Genomic signatures of past and present chromosomal instability in Barrett's esophagus and early esophageal adenocarcinoma.

The progression of precancerous lesions to malignancy is often accompanied by increasing complexity of chromosomal alterations but how these alterations arise is poorly understood. Here we perform haplotype-specific analysis of chromosomal copy-number evolution in the progression of Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) on multiregional whole-genome sequencing data of BE with dysplasia and microscopic EAC foci. We identify distinct patterns of copy-number evolution indicating multigenerational chromosomal instability that is initiated by cell division errors but propagated only after p53 loss. While abnormal mitosis, including whole-genome duplication, underlies chromosomal copy-number changes, segmental alterations display signatures of successive breakage-fusion-bridge cycles and chromothripsis of unstable dicentric chromosomes. Our analysis elucidates how multigenerational chromosomal instability generates copy-number variation in BE cells, precipitates complex alterations including DNA amplifications, and promotes their independent clonal expansion and transformation. In particular, we suggest sloping copy-number variation as a signature of ongoing chromosomal instability that precedes copy-number complexity. These findings suggest copy-number heterogeneity in advanced cancers originates from chromosomal instability in precancerous cells and such instability may be identified from the presence of sloping copy-number variation in bulk sequencing data.

A genetic basis for cancer sex differences revealed in Xp11 translocation renal cell carcinoma.

Xp11 translocation renal cell carcinoma (tRCC) is a female-predominant kidney cancer driven by translocations between the TFE3 gene on chromosome Xp11.2 and partner genes located on either chrX or on autosomes. The rearrangement processes that underlie TFE3 fusions, and whether they are linked to the female sex bias of this cancer, are largely unexplored. Moreover, whether oncogenic TFE3 fusions arise from both the active and inactive X chromosomes in females remains unknown. Here we address these questions by haplotype-specific analyses of whole-genome sequences of 29 tRCC samples from 15 patients and by re-analysis of 145 published tRCC whole-exome sequences. We show that TFE3 fusions universally arise as reciprocal translocations with minimal DNA loss or insertion at paired break ends. Strikingly, we observe a near exact 2:1 female:male ratio in TFE3 fusions arising via X:autosomal translocation (but not via X inversion), which accounts for the female predominance of tRCC. This 2:1 ratio is at least partially attributable to oncogenic fusions involving the inactive X chromosome and is accompanied by partial re-activation of silenced chrX genes on the rearranged chromosome. Our results highlight how somatic alterations involving the X chromosome place unique constraints on tumor initiation and exemplify how genetic rearrangements of the sex chromosomes can underlie cancer sex differences.

Mechanically Strong and Tough Poly(urea-urethane) Thermosets Capable of Being Degraded under Mild Condition.

The development of degradable polymeric materials such as degradable polyurethane or polyurea has been much highlighted for resource conservation and environmental protection. Herein, a facile strategy of constructing mechanically strong and tough poly(urea-urethane) (PUU) thermosets that can be degraded under mild conditions by using triple boron-urethane bonds (TBUB) as cross-linkers is demonstrated. By tailoring the molecular weight of the soft segment of the prepolymers, the mechanical performance can be finely controlled. Based on the cross-linking of TBUB units and hydrogen-binding interactions between TBUB linkages, the as-prepared PUU thermosets have excellent mechanical strength of ≈40.2 MPa and toughness of ≈304.9 MJ m-3 . Typically, the PBUU900 strip can lift a barbell with 60 000 times its own weight, showing excellent load-bearing capacity. Meanwhile, owing to the covalent cross-linking of TBUB units, all the PUU thermosets show initial decomposition temperatures over 290 °C, which are comparable to those of the traditional thermosets. Moreover, the TBUB cross-linked PUU thermosets can be easily degraded in a mild acid solution. The small pieces of the PBUU sample can be fully decomposed in 1 m HCl/THF solution for 3.5 h at room temperature.

Reversible immobilization of laccase onto glycopolymer microspheres via protein-carbohydrate interaction for biodegradation of phenolic compounds.

