All cancers harbor molecular alterations in their genomes. The transcriptional consequences of these somatic mutations have not yet been comprehensively explored in lung cancer. Here we present the ...first large scale RNA sequencing study of lung adenocarcinoma, demonstrating its power to identify somatic point mutations as well as transcriptional variants such as gene fusions, alternative splicing events, and expression outliers. Our results reveal the genetic basis of 200 lung adenocarcinomas in Koreans including deep characterization of 87 surgical specimens by transcriptome sequencing. We identified driver somatic mutations in cancer genes including EGFR, KRAS, NRAS, BRAF, PIK3CA, MET, and CTNNB1. Candidates for novel driver mutations were also identified in genes newly implicated in lung adenocarcinoma such as LMTK2, ARID1A, NOTCH2, and SMARCA4. We found 45 fusion genes, eight of which were chimeric tyrosine kinases involving ALK, RET, ROS1, FGFR2, AXL, and PDGFRA. Among 17 recurrent alternative splicing events, we identified exon 14 skipping in the proto-oncogene MET as highly likely to be a cancer driver. The number of somatic mutations and expression outliers varied markedly between individual cancers and was strongly correlated with smoking history of patients. We identified genomic blocks within which gene expression levels were consistently increased or decreased that could be explained by copy number alterations in samples. We also found an association between lymph node metastasis and somatic mutations in TP53. These findings broaden our understanding of lung adenocarcinoma and may also lead to new diagnostic and therapeutic approaches.
The development of highly active and durable Ir‐based electrocatalysts for the acidic oxygen evolution reaction (OER) is challenging because of the corrosive anodic conditions. Herein, IrOx/Zr2ON2 ...electrocatalyst is demonstrated, employing Zr2ON2 as a support material, to overcome the trade‐off between the activity and stability in the OER. Zr2ON2 is selected due to its excellent electrical conductivity and chemical stability, and the fact that it induces strong interactions with IrOx catalysts. As a result, IrOx/Zr2ON2 electrocatalysts exhibit outstanding OER performances, reaching an overpotential of 255 mV at 10 mA cm−2 and a mass activity of 849 mA mgIr−1 at 1.55 V (vs the reversible hydrogen electrode). The activity of IrOx/Zr2ON2 is maintained at 10 mA cm−2 for 5 h, while in contrast, IrOx/ZrN and an unsupported IrOx catalyst undergo drastic degradation. Combined experimental X‐ray analyses and theoretical interpretations reveal that the reduced oxidation state of Ir and the extended IrO bond distance in IrOx/Zr2ON2 effectively increase the activity and stability of IrOx by altering reaction pathway from a conventional adsorbate evolution mechanism to a lattice oxygen‐participating mechanism. These results demonstrate that it is possible to effectively reduce the Ir content in OER catalysts through interface engineering without sacrificing the catalytic performance.
Newly designed IrOx/Zr2ON2 electrocatalyst, which employs Zr2ON2 as a support material, to break the trade‐off between activity and stability in oxygen evolution reaction. The reduced oxidation state of Ir and the extended IrO bond distance IrOx/Zr2ON2 effectively increase activity and stability of IrOx by altering reaction pathway from a conventional adsorbate evolution mechanism to a lattice oxygen‐participating mechanism.
A wearable surface-enhanced Raman scattering (SERS) sensor has been developed as a patch type to utilize as a molecular sweat sensor. Here, the SERS patch sensor is designed to comprise a ...sweat-absorbing layer, which is an interface to the human skin, an SERS active layer, and a dermal protecting layer that prevents damage and contaminations. A silk fibroin protein film (SFF) is a basement layer that absorbs aqueous solutions and filtrates molecules larger than the nanopores created in the β-sheet matrix of the SFF. On the SFF layer, a plasmonic silver nanowire (AgNW) layer is formed to enhance the Raman signal of the molecules that penetrated through the SERS patch in a label-free method. A transparent dermal protecting layer (DP) allows laser penetration to the AgNW layer enabling Raman measurement through the SERS patch without its detachment from the surface. The molecular detection capability and time-dependent absorption properties of the SERS patch are investigated, and then, the feasibility of its use as a wearable drug detection sweat sensor is demonstrated using 2-fluoro-methamphetamine (2-FMA) on the human cadaver skin. It is believed that the developed SERS patch can be utilized as various flexible and wearable biosensors for healthcare monitoring.
