Control and Characterization of Individual Grains and Grain Boundaries in Graphene Grown by Chemical Vapor Deposition

The strong interest in graphene has motivated the scalable production of high quality graphene and graphene devices. Since large-scale graphene films synthesized to date are typically polycrystalline, it is important to characterize and control grain boundaries, generally believed to degrade graphene quality. Here we study single-crystal graphene grains synthesized by ambient CVD on polycrystalline Cu, and show how individual boundaries between coalescing grains affect graphene's electronic properties. The graphene grains show no definite epitaxial relationship with the Cu substrate, and can cross Cu grain boundaries. The edges of these grains are found to be predominantly parallel to zigzag directions. We show that grain boundaries give a significant Raman "D" peak, impede electrical transport, and induce prominent weak localization indicative of intervalley scattering in graphene. Finally, we demonstrate an approach using pre-patterned growth seeds to control graphene nucleation, opening a route towards scalable fabrication of single-crystal graphene devices without grain boundaries.Comment: New version with additional data. Accepted by Nature Material

LMTK3 confers chemo-resistance in breast cancer

Lemur tyrosine kinase 3 (LMTK3) is an oncogenic kinase that is involved in different types of cancer (breast, lung, gastric, colorectal) and biological processes including proliferation, invasion, migration, chromatin remodeling as well as innate and acquired endocrine resistance. However, the role of LMTK3 in response to cytotoxic chemotherapy has not been investigated thus far. Using both 2D and 3D tissue culture models, we found that overexpression of LMTK3 decreased the sensitivity of breast cancer cell lines to cytotoxic (doxorubicin) treatment. In a mouse model we showed that ectopic overexpression of LMTK3 decreases the efficacy of doxorubicin in reducing tumor growth. Interestingly, breast cancer cells overexpressing LMTK3 delayed the generation of double strand breaks (DSBs) after exposure to doxorubicin, as measured by the formation of γH2AX foci. This effect was at least partly mediated by decreased activity of ataxia-telangiectasia mutated kinase (ATM) as indicated by its reduced phosphorylation levels. In addition, our RNA-seq analyses showed that doxorubicin differentially regulated the expression of over 700 genes depending on LMTK3 protein expression levels. Furthermore, these genes were found to promote DNA repair, cell viability and tumorigenesis processes / pathways in LMTK3-overexpressing MCF7 cells. In human cancers, immunohistochemistry staining of LMTK3 in pre- and postchemotherapy breast tumor pairs from four separate clinical cohorts revealed a significant increase of LMTK3 following both doxorubicin and docetaxel based chemotherapy. In aggregate, our findings show for the first time a contribution of LMTK3 in cytotoxic drug resistance in breast cancer

Prospective Multicenter Feasibility Study of Laparoscopic Sentinel Basin Dissection after Endoscopic Submucosal Dissection for Early Gastric Cancer: SENORITA 2 Trial Protocol

PURPOSE: Although standard radical gastrectomy is recommended after noncurative resection of endoscopic submucosal dissection (ESD) for early gastric cancer in most cases, residual tumor and lymph node metastasis have not been identified after surgery. The aim of this study is to evaluate the feasibility of sentinel node navigation surgery after noncurative ESD. MATERIALS AND METHODS: This trial is an investigator-initiated, multicenter prospective phase II trial. Patients who underwent ESD for clinical stage T1N0M0 gastric cancer with noncurative resections were eligible. Qualified investigators who completed the prior phase III trial (SENORITA 1) are exclusively allowed to participate. In this study, 2 detection methods will be used: 1) intraoperative endoscopic submucosal injection of dual tracer, including radioisotope and indocyanine green (ICG) with sentinel basins detected using gamma-probe; 2) endoscopic injection of ICG, with sentinel basins detected using a fluorescence imaging system. Standard laparoscopic gastrectomy with lymphadenectomy will be performed. Sample size is calculated based on the inferior confidence interval of the detection rate of 95%, and the calculated accrual is 237 patients. The primary endpoint is detection rate, and the secondary endpoints are sensitivity and postoperative complications. CONCLUSIONS: This study is expected to clarify the feasibility of laparoscopic sentinel basin dissection after noncurative ESD. If the feasibility is demonstrated, a multicenter phase III trial will be initiated to compare laparoscopic sentinel node navigation surgery versus laparoscopic standard gastrectomy in early gastric cancer after endoscopic resection. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT0312304

Cycle-consistent adversarial networks improves generalizability of radiomics model in grading meningiomas on external validation