It is challenging to regenerate enzyme carriers when covalently immobilized enzymes suffered from inactivation during continuous operations. Hence, it is urgent to develop a facile strategy to immobilize enzymes reversibly. Herein, the non-covalent interaction between protein and carbohydrate was used to adsorb and desorb enzymes reversibly. Laccase was immobilized onto glycopolymer microspheres via protein-carbohydrate interaction using lectins as the intermediates. The enzyme loading and immobilization yield were up to 49 mg/g and 77.1% with highly expressed activity of 107.9 U/mg. The immobilized laccase exhibited enhanced pH stability and high activity in catalyzing the biodegradation of paracetamol. During ten successive recoveries, the immobilized laccases could be recycled while maintaining relatively high enzyme activity. The glycopolymer microspheres could be efficiently regenerated by elution with an aqueous solution of mannose or acid for further enzyme immobilization. This glycopolymer microspheres has excellent potential to act as reusable carriers for the non-covalent immobilization of different enzymes.

Cellulose-derived polyols as high-capacity adsorbents for rapid boron and organic pollutants removal from water.

Excess boron in water could result in a critical hazard to plants and humans. Traditional treatment approaches cannot efficiently remove boron from water, especially during seawater desalination using reverse osmosis technology. Achieving satisfactory adsorption capacity and rate for boron remains an unmet goal for decades. Herein, we report cellulose-derived polyols as high-performance adsorbents that can rapidly remove boron and organic pollutants from water. Cellulose-derived polyols were synthesized from saccharides and cellulose via controlled radical polymerization and click reaction. Remarkably, CA@NMDG can adsorb boron with an astonishing capacity of ~34 mg g-1 in 10 min, which surpasses all those cellulose-based materials reported thus far, meanwhile, much faster than those of commercial adsorption resin. Moreover, cellulose-derived polyols also showed high removal efficiencies (70-98% in several minutes) toward certain organic pollutants, including Congo red and Reactive Blue 19. The water-insoluble characteristic of cellulose-derived polyols is advantageous to be separated from the treated sewage after adsorption for reuse. This work provides a novel insight into the fabrication of safe, fast, and high-capacity cellulose adsorbents for water purification.

Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence.

Esophageal squamous cell carcinomas (ESCCs) harbor recurrent chromosome 3q amplifications that target the transcription factor SOX2. Beyond its role as an oncogene in ESCC, SOX2 acts in development of the squamous esophagus and maintenance of adult esophageal precursor cells. To compare Sox2 activity in normal and malignant tissue, we developed engineered murine esophageal organoids spanning normal esophagus to Sox2-induced squamous cell carcinoma and mapped Sox2 binding and the epigenetic and transcriptional landscape with evolution from normal to cancer. While oncogenic Sox2 largely maintains actions observed in normal tissue, Sox2 overexpression with p53 and p16 inactivation promotes chromatin remodeling and evolution of the Sox2 cistrome. With Klf5, oncogenic Sox2 acquires new binding sites and enhances activity of oncogenes such as Stat3. Moreover, oncogenic Sox2 activates endogenous retroviruses, inducing expression of double-stranded RNA and dependence on the RNA editing enzyme ADAR1. These data reveal SOX2 functions in ESCC, defining targetable vulnerabilities.

The Active Components of Sunflower (Helianthus annuus L.) Calathide and the Effects on Urate Nephropathy Based on COX-2/PGE2 Signaling Pathway and the Urate Transporter URAT1, ABCG2, and GLUT9.

