Surface-Modified Sulfur Nanorods Immobilized on Radially Assembled Open-Porous Graphene Microspheres for Lithium-Sulfur Batteries.

The assembly of two-dimensional conductive nanomaterials into hierarchical complex architectures precisely controlling internal open porosity and orientation, external morphology, composition, and interaction is expected to provide promising hosts for high-capacity sulfur cathodes. Herein, we demonstrate rod-like nanosulfur (nS) deposited onto radially oriented open-porous microspherical reduced graphene oxide (rGO) architectures for improved rate and cyclic capabilities of lithium-sulfur (Li-S) batteries. The combined chemistry of a spray-frozen assembly and ozonation drives the formation of a radially oriented open-porous structure and an overall microspherical morphology as well as uniform distribution and high loading of rod-like nS. Moreover, an optimum composition and strong bonding of the rGO/nS hybrid enables the optimization of redox kinetics for high sulfur utilization and high-rate capacities. The resulting rGO/nS hybrid provides a specific capacity and first-cycle Coulombic efficiency of 1269.1 mAh g-1 and 98.5%, respectively, which are much greater than those of ice-templated and physically mixed rGO/nS hybrids and radially oriented open-porous rGO/bulk sulfur with the same hybrid composition. A 4C capacity of 510.3 mAhg-1 and capacity decay of 0.08% per cycle over 500 cycles (70.9% of the initial capacity over 300 cycles) also support the synergistic effect of the rod-like nS strongly interacting with the radially oriented open-porous rGO microspheres.

Frameshift mutation of candidate tumor suppressor genes QK1 and TMEFF2 in gastric and colorectal cancers.

BACKGROUND: Both QKI and TMEFF2 genes are considered putative tumor suppressor genes (TSGs). In gastric (GC) and colorectal (CRC) cancers, downregulation of their expressions is known to be frequent. However, QKI and TMEFF2 mutations that could potentially inactivate their functions are not reported in cancers. METHODS: In a genome database, we observed that both QKI and TMEFF2 harbor mononucleotide repeats, which could be mutated in cancers with high microsatellite instability (MSI-H). For this, we studied 79 GCs and 124 CRCs for the mutations and their intratumoral heterogeneity (ITH). RESULTS: Six of 34 GCs (17.6%) and 10 of 79 CRCs (12.7%) with MSI-H exhibited QKI frameshift mutations while five of 79 CRCs (6.3%) with high MSI (MSI-H) exhibited TMEFF2 frameshift mutations. However, we found no such mutation in microsatellite stable/low MSI (MSS/MSI-L) cancers within the mononucleotide repeats. We also studied ITH for the detected frameshift mutations in 16 cases of CRCs and detected that QKI and TMEFF2 frameshift mutations showed regional ITH in 2 (12.5%) and 1 (6.3%) cases, respectively. CONCLUSIONS: Our data show that candidate TSG genes QKI and TMEFF2 harbor mutational ITH as well as the frameshift mutations in GC and CRC with MSI-H. From this observation, frameshift mutations of QKI and TMEFF2 may play a role in tumorigenesis through their TSG inactivation in GC and CRC.

Immune checkpoint blockade resistance-related B2M hotspot mutations in microsatellite-unstable colorectal carcinoma.

ß2-microglobulin (B2M), a component of major histocompatibility complex class I, plays an important role in host immune reaction to tumor, and inactivation of B2M is known to contribute to resistance to immune checkpoint blockade (ICB) treatment. To further characterize the B2M alterations in tumors, we analyzed B2M hotspot mutations in 2765 benign and malignant tumor tissues by Sanger sequencing and found B2M mutations in 9 (7.5%) microsatellite-unstable (MSU) colorectal cancers (CRCs) and 3 leukemias (0.6-1.3%), but not in other tumors. Targeted sequencing panel analysis for MSU CRCs showed that B2M-mutated MSU CRCs harbored more driver mutations including TP53 than B2M-wild-type MSU CRCs. Of note, bi-allelic B2M alterations, which had been known to be accumulated during ICB treatment, were frequently found (3/9) in ICB treatment-naive CRCs. Clinicopathologic parameters including CD8 + T cell numbers, cancer stages and patients' survival, however, were not significantly different between B2M-mutated and B2M-wild-type MSU CRCs. Our results indicate that B2M mutation abundance is tissue type-specific (e.g., MSU CRCs) and that genetic makeup of B2M mutation might possibly shape the MSU CRC genomes even before the ICB therapies. Our results show that B2M mutation is common in MSU CRCs, which is one of the main targets for ICB treatment, suggesting that frequent B2M mutation status should be reminded for MSU CRCs in patient selection of ICB.

