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Supplementary Figure S1-S16: Figure S1: landscape of variants in all samples; Figure S2: cancer cell fraction of each mutation; Figure S3: patient screen; Figure S4: high frequency CNV in each sample; Figure S5: SNV disparity between PT and MT; Figure S6: SV features; Figure S7: gene enrichment of each gene category; Figure S8: Jaccard similarity in each patient; Figure S9: clonal status of potential driver genes; Figure S10: mutation signature enrichment in trunk, PTun and MTun; Figure S11: mutation signature enrichment in PT and MT; Figure S12: mutation spectrum in PT and MT; Figure S13: immunohistochemistry of PD-L1 and CD8 in PT and MT; Figure S14: CNV of immune regulatory genes in all samples; Figure S15: response to immune checkpoint inhibitor in patient OS06. Figure S16: The genomic microsatellite stability state in all tumor samples.

Osteosarcoma is the most common primary bone malignancy, and the lung is the most frequent site of metastasis. The limited understanding of the tumoral heterogeneity and evolutionary process of genomic alterations in pulmonary metastatic osteosarcoma impedes development of novel therapeutic strategies. Here we systematically illustrate the genomic disparities between primary tumors and corresponding pulmonary metastatic tumors by multiregional whole-exome and whole-genome sequencing in 86 tumor regions from 10 patients with osteosarcoma. Metastatic tumors exhibited a significantly higher mutational burden and genomic instability compared with primary tumors, possibly due to accumulation of mutations caused by a greater number of alterations in DNA damage response genes in metastatic tumors. Integrated analysis of the architecture and relationships of subclones revealed a dynamic mutational process and diverse dissemination patterns of osteosarcoma during pulmonary metastasis (6/10 with linear and 4/10 with parallel evolutionary patterns). All patients demonstrated more significant intertumoral rather than intratumoral heterogeneity between primary tumors and metastatic tumors. Mutated genes were enriched in the PI3K–Akt pathway at both the early and late stages of tumor evolution and in the MAPK pathway at the metastatic stage. Conversely, metastatic tumors showed improved immunogenicity, including higher neoantigen load, elevated PD-L1 expression, and tumor-infiltrating lymphocytes than the corresponding primary tumors. Our study is the first to report the dynamic evolutionary process and temporospatial tumor heterogeneity of pulmonary metastatic osteosarcoma, providing new insights for diagnosis and potential therapeutic strategies for pulmonary metastasis.Significance:High-throughput sequencing of primary and metastatic osteosarcoma provides new insights into the diagnosis of and potential clinical therapeutic strategies for pulmonary metastasis.

Background & aims Intrahepatic cholangiocarcinoma (ICC) is aggressive and has high rates of relapse, conferring poor long-term survival after curative resection. Little is known about the genomic evolution that occurs during ICC relapse. Approach & results We conducted whole-exome sequencing (WES) of 30 paired primary and relapsed tumors from 10 patients with ICC who received curative resection. We sought to identify frequently altered genes, infer tumor subclonal architectures, and track genomic evolution from primary to relapsed tumors. We examined functional effects and the mechanism of action of SLIT2, a gene specifically mutated in relapsed tumors, on tumor growth and metastasis and the tumor microenvironment. Our results indicated that relapsed ICCs were genetically derived from intrahepatic dissemination of primary tumors. But, they acquired additional mutations while maintaining most drivers, such as TP53 and IDH1. Multiregion sequencing suggested polyclonal seeding of ICC dissemination. Four of 10 relapsed ICCs acquired SLIT2 mutations that were not present in the corresponding primary tumors. Validation in an expanded sample revealed SLIT2 mutations in 2.3% (1/44) of primary ICCs and 29.5% (13/44) of relapsed ICCs. Biofunctional investigations revealed that inactivating mutation of SLIT2 resulted in activation of PI3K-Akt signaling in ICC cells, directly enhanced neutrophil chemotaxis, mediated tumor-associated neutrophil infiltration, and contributed to ICC growth and metastasis. Conclusions We characterized genomic evolution during ICC relapse and identified SLIT2 as a driver of tumor dissemination and tumor-associated neutrophil infiltration.