The sunflower (Helianthus annuus L.) calathide is gradually used as an alternative treatment for hyperuricemia; nevertheless, evidence regarding its main components and therapeutic capacity for urate nephropathy is lacking. Identification of sunflower calathide aqueous extract (SCE) was rapidly done by UPLC-ESI-Q-Orbitrap, and 32 water-soluble compounds with a comprehensive score >80 were discovered. Besides, yeast extract was administrated to induce high UA levels and hyperuricemic renal injury. We found that SCE treatment not only decreased UA levels to a comparable degree as allopurinol and benzbromarone, but also reduced the BUN levels and participated in kidney injury repair induced by uric acid. Moreover, it regulated the expression of URAT1 and ABCG2, especially inhibiting the GLUT9 in the normal kidney. Results were multifacetedly evaluated with a view to suggesting a possible mechanism of action as compared with those of allopurinol and benzbromarone by western blotting, H&E staining, and immunohistochemistry. However, the H&E staining showed histological changes in model, benzbromarone, and allopurinol groups rather than SCE treatments, and at the same time, the uric acid was identified as a cause of renal damage. The antiinflammatory effects and the regulations of COX-2/PGE2 signaling pathway were revealed on the LPS-induced RAW264.7 cells, indicating that the SCE not only increased cellular proliferation but also downregulated the COX-2, PGE2, NO, and IFN-γ cytokines in the RAW264.7 cells. To conclude, the SCE acts on urate transporters and contributes to prevent urate nephropathy via alleviating inflammatory process involving COX-2/PGE2 signaling pathway. It is available to develop SCE as food supplemental applications for hyperuricemia and nephritic inflammation.

The Mutational and Transcriptional Landscapes of Hepatocarcinogenesis in a Rat Model.

Hepatocellular carcinoma (HCC) initiation is characterized by stepwise accumulation of molecular alterations, during which the early events are largely unknown. Here, we presented a comprehensive genomic and transcriptomic landscape at stages of hepatitis, cirrhosis, and HCC by using a diethylnitrosamine-induced rat HCC model. We observed the early occurrence of gene instability and aberrant cancer associated signaling pathways in liver hepatitis. We further characterized the progressive molecular changes during hepatocarcinogenesis, wherein the intense rivalry between tumor-suppressive and oncogenic strengths occurred in cirrhosis stage. Despite the significant pathological difference, mutation signatures and expression landscape are highly similar between hepatitis and cirrhosis stages. Furthermore, we identified PI3K-Akt signaling pathway as a key pathway in the process of hepatocarcinogenesis through integrative analysis, and PIK3CD is a potential biomarker indicating HCC recurrence. The dynamic immune response during hepatocarcinogenesis, such as continuous decline of monocytes, suggests an immunological intervention strategy beyond chemoprevention for liver cancer.

Supramolecular assemblies of glycoclusters with aggregation-induced emission for sensitive phenol detection.

Supramolecular assemblies with reversible boronate ester linkages are facilely prepared via self-assembly between cyclodextrin-centered glycoclusters and 4,4'-(1,2-diphenylethene-1,2-diyl)bis(1,4-phenylene)diboronic acid (TPEDB). Such sphere-like assemblies have shown a typical aggregation-induced emission (AIE) effect and could act as fluorescent probes for the sensitive detection of phenols in water.

Early TP53 alterations engage environmental exposures to promote gastric premalignancy in an integrative mouse model.

Somatic alterations in cancer genes are being detected in normal and premalignant tissue, thus placing greater emphasis on gene-environment interactions that enable disease phenotypes. By combining early genetic alterations with disease-relevant exposures, we developed an integrative mouse model to study gastric premalignancy. Deletion of Trp53 in gastric cells confers a selective advantage and promotes the development of dysplasia in the setting of dietary carcinogens. Organoid derivation from dysplastic lesions facilitated genomic, transcriptional and functional evaluation of gastric premalignancy. Cell cycle regulators, most notably Cdkn2a, were upregulated by p53 inactivation in gastric premalignancy, serving as a barrier to disease progression. Co-deletion of Cdkn2a and Trp53 in dysplastic gastric organoids promoted cancer phenotypes but also induced replication stress, exposing a susceptibility to DNA damage response inhibitors. These findings demonstrate the utility of mouse models that integrate genomic alterations with relevant exposures and highlight the importance of gene-environment interactions in shaping the premalignant state.

Controlled synthesis of sugar-containing poly(ionic liquid)s.

A facile synthetic route is reported toward sugar-containing pyridinium-based poly(ionic liquid)s (PILs). Reversible deactivation radical polymerization of 4-vinyl pyridine could generate a well-defined poly(4-vinyl pyridine) in a self-generating biphasic system. Subsequent quaternization and anion exchange reaction could yield a library of functional PILs with pendent sugar units and varied anions.