DAB2IP with tumor-inhibiting activities exhibits frameshift mutations in gastrointestinal cancers.

A scaffold protein DAB2 and its interaction partner DAB2IP have putative tumor suppressor gene (TSG) functions. Previous studies identified that both DAB2 and DAB2IP genes were inactivated by promoter hypermethylation in human cancers, but their mutational alterations in cancers remain largely unknown. The aim of our study was to find whether DAB2 and DAB2IP were mutated in gastric (GCs) and colorectal cancers (CRCs) by DNA sequencing. Both DAB2 and DAB2IP have mononucleotide repeats in their coding sequence that could be mutation targets in high microsatellite instability (MSI-H) cancers. We analyzed GC and CRC tissues and found that 8 of 34 GCs (23.5%) and 15 of 79 CRCs (20.0%) with MSI-H harbored DAB2IP frameshift mutations. DAB2 frameshift mutations were found in 2 of 79 CRCs (2.5%) with MSI-H. These mutations were not detected in microsatellite stable (MSS) cancers. We also found intratumoral heterogeneity (ITH) of DAB2IP frameshift mutations in 7 of 16 CRCs (43.8%). Loss of DAB2IP protein expression was found in approximately 20% of GCs and CRCs irrespective of MSI and DAB2IP frameshift mutation status. Our study shows that the TSG DAB2IP harbored frameshift mutations and ITH as well as expression loss. Together these tumor alterations might play a role in tumorigenesis of GC and CRC with MSI-H by down-regulating the tumor-inhibiting activities of DAB2IP.

Somatic Mutations and Intratumoral Heterogeneity of MYH11 Gene in Gastric and Colorectal Cancers.

MYH11 functions as a contractile protein, converting chemical energy into mechanical energy through adenosine triphosphate hydrolysis. In cancers, an oncogenic fusion CBFB/MYH11 and frameshift mutations have been reported. Truncating mutants of MYH11 exhibited increased ATPase and motor activity, suggesting their roles in energy balance and movement of cancer cells. MYH11 gene has a mononucleotide repeat (C8) in the coding sequences that could be a mutational target in the cancers exhibiting microsatellite instability (MSI). We analyzed the C8 repeat in 79 gastric cancers (GCs) and 124 colorectal cancers (CRCs) including 113 high MSI (MSI-H) and 90 microsatellite stable/low MSI cases. We detected MYH11 frameshift mutations in 4 (11.8%) GCs and 17 (21.5%) CRCs with MSI-H (21/113, 18.6%), but not in microsatellite stable/low MSI cancers (0/90) (P<0.001). We also analyzed intratumoral heterogeneity (ITH) of the MYH11 frameshift mutations and found that 10 of 16 CRCs (62.5%) harbored the regional ITH. Our results show that MYH11 gene harbors somatic frameshift mutations mostly associated with mutational ITH, which together may be features of MSI-H GCs and CRCs. Practically, the data suggest that multiregional analysis is needed for a better evaluation of mutation status in MSI-H tumors to overcome ITH.

Frameshift Mutations in Repeat Sequences of ANK3, HACD4, TCP10L, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 Genes in Colon Cancers.

