ITDetect: a method to detect internal tandem duplication of FMS-like tyrosine kinase (FLT3) from next-generation sequencing data with high sensitivity and clinical application.

Internal tandem duplication (ITD) of the FMS-like tyrosine kinase (FLT3) gene is associated with poor clinical outcomes in patients with acute myeloid leukemia. Although recent methods for detecting FLT3-ITD from next-generation sequencing (NGS) data have replaced traditional ITD detection approaches such as conventional PCR or fragment analysis, their use in the clinical field is still limited and requires further information. Here, we introduce ITDetect, an efficient FLT3-ITD detection approach that uses NGS data. Our proposed method allows for more precise detection and provides more detailed information than existing in silico methods. Further, it enables FLT3-ITD detection from exome sequencing or targeted panel sequencing data, thereby improving its clinical application. We validated the performance of ITDetect using NGS-based and experimental ITD detection methods and successfully demonstrated that ITDetect provides the highest concordance with the experimental methods. The program and data underlying this study are available in a public repository.

When Chirophotonic Film Meets Wrinkles: Viewing Angle Independent Corrugated Photonic Crystal Paper.

Light manipulation strategies of nature have fascinated humans for centuries. In particular, structural colors are of considerable interest due to their ability to control the interaction between light and matter. Here, wrinkled photonic crystal papers (PCPs) are fabricated to demonstrate the consistent reflection of colors regardless of viewing angles. The nanoscale molecular self-assembly of a cholesteric liquid crystal (CLC) with a microscale corrugated surface is combined. Fully polymerizable CLC paints are uniaxially coated onto a wrinkled interpenetrating polymer network (IPN) substrate. Photopolymerization of the helicoidal nanostructures results in a flexible and free-standing PCP. The facile method of fabricating the wrinkled PCPs provides a scalable route for the development of novel chirophotonic materials with precisely controlled helical pitch and curvature dimensions. The reflection notch position of the flat PCP shifts to a lower wavelength when the viewing angle increased, while the selective reflection wavelength of wrinkled PCP is remained consistent regardless of viewing angles. The optical reflection of the 1D stripe-wrinkled PCP is dependent on the wrinkle direction. PCPs with different corrugated directions can be patterned to reduce the angular-dependent optical reflection of wrinkles. Furthermore, 2D wavy-wrinkled PCP is successfully developed that exhibit directionally independent reflection of color.

Ultrastrong Hybrid Fibers with Tunable Macromolecular Interfaces of Graphene Oxide and Carbon Nanotube for Multifunctional Applications.

Individual carbon nanotubes (CNT) and graphene have unique mechanical and electrical properties; however, the properties of their macroscopic assemblies have not met expectations because of limited physical dimensions, the limited degree of dispersion of the components, and various structural defects. Here, a state-of-the-art assembly for a novel type of hybrid fiber possessing the properties required for a wide variety of multifunctional applications is presented. A simple and effective multidimensional nanostructure of CNT and graphene oxide (GO) assembled by solution processing improves the interfacial utilization of the components. Flexible GOs are effectively intercalated between nanotubes along the shape of CNTs, which reduces voids, enhances orientation, and maximizes the contact between elements. The microstructure is finely controlled by the elements content ratio and dimensions, and an optimal balance improves the mechanical properties. The hybrid fibers simultaneously exhibit exceptional strength (6.05 GPa), modulus (422 GPa), toughness (76.8 J g-1 ), electrical conductivity (8.43 MS m-1 ), and knot strength efficiency (92%). Furthermore, surface and electrochemical properties are significantly improved by tuning the GO content, further expanding the scope of applications. These hybrid fibers are expected to offer a strategy for overcoming the limitations of existing fibers in meeting the requirements for applications in the fiber industry.

Ultrahigh strength, modulus, and conductivity of graphitic fibers by macromolecular coalescence.