LncRNA ID2-AS1 suppresses tumor metastasis by activating the HDAC8/ID2 pathway in hepatocellular carcinoma.

Metastasis is a core hallmark of cancer that leads to high mortality of cancer patients, especially in hepatocellular carcinoma (HCC). However, the underlying mechanisms of long noncoding RNAs (lncRNAs) in HCC metastasis remain largely unknown. We found that ID2-AS1 expression decreased in metastatic HCC cell lines and HCC tissues, and lower ID2-AS1 expression predicted reduced overall survival in HCC patients. ID2-AS1 significantly suppressed the migration, invasion and metastasis of HCC cells in vitro and in vivo. Mechanistically, ID2-AS1 regulated the transcription of its adjacent gene inhibitor of DNA binding 2 (ID2) by blocking the binding of histone deacetylase 8 (HDAC8) on the ID2 enhancer. Furthermore, ID2-AS1 and ID2 suppressed the Twist-induced epithelial-mesenchymal transition (EMT) in HCC cells. In addition, ID2 expression was also significantly decreased in HCC tissues and was positively correlated with ID2-AS1 in HCC tissues and HCC cell lines. Taken together, our findings demonstrated that ID2-AS1 regulated adjacent ID2 transcription by manipulating chromatin modification and that the newly identified ID2-AS1/ID2 axis suppressed HCC metastasis by regulating EMT processes. Our findings provide insights into the molecular mechanisms underlying the metastasis of HCC cells.

Nitrogen-Coordinated Boroxines Enable the Fabrication of Mechanically Robust Supramolecular Thermosets Capable of Healing and Recycling under Mild Conditions.

The fabrication of mechanically robust polymeric materials capable of self-healing and recycling remains challenging because the mobility of polymer chains in such polymers is very limited. In this work, mechanically robust supramolecular thermosets capable of healing physical damages and recycling under mild conditions are fabricated by trimerization of bi-( ortho-aminomethyl-phenylboronic acid)- and tri-( ortho-aminomethyl-phenylboronic acid)-terminated poly(propylene glycol) oligomers (denoted as Bi-PBA-PPG and Tri-PBA-PPG, respectively). The resultant supramolecular thermosets are cross-linked by dynamic covalent bonds of nitrogen-coordinated boroxines. The mechanical properties of the supramolecular thermosets can be systematically tailored by varying the ratios between Tri-PBA-PPG and Bi-PBA-PPG, which changes the cross-linking density of nitrogen-coordinated boroxines and the topology of the supramolecular thermosets. The mechanically strongest supramolecular thermosets with a molar ratio of Tri-PBA-PPG to Bi-PBA-PPG being 1:2 have a glass transition temperature of ∼36 °C, a tensile strength of ∼31.96 MPa, and a Young's modulus of ∼298.5 MPa. The high reversibility of nitrogen-coordinated boroxines and the flexibility of poly(propylene glycol) chains enable the supramolecular thermosets with the strongest mechanical strength to be highly efficiently healed at 55 °C and recycled under a pressure of 4 MPa at 60 °C to regain their original mechanical strength and integrity.

Synthesis and Assembly of Laccase-Polymer Giant Amphiphiles by Self-Catalyzed CuAAC Click Chemistry.