Background:
Although many clinical studies have assessed the efficacy of mesenchymal stem cells (MSCs) in knee osteoarthritis, evidence on their efficacy remains unclear owing to heterogeneity of ...cell entity and concomitant procedures.
Purpose:
To determine the efficacy of culture-expanded MSCs in knee osteoarthritis in terms of clinical outcome and cartilage repair via meta-analysis of randomized controlled trials (RCTs) without adjuvant surgery.
Study Design:
Meta-analysis.
Methods:
PubMed, Embase, the Cochrane Library, CINAHL, and Scopus were searched from inception to December 31, 2018. RCTs with culture-expanded MSCs for treating knee osteoarthritis were included. Studies with adjuvant surgery or cell concentrate were excluded. Quality was assessed by the Cochrane Collaboration risk-of-bias tool. For meta-analysis, data on clinical outcomes were measured using a visual analog scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and data on cartilage repair were measured using the Whole-Organ Magnetic Resonance Imaging Score (WORMS); categorization related to improvement was extracted.
Results:
Six RCTs (203 patients) were included. Two studies were deemed to have a low risk of bias. In pooled analysis, the only significant difference was in the VAS score (mean difference, –13.55; 95% CI, –22.19 to −4.9). In cumulative pain analysis with VAS and WOMAC pain scores, there was significant improvement after treatment (standardized mean difference, –0.54; 95% CI, –0.85 to −0.23). There was no significant difference in cartilage repair assessed by magnetic resonance imaging (standardized mean difference, 0.11; 95% CI, –0.51 to 0.73), WORMS (standardized mean difference, 1.68; 95% CI −14.84 to 18.21), or categorical results (odds ratio, 1.56; 95% CI, 0.32-7.59).
Conclusion:
Intra-articular injection of culture-expanded MSCs without adjuvant surgery can improve pain for patients experiencing knee osteoarthritis at short-term follow-up (6-12 months). However, evidence regarding function and cartilage repair remains limited.
Introduction
Mesenchymal stem cells (MSCs) have gained popularity for articular cartilage repair. However, efficacy of intra-articular MSCs in osteoarthritis remains unclear. In the setting of a ...meta-analysis of randomized controlled trials (RCTs), we aimed to investigate the efficacy of intra-articular MSCs on clinical outcomes and cartilage repair in patients with knee osteoarthritis.
Materials and methods
PubMed, EMBASE, Cochrane Library, CINAHL, and Scopus were searched from inception to March 31, 2017. This study included RCTs using cell population containing MSCs for treatment of knee osteoarthritis. The quality was assessed by Cochrane Collaboration`s risk of bias tool. For meta-analysis, data on clinical outcomes measured by visual analog scale (VAS), Lysholm score, WOMAC and data on cartilage repair measured by MOCART and WORMS were extracted. In studies with several cell concentrations, outcomes of recommended concentration were used mainly to ensure robustness.
Results
A total of five RCTs (220 patients) were included. Two studies were deemed to have low risk of bias. In pooled analysis, there was significant difference in VAS score (mean difference MD, − 9.2; 95% CI: − 17.21, − 1.20) and Lysholm score (MD, 8.70; 95% CI 0.06, 17.34), but not WOMAC (MD, − 7.44; 95% CI − 20.38, 5.50). In cumulative functional analysis using Lysholm score and WOMAC in recommended concentration, there was a significant improvement (standard mean difference SMD, 0.53; 95% CI 0.13, 0.94) after treatment. In cartilage repair assessed by MRI, there was no significant difference (SMD, 0.53; 95% CI− 0.28, 1.34).
Conclusions
This meta-analysis demonstrated that intra-articular MSCs have a limited evidence in pain relief and functional improvement in knee osteoarthritis. While MSCs may result in favorable clinical outcomes with a recommended concentration, use of concomitant treatment should be considered. In addition, current evidence does not support the use of intra-articular MSCs for improving cartilage repair in knee osteoarthritis.
Level of evidence
Systematic review of Level-II studies.