The heterogeneity of MRI is one of the major reasons for decreased performance of a radiomics model on external validation, limiting the model's generalizability and clinical application. We aimed to establish a generalizable radiomics model to predict meningioma grade on external validation through leveraging Cycle-Consistent Adversarial Networks (CycleGAN). In this retrospective study, 257 patients with meningioma were included in the institutional training set. Radiomic features (n = 214) were extracted from T2-weighted (T2) and contrast-enhanced T1 (T1C) images. After radiomics feature selection, extreme gradient boosting classifiers were developed. The models were validated in the external validation set consisting of 61 patients with meningiomas. To reduce the gap in generalization associated with the inter-institutional heterogeneity of MRI, the smaller image set style of the external validation was translated into the larger image set style of the institutional training set using CycleGAN. On external validation before CycleGAN application, the performance of the combined T2 and T1C models showed an area under the curve (AUC), accuracy, and F1 score of 0.77 (95% confidence interval 0.63-0.91), 70.7%, and 0.54, respectively. After applying CycleGAN, the performance of the combined T2 and T1C models increased, with an AUC, accuracy, and F1 score of 0.83 (95% confidence interval 0.70-0.97), 73.2%, and 0.59, respectively. Quantitative metrics (by Frechet Inception Distance) showed that CycleGAN can decrease inter-institutional image heterogeneity while preserving predictive information. In conclusion, leveraging CycleGAN may be helpful to increase the generalizability of a radiomics model in differentiating meningioma grade on external validation

Forced arterial suction thrombectomy with the penumbra reperfusion catheter in acute basilar artery occlusion: a retrospective comparison study in 2 Korean university hospitals.

Background and purpose: A performance of forced arterial suction thrombectomy was not reported for the treatment of acute basilar artery occlusion. This study compared revascularization performance between intra-arterial fibrinolytic treatment and forced arterial suction thrombectomy with a Penumbra reperfusion catheter in patients with acute basilar artery occlusion. Materials and methods: Fifty-seven patients with acute basilar artery occlusion were treated with intra-arterial fibrinolysis (n = 25) or forced arterial suction thrombectomy (n = 32). Baseline characteristics, successful revascularization rate, and clinical outcomes were compared between the groups. Results: Baseline characteristics, the frequency of patients receiving intravenous recombinant tissue plasminogen activator, and mean time interval between symptom onset and femoral puncture did not differ between groups. The forced arterial suction thrombectomy group had a shorter procedure duration (75.5 minutes versus 113.3 minutes, P = .016) and higher successful revascularization rate (88% versus 60%, P = .017) than the fibrinolysis group. Fair outcome, indicated by a modified Rankin Scale 0-3, at 3 months was achieved in 34% of patients undergoing forced arterial suction thrombectomy and 8% of patients undergoing fibrinolysis (P = .019), and the mortality rate was significantly higher in the fibrinolysis group (25% versus 68%, P = .001). Multiple logistic regression analysis identified the forced arterial suction thrombectomy method as an independent predictor of fair outcome with adjustment for age, sex, initial NIHSS score, and the use of intravenous recombinant tissue plasminogen activator (odds ratio, 7.768; 95% CI, 1.246-48.416; P = .028). Conclusions: In acute basilar artery occlusion, forced arterial suction thrombectomy demonstrated a higher revascularization rate and improved clinical outcome compared with traditional intra-arterial fibrinolysis. Further clinical trials with the newer Penumbra catheter are warranted

Laparoscopic Sentinel Node Navigation Surgery for Stomach Preservation in Patients with Early Gastric Cancer: A Randomized Clinical Trial

PURPOSE: To compare postoperative complications, long-term survival, and quality of life (QOL) after laparoscopic sentinel node navigation surgery (LSNNS) and laparoscopic standard gastrectomy (LSG). METHODS: Five hundred eighty patients with preoperatively diagnosed stage IA gastric adenocarcinoma

Feasibility of Regional Lymphadenectomy for Stomach-Preserving Surgery in Early Gastric Cancer Omitting Sentinel Node Navigation: A Post Hoc Analysis of the SENORITA Trial

Background: Sentinel node navigation (SNN) has been known as the effective treatment for stomach-preserving surgery in early gastric cancer; however, SNN presents several technical difficulties in real practice. Objective: This study aimed to evaluate the feasibility of regional lymphadenectomy omitting SNN, using the post hoc analysis of a randomized controlled trial. Methods: Using data from the SENORITA trial that compared laparoscopic standard gastrectomy with lymphadenectomy and laparoscopic SNN, 237 patients who underwent SNN were included in this study. Tumor location was divided into longitudinal and circumferential directions. According to the location of the tumor, the presence or absence of lymph node (LN) metastases between sentinel and non-sentinel basins were analyzed. Proposed regional LN stations were defined as the closest area to the primary tumor. Sensitivities, specificities, positive predictive values, and negative predictive values (NPV) of SNN and regional lymphadenectomy were compared. Results: Metastasis to non-sentinel basins with tumor-free in sentinel basins was observed in one patient (0.4%). The rate of LN metastasis to non-regional LN stations without regional LN metastasis was 2.5% (6/237). The sensitivity and NPV of SNN were found to be significantly higher than those of regional lymphadenectomy (96.8% vs. 80.6% [p = 0.016] and 99.5% vs. 97.2% [p = 0.021], respectively). Conclusions: This study showed that regional lymphadenectomy for stomach-preserving surgery, omitting SNN, was insufficient; therefore, SNN is required in stomach-preserving surgery