Diminished ANK3 contributes to cell survival by inhibiting detachment-induced apoptosis. TP53BP1 that interacts with p53 and MFN1 that encodes a mitochondrial membrane protein are considered to have tumor suppressor gene (TSG) functions. HACD4 involving fatty acid synthesis and TCPL10 with transcription regulation functions are considered TSGs. Many genes involved in DNA methylations such as LCMT2, RNMT, TRMT6, METTL8 and METTL16 are often perturbed in cancer. The aim of our study was to find whether these genes were mutated in colorectal cancer (CRC). In a genome database, we observed that each of these genes harbored mononucleotide repeats in the coding sequences, which could be mutated in cancers with high microsatellite instability (MSI-H). For this, we studied 124 CRCs for the frameshift mutations of these genes and their intratumoral heterogeneity (ITH). ANK3, HACD4, TCP10L, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 harbored 11 (13.9%), 3 (3.8%), 0 (0%), 5 (6.3%), 1 (1.3%), 2 (2.5%), 4 (5.1%), 3 (3.8%), 2 (2.5%) and 2 (2.5%) of 79 CRCs with MSI-H, respectively. However, we found no such mutations in microsatellite stable (MSS) cancers in the nucleotide repeats. There were ITH of the frameshift mutations of ANK3, MFN1 and TP53BP1 in 1 (6.3%), 1 (6.3%) and 1 (6.3%) cases, respectively. Our data exhibit that cancer-related genes ANK3, HACD4, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 harbor mutational ITH as well as the frameshift mutations in CRC with MSI-H. Also, the results suggest that frameshift mutations of these genes might play a role in tumorigenesis through their inactivation in CRC.

Intratumoral heterogeneity for inactivating frameshift mutation of CUX1 and SIRT1 genes in gastric and colorectal cancers.

Both CUX1 and SIRT1 are considered tumor suppressor genes (TSGs), but it is not known whether CUX1 and SIRT1 alterations are different between high microsatellite instability (MSI-H) and microsatellite stable MSI (MSS) cancers. We identified frameshift mutations of CUX1 in 4 cases of colorectal cancer (CRC) and of SIRT1 in 1 case of gastric cancer (GC) and 3 cases of CRC. All of them were found in GC or CRC with MSI-H (3.5% of MSI-H for each gene), but neither in GC nor CRC with MSS. In addition, we analyzed intratumoral heterogeneity (ITH) of the CUX1 frameshift mutation and found that two CRCs (12.5%) harbored regional ITH of the frameshift mutation. Our data indicate that there exist frameshift mutations of CUX1 and SIRT1 genes as well as ITH of CUX1 frameshift mutation in MSI-H cancers, which together might play a role in tumorigenesis of GC and CRC with MSI-H.

Cartilage-inspired superelastic ultradurable graphene aerogels prepared by the selective gluing of intersheet joints.

In this study, we demonstrate a cartilage-inspired superelastic and ultradurable nanocomposite strategy for the selective inclusion of viscoelastic poly(dimethylsiloxane) (PDMS) into graphene sheet junctions to create effective stress-transfer pathways within three-dimensional (3D) graphene aerogels (GAs). Inspired by the joint architectures in the human body, where small amounts of soft cartilage connect stiff (or hard) but hollow (and thus lightweight) bones, the 3D internetworked GA@PDMS achieves synergistic toughening. The resulting GA@PDMS nanocomposites exhibit fully reversible structural deformations (99.8% recovery even at a 90% compressive strain) and high compressive mechanical strength (448.2 kPa at a compressive strain of 90%) at repeated compression cycles. Owing to the combination of excellent mechanical and electrical properties, the GA@PDMS nanocomposites are used as signal transducers for strain sensors, showing very short response and recovery times (in the millisecond range) with reliable sensitivity and extreme durability. Furthermore, the proposed system is applied to electronic scales with a large detectable weight of about 4600 times greater than its own weight. Such bio-inspired cartilage architecture opens the door to fabricate new 3D multifunctional and mechanically durable nanocomposites for emerging applications, which include sensors, actuators, and flexible devices.