Covalent coupling of hydrophobic polymers to the exterior of hydrophilic proteins would mediate unique macroscopic assembly of bioconjugates to generate amphiphilic superstructures as novel nanoreactors or biocompatible drug delivery systems. The main objective of this study was to develop a novel strategy for the synthesis of protein-polymer giant amphiphiles by the combination of copper-mediated living radical polymerization and azide-alkyne cycloaddition reaction (CuAAC). Azide-functionalized succinimidyl ester was first synthesized for the facile introduction of azide groups to proteins such as albumin from bovine serum (BSA) and laccase from Trametes versicolor. Alkyne-terminal polymers with varied hydrophobicity were synthesized by using commercial copper wire as the activators from a trimethylsilyl protected alkyne-functionalized initiator in DMSO under ambient temperature. The conjugation of alkyne-functionalized polymers to the azide-functionalized laccase could be conducted even without additional copper catalyst, which indicated a successful self-catalyzed CuAAC reaction. The synthesized amphiphiles were found to aggregate into spherical nanoparticles in water and showed strong relevance to the hydrophobicity of coupled polymers. The giant amphiphiles showed decreased enzyme activity yet better stability during storage after chemical modification and self-assembly. These findings will deepen our understanding on protein folding, macroscopic self-assembly, and support potential applications in bionanoreactor, enzyme immobilization, and water purification.

Circular RNA profile identifies circPVT1 as a proliferative factor and prognostic marker in gastric cancer.

Circular RNAs (circRNAs) comprise a novel class of widespread non-coding RNAs that may regulate gene expression in eukaryotes. However, the characterization and function of circRNAs in human cancer remain elusive. Here we identified at least 5500 distinct circRNA candidates and a series of circRNAs that are differentially expressed in gastric cancer (GC) tissues compared with matched normal tissues. We further characterized one circRNA derived from the PVT1 gene and termed it as circPVT1. The expression of circPVT1 is often upregulated in GC tissues due to the amplification of its genomic locus. circPVT1 may promote cell proliferation by acting as a sponge for members of the miR-125 family. The level of circPVT1 was observed as an independent prognostic marker for overall survival and disease-free survival of patients with GC. Our findings suggest that circPVT1 is a novel proliferative factor and prognostic marker in GC.

Circular RNA expands its territory.

Circular RNAs (circRNAs) represent a novel class of widespread non-coding RNAs in eukaryotes. They are unusually stable RNA molecules with cell type-specific expression patterns, and are predominantly present in the cytoplasm. We recently demonstrated the existence of abundant circRNAs in exosomes and suggest a potential application of exosomal circRNAs for cancer detection.

Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs.

Circular RNAs (circRNAs) represent a class of widespread and diverse endogenous RNAs that may regulate gene expression in eukaryotes. However, the regulation and function of human circRNAs remain largely unknown. Here we generate ribosomal-depleted RNA sequencing data from six normal tissues and seven cancers, and detect at least 27,000 circRNA candidates. Many of these circRNAs are differently expressed between the normal and cancerous tissues. We further characterize one abundant circRNA derived from Exon2 of the HIPK3 gene, termed circHIPK3. The silencing of circHIPK3 but not HIPK3 mRNA significantly inhibits human cell growth. Via a luciferase screening assay, circHIPK3 is observed to sponge to 9 miRNAs with 18 potential binding sites. Specifically, we show that circHIPK3 directly binds to miR-124 and inhibits miR-124 activity. Our results provide evidence that circular RNA produced from precursor mRNA may have a regulatory role in human cells.

Near-Infrared Light-Stimulus-Responsive Film as a Sacrificial Layer for the Preparation of Free-Standing Films.

It remains a challenge to fabricate sacrificial films that are stable in most of solvents and can be readily decomposed on demand. Here we report the fabrication of a near-infrared (NIR) light decomposable sacrificial film by layer-by-layer (LbL) assembly of UV-light-decomposable poly((4-(2-bromoethoxy)-5-methoxy-2-nitrobenzyl acrylate) triethylammonium bromide) (PNBA-TEA), poly(sodium 4-styrene-sulfonate) (PSS), branched polyethyleimine (bPEI), and lanthanide-doped upconversion nanoparticles (UCNPs). The [(PNBA-TEA/PSS)*2/(bPEI/UCNPs)*3]*2 films are stable in deposition solutions of various materials and decompose upon NIR light irradiation. In the [(PNBA-TEA/PSS)*2/(bPEI/UCNPs)*3]*2 films, UCNPs can convert NIR light into UV light, which can decompose PNBA-TEA. After immersing the NIR light-irradiated [(PNBA-TEA/PSS)*2/(bPEI/UCNPs)*3]*2 films in 0.1 M aqueous NaHCO3 solution, the disintegration of the entire films occurs because of the repulsive force between the negatively charged photoproduct of PNBA-TEA and PSS. LbL-assembled (PAH/PAA)*50 films deposited on top of the NIR-light-decomposable [(PNBA-TEA/PSS)*2/(bPEI/UCNPs)*3]*2 films can be conveniently released to produce large-area and defect-free (PAH/PAA)*50 free-standing films after NIR light irradiation and subsequent immersion in 0.1 M aqueous NaHCO3 solution. Because of the satisfactory stability and on-demand decomposable property, the [(PNBA-TEA/PSS)*2/(bPEI/UCNPs)*3]*2 films are promising as sacrificial layers for the fabrication of various free-standing films.