To define prognostic impact of Epstein-Barr virus (EBV) infection in diffuse large B-cell lymphoma (DLBCL), we investigated EBV status in patients with DLBCL. In all, 380 slides from ...paraffin-embedded tissue were available for analysis by EBV-encoded RNA-1 (EBER) in situ hybridization, and 34 cases (9.0%) were identified as EBER-positive. EBER positivity was significantly associated with age greater than 60 years (P = .005), more advanced stage (P < .001), more than one extranodal involvement (P = .009), higher International Prognostic Index (IPI) risk group (P = .015), presence of B symptom (P = .004), and poorer outcome to initial treatment (P = .006). The EBER+ patients with DLBCL demonstrated substantially poorer overall survival (EBER+ vs EBER− 35.8 months 95% confidence interval (CI), 0-114.1 months vs not reached, P = .026) and progression-free survival (EBER+ vs EBER− 12.8 months 95% CI, 0-31.8 months vs 35.8 months 95% CI, 0-114.1 months, respectively (P = .018). In nongerminal center B-cell–like subtype, EBER in situ hybridization positivity retained its statistical significance at the multivariate level (P = .045). Nongerminal center B-cell–like patients with DLBCL with EBER positivity showed substantially poorer overall survival with 2.9-fold (95% CI, 1.1-8.1) risk for death. Taken together, DLBCL patients with EBER in situ hybridization+ pursued more rapidly deteriorating clinical course with poorer treatment response, survival, and progression-free survival.
We investigated the effects of nilotinib plus multiagent chemotherapy, followed by consolidation/maintenance or allogeneic hematopoietic cell transplantation (allo-HCT) for adult patients with newly ...diagnosed Philadelphia-positive (Ph-pos) acute lymphoblastic leukemia (ALL). Study subjects received induction treatment that comprised concurrent vincristine, daunorubicin, prednisolone, and nilotinib. After achieving complete hematologic remission (HCR), subjects received either 5 courses of consolidation, followed by 2-year maintenance with nilotinib, or allo-HCT. Minimal residual disease (MRD) was assessed at HCR, and every 3 months thereafter. The molecular responses (MRs) were defined as MR3 for BCR-ABL1/G6PDH ratios ≤10−3 and MR5 for ratios <10−5. Ninety evaluable subjects, ages 17 to 71 years, were enrolled in 17 centers. The HCR rate was 91%; 57 subjects received allo-HCT. The cumulative MR5 rate was 94%; the 2-year hematologic relapse-free survival (HRFS) rate was 72% for 82 subjects that achieved HCR, and the 2-year overall survival rate was 72%. Subjects that failed to achieve MR3 or MR5 were 9.1 times (P = .004) or 6.3 times (P = .001) more prone to hematologic relapse, respectively, than those that achieved MR3 or MR5. MRD statuses just before allo-HCT and at 3 months after allo-HCT were predictive of 2-year HRFS. Adverse events occurred mainly during induction, and most were reversible with dose reduction or transient interruption of nilotinib. The combination of nilotinib with high-dose cytotoxic drugs was feasible, and it effectively achieved high cumulative complete molecular remission and HRFS rates. The MRD status at early postremission time was predictive of the HRFS. This trial was registered at www.clinicaltrials.gov as #NCT00844298.
•Nilotinib plus multiagent chemotherapy was feasible and showed a comparable outcome to previous results with imatinib for Ph-pos ALL.•The achievement of deep MR with nilotinib at postremission correlated well with the clinical outcomes for Ph-pos ALL.
The placenta is a very attractive source of mesenchymal stem cells (MSCs) for regenerative medicine due to readily availability, non-invasive acquisition, and avoidance of ethical issues. Isolating ...MSCs from parts of placenta tissue has obtained growing interest because they are assumed to exhibit different proliferation and differentiation potentials due to complex structures and functions of the placenta. The objective of this study was to isolate MSCs from different parts of the placenta and compare their characteristics.
Placenta was divided into amniotic epithelium (AE), amniotic membrane (AM), chorionic membrane (CM), chorionic villi (CV), chorionic trophoblast without villi (CT-V), decidua (DC), and whole placenta (Pla). Cells isolated from each layer were subjected to analyses for their morphology, proliferation ability, surface markers, and multi-lineage differentiation potential. MSCs were isolated from all placental layers and their characteristics were compared.