Assessment of laparoscopic stomach preserving surgery with sentinel basin dissection versus standard gastrectomy with lymphadenectomy in early gastric cancer-A multicenter randomized phase III clinical trial (SENORITA trial) protocol

BACKGROUND: Along with the marked increase in early gastric cancer (EGC) in the Eastern countries, there has been an effort to adopt the sentinel node concept in EGC to preserve gastric function and reduce the occurrence of postoperative complications. Based on promising results from a previous quality control study, this prospective multicenter randomized controlled phase III clinical trial aims to elucidate the oncologic safety of laparoscopic stomach-preserving surgery with sentinel basin dissection (SBD) compared to a standard laparoscopic gastrectomy. METHODS/DESIGN: This trial is an investigator-initiated, open-label, multicenter randomized controlled phase III trial with a non-inferiority design. Patients diagnosed with a single lesion of clinical stage T1N0M0 gastric adenocarcinoma, with a diameter of 3 cm or less are eligible for the present study. A total of 580 patients (290 per group) will be randomized to either laparoscopic stomach-preserving surgery with SBD or standard surgery. The primary end-point is 3-year disease-free survival (DFS) and the secondary endpoints include postoperative morbidity and mortality, quality of life, 5-year DFS, and overall survival. Qualified investigators who completed the prior quality control study are exclusively allowed to participate in this phase III clinical trial. DISCUSSION: The proposed trial is expected to verify whether laparoscopic stomach-preserving surgery with SBD achieves similar oncologic outcomes and improved quality of life compared to a standard gastrectomy in EGC patients. TRIAL REGISTRATION: This study was registered at the NIH ClinicalTrial.gov database ( NCT01804998 ) on March 4th, 2013

Prospective Multicenter Feasibility Study of Laparoscopic Sentinel Basin Dissection for Organ Preserving Surgery in Gastric Cancer: Quality Control Study for Surgical Standardization Prior to Phase III Trial.

The clinical application of sentinel node biopsies in early gastric cancer is still controversial even though it appears promising. This study was conducted as a prerequisite quality control for surgical standardization of laparoscopic sentinel basin dissection (SBD) prior to the initiation of a phase III trial.Laparoscopic SBD was performed in patients with preoperative stage T1-2N0 and tumor size <4 cm in diameter. Intraoperative endoscopic submucosal injection of a standardized dual tracer was administered. All retrieved sentinel basin nodes (SBN) were investigated with intraoperative frozen hematoxylin and eosin (H&E) staining. A strict checklist consisting of 7 essential steps was followed during laparoscopic SBD as the quality control study for a phase III trial. Completion of all essential steps in the checklist for 10 cases was used to define a qualified institution.Seven institutions participated and 112 patients were enrolled in this study. However, 4 patients were excluded owing to screening failure. The mean number of cases required for institutional qualification was 15 cases (range, 13-20 cases). Sentinel basins (SB) were detected and dissected in 100 of the 108 patients (92.6%); the median number of SB and SBN was 2 and 7, respectively. Lymph node metastases were detected in 10 patients by postoperative permanent H&E staining and they were detected by SBD in all 10 patients. Frozen results of SBN were compatible with permanent staining reports.Laparoscopic SBD is feasible and demonstrated improved sensitivity in detecting metastatic lymph nodes compared to the previous study. A future phase III randomized trial comparing laparoscopic SBD with organ-preserving gastrectomy and laparoscopic standard gastrectomy seems promising for qualified institutions

p38 MAPK and JNK Antagonistically Control Senescence and Cytoplasmic p16INK4A Expression in Doxorubicin-Treated Endothelial Progenitor Cells

Patients treated with low-dose anthracyclines often show late onset cardiotoxicity. Recent studies suggest that this form of cardiotoxicity is the result of a progenitor cell disease. In this study we demonstrate that Cord Blood Endothelial Progenitor Cells (EPCs) exposed to low, sub-apoptotic doses of doxorubicin show a senescence phenotype characterized by increased SA-b-gal activity, decreased TRF2 and chromosomal abnormalities, enlarged cell shape, and disarrangement of F-actin stress fibers accompanied by impaired migratory ability. P16 INK4A localizes in the cytoplasm of doxorubicin-induced senescent EPCs and not in the nucleus as is the case in EPCs rendered senescent by different stimuli. This localization together with the presence of an arrest in G2, and not at the G1 phase boundary, which is what usually occurs in response to the cell cycle regulatory activity of p16INK4A, suggests that doxorubicin-induced p16 INK4A does not regulate the cell cycle, even though its increase is closely associated with senescence. The effects of doxorubicin are the result of the activation of MAPKs p38 and JNK which act antagonistically. JNK attenuates the senescence, p16 INK4A expression and cytoskeleton remodeling that are induced by activated p38. We also found that conditioned medium from doxorubicin-induced senescent cardiomyocytes does not attract untreated EPCs, unlike conditioned medium from apoptotic cardiomyocytes which has a strong chemoattractant capacity. In conclusion, this study provides a better understanding of the senescence of doxorubicin-treated EPCs, which may be helpful in preventing and treating late onset cardiotoxicity