Background & Aims Early recurrence of hepatocellular carcinoma (HCC) after curative resection is common. However, the association between genetic mechanisms and early HCC recurrence, especially in Chinese patients, remains largely unknown. Methods We performed whole-genome sequencing (49 cases), whole-exome sequencing (18 cases), and deep targeted sequencing (115 cases) on 182 primary HCC samples. Focusing on WNK2, we used Sanger sequencing and qPCR to evaluate all the coding exons and copy numbers of that gene in an additional 554 HCC samples. We also explored the functional effect and mechanism of WNK2 on tumor growth and metastasis. Results We identified 5 genes (WNK2, RUNX1T1, CTNNB1, TSC1, and TP53) harboring somatic mutations that correlated with early tumor recurrence after curative resection in 182 primary HCC samples. Focusing on WNK2, the overall somatic mutation and copy number loss occurred in 5.3% (39/736) and 27.2% (200/736), respectively, of the total 736 HCC samples. Both types of variation were associated with lower WNK2 protein levels, higher rates of early tumor recurrence, and shorter overall survival. Biofunctional investigations revealed a tumor-suppressor role of WNK2: its inactivation led to ERK1/2 signaling activation in HCC cells, tumor-associated macrophage infiltration, and tumor growth and metastasis. Conclusions Our results delineate genomic events that characterize Chinese HCCs and identify WNK2 as a driver of early HCC recurrence after curative resection. Lay summary We applied next-generation sequencing and conducted an in-depth genomic analysis of hepatocellular carcinomas from a Chinese patient cohort. The results delineate the genomic events that characterize hepatocellular carcinomas in Chinese patients and identify WNK2 as a driver associated with early tumor recurrence after curative resection.

In this work, (Zr55Cu30Al10Ni5)100−xScx (x = 0, 0.5, 1.0, and 1.5) amorphous alloys were fabricated through steel die casting. The effects of scandium on the properties of zirconium-based amorphous alloys have been studied. The results show that the glass-forming ability of amorphous alloys increases at first and then decreases with the increase of Sc content. The highest glass-forming ability is obtained when the atomic fraction of Sc is 0.5%, which enables the production of 2-mm-thick amorphous alloy ingots. Meanwhile, the thermal stability and mechanical properties of the alloy are optimised with the atomic fraction of Sc of 1.0%. In addition, by adding an appropriate amount of Sc, the corrosion resistance of Zr–Cu–Al–Ni alloys is enhanced, particularly in the acid solution. The lowest average corrosion rate for samples in acid solution is obtained with the alloy containing atomic fraction of Sc of 1.0%. Therefore, results of this study indicate that the Zr-based amorphous alloy containing scandium has the potential for manufacturing fracture internal fixation or surgical devices.

Osteosarcoma is the most common primary bone malignancy, and the lung is the most frequent site of metastasis. The limited understanding of the tumoral heterogeneity and evolutionary process of genomic alterations in pulmonary metastatic osteosarcoma impedes development of novel therapeutic strategies. Here we systematically illustrate the genomic disparities between primary tumors and corresponding pulmonary metastatic tumors by multiregional whole-exome and whole-genome sequencing in 86 tumor regions from 10 patients with osteosarcoma. Metastatic tumors exhibited a significantly higher mutational burden and genomic instability compared with primary tumors, possibly due to accumulation of mutations caused by a greater number of alterations in DNA damage response genes in metastatic tumors. Integrated analysis of the architecture and relationships of subclones revealed a dynamic mutational process and diverse dissemination patterns of osteosarcoma during pulmonary metastasis (6/10 with linear and 4/10 with parallel evolutionary patterns). All patients demonstrated more significant intertumoral rather than intratumoral heterogeneity between primary tumors and metastatic tumors. Mutated genes were enriched in the PI3K–Akt pathway at both the early and late stages of tumor evolution and in the MAPK pathway at the metastatic stage. Conversely, metastatic tumors showed improved immunogenicity, including higher neoantigen load, elevated PD-L1 expression, and tumor-infiltrating lymphocytes than the corresponding primary tumors. Our study is the first to report the dynamic evolutionary process and temporospatial tumor heterogeneity of pulmonary metastatic osteosarcoma, providing new insights for diagnosis and potential therapeutic strategies for pulmonary metastasis. Significance: High-throughput sequencing of primary and metastatic osteosarcoma provides new insights into the diagnosis of and potential clinical therapeutic strategies for pulmonary metastasis.