miR-192, a prognostic indicator, targets the SLC39A6/SNAIL pathway to reduce tumor metastasis in human hepatocellular carcinoma.

Metastasis is one of the causes of cancer death. Functions and mechanisms of microRNAs (miRNAs) involved in hepatocellular carcinoma (HCC) metastasis are largely unknown. Here, a miRNA microarray analysis was performed in MHCC-97L, MHCC-97H and HCC-LM3 cells with gradually increasing metastatic potential to disclose crucial miRNAs involved in HCC metastasis. miR-192 expression decreased and negatively correlated with vascular invasion in HCC specimens. Gain and loss of function studies revealed that miR-192 significantly suppressed metastasis of HCC cells in vitro and in vivo. Solute carrier family 39 member 6 (SLC39A6) was identified as a direct and functional target of miR-192. In addition, SLC39A6 negatively correlated with miR-192 in HCC samples and promoted HCC cell migration and invasion. Moreover, miR-192 decreased SLC39A6 expression, subsequently downregulating SNAIL and upregulating E-cadherin expression. Suppression of migration and invasion caused by miR-192 overexpression was alleviated by exogenous Snail expression. Intriguingly, lower miR-192 expression and higher SLC39A6 expression significantly contributed to poorer outcomes in HCC patients. Multivariate analysis indicated that miR-192 was an independent and significant predictor of HCC patient overall survival. In conclusion, we newly determined that miR-192 targeted the SLC39A6/SNAIL pathway to reduce tumor metastasis in HCC cells. This axis provided insights into the mechanism underlying miRNA regulation of HCC metastasis and a novel therapeutic target for HCC treatment.

MicroRNA-127-5p targets the biliverdin reductase B/nuclear factor-κB pathway to suppress cell growth in hepatocellular carcinoma cells.

Nuclear factor-κB (NF-κB) activation is one of the major mediators of inflammation-induced cancer cell growth and progression. In previous studies, we screened a series of microRNAs (miRNAs) that targeted the NF-κB signaling pathway. In this study, we showed that miR-127-5p suppressed NF-κB activity through inhibition of p65 nuclear translocation. In addition, miR-127-5p also inhibited the transcription of downstream targets of the NF-κB signaling pathway. While exploring the mechanism of the inhibition of NF-κB activity by miR-127-5p, we found that miR-127-5p decreased the phosphorylation of p65. MicroRNA-127-5p inhibited the growth and colony formation of hepatocellular carcinoma (HCC) cells and decreased biliverdin reductase B (BLVRB) expression by directly binding to its 3'-UTR. RNA interference of BLVRB suppressed HCC cell growth, whereas the overexpression of BLVRB promoted HCC cell growth. Furthermore, BLVRB blockade inhibited the phosphorylation of p65 protein and the expression of downstream targets of the NF-κB signaling pathway, mimicking the function of miR-127-5p. The restoration of BLVRB in HCC cells overexpressing miR-127-5p impaired the suppression of HCC growth by miR-127-5p. Moreover, miR-127-5p was downregulated in 58% of HCC samples. In summary, we found that miR-127-5p suppressed NF-κB activity by directly targeting BLVRB in HCC cells, and this finding improves our understanding of the molecular mechanism of inflammation-induced HCC growth and proliferation and the successful inhibition of NF-κB activity by cancer treatment.