Surface antigen phenotype, morphology, and differentiation characteristics of cells from all layers indicated that they exhibited properties of MSCs. MSCs from different placental layers had different proliferation rates and differentiation potentials. MSCs from CM, CT-V, CV, and DC had better population doubling time and multi-lineage differentiation potentials compared to those from other layers.
Our results indicate that MSCs with different characteristics can be isolated from all layers of term placenta. These finding suggest that it is necessary to appropriately select MSCs from different placental layers for successful and consistent outcomes in clinical applications.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background The clinical outcome of extranodal natural killer T-cell lymphoma (ENKTL) has improved substantially as a result of new treatment strategies with non-anthracycline-based ...chemotherapies and upfront use of concurrent chemoradiotherapy or radiotherapy. A new prognostic model based on the outcomes obtained with these contemporary treatments was warranted. Methods We did a retrospective study of patients with newly diagnosed ENKTL without any previous treatment history for the disease who were given non-anthracycline-based chemotherapies with or without upfront concurrent chemoradiotherapy or radiotherapy with curative intent. A prognostic model to predict overall survival and progression-free survival on the basis of pretreatment clinical and laboratory characteristics was developed by filling a multivariable model on the basis of the dataset with complete data for the selected risk factors for an unbiased prediction model. The final model was applied to the patients who had complete data for the selected risk factors. We did a validation analysis of the prognostic model in an independent cohort. Findings We did multivariate analyses of 527 patients who were included from 38 hospitals in 11 countries in the training cohort. Analyses showed that age greater than 60 years, stage III or IV disease, distant lymph-node involvement, and non-nasal type disease were significantly associated with overall survival and progression-free survival. We used these data as the basis for the prognostic index of natural killer lymphoma (PINK), in which patients are stratified into low-risk (no risk factors), intermediate-risk (one risk factor), or high-risk (two or more risk factors) groups, which were associated with 3-year overall survival of 81% (95% CI 75–86), 62% (55–70), and 25% (20–34), respectively. In the 328 patients with data for Epstein-Barr virus DNA, a detectable viral DNA titre was an independent prognostic factor for overall survival. When these data were added to PINK as the basis for another prognostic index (PINK-E)—which had similar low-risk (zero or one risk factor), intermediate-risk (two risk factors), and high-risk (three or more risk factors) categories—significant associations with overall survival were noted (81% 95% CI 75–87%, 55% (44–66), and 28% (18–40%), respectively). These results were validated and confirmed in an independent cohort, although the PINK-E model was only significantly associated with the high-risk group compared with the low-risk group. Interpretation PINK and PINK-E are new prognostic models that can be used to develop risk-adapted treatment approaches for patients with ENKTL being treated in the contemporary era of non-anthracycline-based therapy. Funding Samsung Biomedical Research Institute.
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•Bimetallic Au@Pt NPs as core-shell structures demonstrate the enhanced catalytic performance for glucose oxidation.•Nafion layer and dendritic Pt shells prevent passivation of the Au ...core.•Additional Au plating further enhances catalytic performance.•Rationally designed Au-decorated Au@Pt NPs show enhanced sensitivity, stability, and selectivity towards glucose detection.
Core-shell structured Au@Pt nanoparticles (NPs) with Au cores and dendritic Pt shells have been synthesized using the sonochemical method. Then, the Au is electrochemically incorporated into nano-channels between the Pt shells on the Au@Pt NPs (Au@Pt/Au NPs) to form a non-enzymatic glucose sensor. The electrochemically active surface area (ECSA) of the obtained Au@Pt/Au NPs is enlarged compared with that of Au@Pt NPs, which leads to enhanced glucose sensing performance. The particle sizes of Au@Pt/Au NPs are in the range from 35 nm to 60 nm. The ECSA of Au@Pt/Au NPs is calculated to be 6.19 m2 g(Pt)−1 and 0.8 m2 g(Au)−1 by cyclic voltammetry. The Au incorporation into the Pt shell region can boost the glucose oxidation process even at neutral pH. The sensor performance under the optimized experimental conditions has been confirmed in phosphate buffered saline (PBSsal) solution, showing two wide dynamic ranges for glucose (0.5–10.0 μM and 0.01–10.0 mM) with the correlation coefficient of 0.99. The detection limit of glucose in PBS saline solution has been determined to be 445.7 (±10.3) nM.
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