Graphitic carbon nitrides were employed to prepare the Ruthenium-based ammonia synthesis catalysts by thermal decomposition of Ru3(CO)12 under N2 or H2 atmosphere. Different pretreatment atmospheres significantly affected the interaction between Ru nanoparticles and the graphitic carbon nitride. The strong metal support interaction enhanced the electronic density transfer from rich-electron π-plane of the support to the Ru nanoparticles. And it further caused the upshift of d-band center of Ru nanoparticles. The upshift of d-band center improved the ability of surface to bond to N2, and consequently the ammonia synthesis activity was enhanced. Electron-rich and graphitic carbon nitride enhanced the electron density of Ru nanoparticles. And that caused the upshift of d-band center of Ru nanoparticles. This upshift of d-band center improved the ability of surface to bond to N2, and consequently the ammonia synthesis activity was enhanced.

Here we report that the electronic metal–support interaction influences the catalytic activity of ammonia synthesis. This effect produces an upwards shift of the d-band center of Ru nanoparticles. The upward shift of the d-band center of the Ru nanoparticles is considered to enhance the dissociation of the N2 molecule.

A combined experimental and theoretical study was carried out to investigate the ambipolar charge transport properties of a series of N-heteropentacenes in organic field-effect transistors (OFETs). Introduction of nitrogen atoms in the core and halogen atoms around the periphery of the pentacene framework can efficiently tune the highest occupied molecular orbitals (HOMOs) of the N-heteropentacenes from −5.18 eV to −5.53 eV and the lowest unoccupied molecular orbitals (LUMOs) from −3.08 eV to −3.69 eV. By lowering their HOMO and LUMO energy levels with respect to the Fermi level of the gold electrode, the transistors of these molecules exhibited a transition from hole-dominant bipolar, to balanced ambipolar, and to electron-dominant bipolar transport characteristics. Meanwhile, with the lowering of the frontier molecular orbital energy levels, the transistors also exhibited a decrease of the electron threshold voltage and an increase of the hole threshold voltage. Charge carrier mobility calculations based on Marcus theory and first principle molecular dynamics were conducted to simulate the carrier transport dynamics. The comparison between experimental and theoretical results revealed that for the given device structure, the ratio of electron and hole mobilities of the ambipolar OFETs was strongly affected by the charge injection barrier. This result provides useful guidelines for future molecular design of ambipolar OFETs.

Many access devices have been developed for laparoendoscopic single-site surgery (LESS) during recent years. However, investigations are needed to determine which port is most suitable for this relatively new technique. The aim of this study was to evaluate commonly used ports using mechanical approaches in a training simulator. Any port that required less force and shorter surgery times had superior maneuverability.The following three commercially available access devices were evaluated: Multi-ports, TriPort, and single-incision laparoscopic surgery (SILS) Port. A LESS mechanical evaluation platform was developed to investigate the forces that acted on the instruments in the ports while moving along horizontal and vertical axes. In addition, a strain-force measurement system was used to compare the average load on the ports when performing standard maneuvers. Additionally, the task completion time was recorded when the maneuvers in these ports were completed.During the horizontal displacement of the instrument, the traction forces of the Multi-ports were lower than those of the SILS Port, which were lower than those of the TriPort. The average traction forces were significantly different in pairwise multiple comparisons (P0.05). When the instrument was inserted into the ports, the vertical friction forces of the Multi-ports were the lowest and those of the TriPort were the highest. On extraction of the instrument, the friction forces of the Multi-ports remained the lowest, followed by those of the TriPort and SILS Port. There were statistically significant results among all the devices (P0.05). The average load required to perform the task was less for the SILS Port than that for the TriPort (P0.05). Similarly, the average load for the Multi-ports was significantly less than that for the TriPort (P0.001). The participants who used the Multi-ports had significantly faster task times than those who used the SILS Port or TriPort (P0.005).Compared with the TriPort and SILS Port, the Multi-ports was associated with the least average load and the shortest task performance times in a training simulator. This study demonstrates that the Multi-ports may offer superior maneuverability for LESS.

Two K/Mn-MgO supported catalysts were prepared by Fe(CO) 5 and Fe(NO 3 ) 3 as precursor respectively. The obtained Fe-K/Mn-MgO catalysts were tested for CO hydrogenation to light alkenes and characterized by X-ray powder diffraction (XRD), X-ray photoelectron spectra (XPS), H 2 temperature-programmed reduction (H 2 -TPR), H 2 , CO and CO 2 temperature-programmed desorption (H 2 , CO/CO 2 -TPD) and transmission electron microscope (TEM). The results indicated that the catalyst with 10 wt% Fe loading prepared by Fe(CO) 5 as precursor showed better performance in syngas to light alkenes than ones obtained from Fe(NO 3 ) 3 as precursor, where the CO conversion was 62.50% and the selectivity was 55.95% at 350 ℃, 1.5 MPa and 1000 h −1 , respectively.

