions among cell subpopulations in restoring the optimal equilibrium of tumor cell types. Both our experimental data and mathematical modeling demonstrated that the complexity of tumor heterogeneity could be enhanced by the existence of chromosomes with structural abnormality, in addition to their mis-segregations. Overall, our findings show, for the first time, the involvement of chromosome instability in maintaining tumor heterogeneity, which underlies the enhanced growth, persistence and treatment resistance of cancers.