Currently CNG has been widely used as an automotive fuel, and the security problems about CNG storage well are prominent which poses a serious threat to life and property.This indicates that the safety of the underground gas storage well stored CNG is of great importance. The purpose of this paper is to analyze the section of gas storage well that is the joint of casing and coupling based on the finite element method,as this section is the most dangerous.Using ANSYS software,the stress field of this section will be acquired.An example of a finite element model will be used to demonstrate the main section related to gas storage well failure is the root of the first engaged tooth of a joint between coupling and casing.

With various contents, Mn was introduced into carbon nanotubes (CNTs) supported cobalt catalysts and the obtained Mn-Co/CNTs catalysts were investigated for CO hydrogenation to light alkenes and characterized by N 2 adsorption, X-ray diffraction (XRD), X-ray photoelectron spectra (XPS), H 2 temperature programmed reduction (TPR), CO temperature programmed desorption (TPD) and transmission electron microscope (TEM). The results indicate that the addition of a small amount of Mn (0.3 wt%) to CNTs-supported Co catalyst significantly increased the selectivity of C 2 －C 4 olefins and decreased the selectivity of CH 4 . However, with further addition of Mn to the cobalt catalysts, the CH 4 selectivity decreased obviously along with the increase of the C 5 ＋ selectivity. Compared with the unpromoted catalysts, the Mn-promoted cobalt catalysts increased the C 2 ＝ －C 4 ＝ /C 2 0 －C 4 0 molar ratio.

Minimally invasive robotic surgery has been investigated in various surgical application due to high accuracy, fine manipulation capability, tele-operation. Haptic feedback plays a significant role in MIS. In this paper, a dynamics model of a haptic robot is established, and PID algorithm is proposed. To prove the proposed method, an experimental system has been developed. Simulations and experiments show proposed methods is an effective method to master-slave MIRS.

Two new azapentacene derivatives 9,10-dibromo-6,13-bis(triisopropylsilylethynyl)-1-azapentacene (a) and 8,9,10,11-tetrachloro-6,13-bis(triisopropylsilylethynyl)-1-azapentacene (b) were synthesized, and their FET properties were investigated. Compound b exhibits high and balanced ambipolar transport properties, with the hole and electron mobilities reaching up to 0.12 and 0.14 cm(2) V(-1) s(-1), respectively. This work suggests that chlorination to the N-heteropentacene framework is an efficient way for producing high performance ambipolar organic semiconductors.

Based on the sequence of a resistance gene analog FZ14 derived from Zizania latifolia (Griseb.), a pair of specific PCR primers FZ14P1/FZ14P2 was designed to isolate candidate disease resistance gene. The pooled-PCR approach was adopted using the primer pair to screen a genomic transformation-competent artificial chromosome (TAC) library derived from Z. latifolia. A positive TAC clone (ZR1) was obtained and confirmed by sequence analysis. The results indicated that ZR1 consisted of conserved motifs similar to P-loop (kinase 1a), kinase 2, kinase 3a and GLPL (Gly-Leu-Pro-Leu), suggesting that it could be a portion of NBS-LRR type of resistance gene. Using Agrobacterium-mediated transformation of Nipponbare mature embryo, a total of 48 independent transgenic T0 plants were obtained. Among them, 36 plants were highly resistant to the virulent bacterial blight strain PXO71. The results indicate that ZR1 contains at least one functional bacterial blight resistance gene.

Planar shock compression experiments are performed at 9–105 GPa on polycrystalline ferropericlase (Mg0.94Fe0.06)O to investigate its Fe2+ spin transition. Forward and reverse impact configurations are used to obtain Hugoniot and shock-state sound velocities. While wave profiles, shock velocity–particle velocity and pressure–density measurements show negligible/weak indications of a phase transition, the shock-state sound speed data clearly manifest a phase transition in the range of 36–62 GPa at the nanosecond time scales. These shock data reveal the phase transition as the spin transition identified in static compression experiments and first-principles calculations.

To evaluate the safety and feasibility of laparoscopic abdominoperineal resection compared with the open procedure in multimodality management of rectal cancer.A total of 106 rectal cancer patients who underwent open abdominoperineal resection (OAPR) were matched with 106 patients who underwent laparoscopic abdominoperineal resection (LAPR) in a 1 to 1 fashion, between 2009 and 2013 at Fudan University Shanghai Cancer Center. Propensity score matching was carried out based on age, gender, pathological staging of the disease and administration of neoadjuvant chemoradiation. Data regarding preoperative staging, surgical technique, pathological results, postoperative recovery and complications were reviewed and compared between the LAPR and OAPR groups. Perineal closure around the stoma and pelvic floor reconstruction were performed only in OAPR, not in LAPR. Therefore, abdominoperineal resection procedure-specific surgical complications including parastomal hernia and perineal wound complications were compared between the open and laparoscopic procedure. Regular surveillance of the two cohorts was carried out to gather prognostic data. Disease-free survival was analyzed using Kaplan-Meier estimate and log-rank test. Subgroup analysis was performed in patients with locally advanced disease treated with preoperative chemoradiation followed by surgical resection.No significant difference was found between the LAPR group and the OAPR group in terms of clinicopathological features. The operation time (180.8 ± 47.8 min vs 172.1 ± 49.2 min, P = 0.190), operative blood loss (93.9 ± 60.0 mL vs 88.4 ± 55.2 mL, P = 0.494), total number of retrieved lymph nodes (12.9 ± 6.9 vs 12.9 ± 5.4, P = 0.974), surgical complications (12.3% vs 15.1%, P = 0.549) and pathological characteristics were comparable between the LAPR and OAPR group, respectively. Compared with OAPR patients, LAPR patients showed significantly shorter postoperative analgesia (2.4 ± 0.7 d vs 2.7 ± 0.6 d, P0.001), earlier first flatus (57.3 ± 7.9 h vs 63.5 ± 9.2 h, P0.001), shorter urinary drainage time (6.5 ± 3.4 d vs 7.8 ± 1.3 d, P0.001), and shorter postoperative admission (11.2 ± 4.7 d vs 12.6 ± 4.0 d, P = 0.014). With regard to APR-specific complications (perineal wound complications and parastomal hernia), there were no significant differences between the two groups. Similar results were found in the 26 pairs of patients administered neoadjuvant chemoradiation in subgroup analysis. During the follow-up period, no port site recurrences were observed.Laparoscopic abdominoperineal resection for multidisciplinary management of rectal cancer is safe, and is associated with earlier recovery and shorter admission time in combination with neoadjuvant chemoradiation.

The tribe Oryzeae consists of 12 genera and 71 species with a world distribution.Zizania latifolia (Griseb.) Turcz. ex Stapf is included in this tribe and possesses numerous traits valuable for rice breeding, such as disease and insect resistance, cold and flood tolerance, and high grain quality. The genetics and breeding ofZ. latifolia are still in their infancy. To facilitate genomic studies ofZizania, a genomic DNA library was constructed using a transformation-competent artificial chromosome (TAC) vector system. The TAC library contains 91, 584 TAC clones with an average insert size of approximately 45 kb, covering six haploidZizania genome equivalents. Very low signals after hybridization with chloroplast and mitochondrial genes indicate that the TAC library is predominantly composed of nuclear DNA. The TAC clones were stable inE. coli for 100 generations. Clones containing thedihydrodipicolinate synthase (DHPS) gene were screened by pooled PCR. The positive clones can be used forZ. latifolia DHPS gene cloning and functional analysis. The library will be useful in studies of genome structure, gene cloning and evolution of rice.

Two series of new oligothiophene-pentacene hybrid compounds were successfully synthesized and characterized, which consist of pentacene and anthradithiophene skeletons modified by different oligothienyl groups at 6,13 sites or 5,11 sites, respectively. Their optical, thermal, and electrochemical properties show regular variations with the length change of the side groups. These materials exhibit much higher solubility and significantly improved thermal and photooxidation stabilities compared with unmodified pentacene and anthradithiophene.

We report the fabrication of simply structured and high performance organic complementary inverters based on an ambipolar organic semiconductor, 8,9,10,11-tetrachloro-6,13-bis-(triisopropylsilylethynyl)-1-azapentacene (4Cl-Azapen). Individual transistors using symmetric Au electrodes showed high and balanced performance, with good hole (up to 0.23 cm2V−1s−1) and electron (up to 0.21 cm2V−1s−1) mobilities. Integrated complementary inverters showed sharp inversions with high gains (>180) and negligible hysteresis. The inverters using low-cost electrodes, Ag and Cu, also exhibited high gains and high noise margins (>75% of the ideal value).