Theoretical considerations suggest that the strength of carbon nanotube (CNT) fibers be exceptional; however, their mechanical performance values are much lower than the theoretical values. To achieve macroscopic fibers with ultrahigh performance, we developed a method to form multidimensional nanostructures by coalescence of individual nanotubes. The highly aligned wet-spun fibers of single- or double-walled nanotube bundles were graphitized to induce nanotube collapse and multi-inner walled structures. These advanced nanostructures formed a network of interconnected, close-packed graphitic domains. Their near-perfect alignment and high longitudinal crystallinity that increased the shear strength between CNTs while retaining notable flexibility. The resulting fibers have an exceptional combination of high tensile strength (6.57 GPa), modulus (629 GPa), thermal conductivity (482 W/m·K), and electrical conductivity (2.2 MS/m), thereby overcoming the limits associated with conventional synthetic fibers.

Domain-selective thermal decomposition within supramolecular nanoribbons.

Self-assembly of small molecules in water provides a powerful route to nanostructures with pristine molecular organization and small dimensions (<10 nm). Such assemblies represent emerging high surface area nanomaterials, customizable for biomedical and energy applications. However, to exploit self-assembly, the constituent molecules must be sufficiently amphiphilic and satisfy prescribed packing criteria, dramatically limiting the range of surface chemistries achievable. Here, we design supramolecular nanoribbons that contain: (1) inert and stable internal domains, and (2) sacrificial surface groups that are thermally labile, and we demonstrate complete thermal decomposition of the nanoribbon surfaces. After heating, the remainder of each constituent molecule is kinetically trapped, nanoribbon morphology and internal organization are maintained, and the nanoribbons are fully hydrophobic. This approach represents a pathway to form nanostructures that circumvent amphiphilicity and packing parameter constraints and generates structures that are not achievable by self-assembly alone, nor top-down approaches, broadening the utility of molecular nanomaterials for new targets.

The transfer and amplification of cyanostilbene molecular function to advanced flexible optical paints through self-crosslinkable side-chain liquid crystal polysiloxanes.

A self-crosslinkable side-chain liquid crystal polysiloxane containing cyanostilbene (Si-CSM) was newly synthesized for the development of a new generation of flexible optical paints. The photoisomerization of the cyanostilbene moiety at the molecular level was transferred and amplified to the phase transition of Si-CSM, resulting in changes in the macroscopic optical properties of the Si-CSM thin film. The self-crosslinking reaction between Si-H groups in the Si-CSM polymer backbone caused the self-crosslinked Si-CSM thin film to be very elastic and both thermally and chemically stable. Therefore, the self-crosslinked Si-CSM thin film endured stretching and bending deformations under relatively harsh conditions. In addition, the uniaxially oriented and self-crosslinked Si-CSM thin film generated linearly polarized light emission. Polarization-dependent and photopatternable secret coatings were fabricated via a spontaneous self-crosslinking reaction after coating the Si-CSM paint and irradiating ultraviolet (UV) light through a photomask. This newly developed flexible optical Si-CSM paint can be applied in next-generation optical coatings.

Development of Diketopyrrolopyrrole-Based Smart Inks by Substituting Ionic Pendants and Engineering Molecular Packing Structures.

A series of diketopyrrolopyrrole (DPP) luminogen amphiphiles were newly designed and synthesized by a single-step anionic exchange reaction for controlling the photoluminescence properties in both solution and solid states. Multicolor emission in response to thermal, mechanical, and chemical stimuli was successfully demonstrated by engineering well-defined supramolecular assemblies. Phase transformation from the metastable amorphous solid to the stable orthorhombic crystal of [DP-Im][Br] provided the reversibly patternable light emission. Self-organization into the smectic crystalline phase of [DP-Im][TFSI] allowed us to show the linearly polarized light emission. By simultaneously applying [DP-Im][Br] and [DP-Im][TFSI], we demonstrated the fabrication of smart sensors for packaging of food or vaccines that can detect thermal attacks.

Morphological Transitions of a Photoswitchable Aramid Amphiphile Nanostructure.

Self-assembly of small amphiphilic molecules in water can lead to nanostructures of varying geometries with pristine internal molecular organization. Here we introduce a photoswitchable aramid amphiphile (AA), designed to exhibit extensive hydrogen bonding and robust mechanical properties upon self-assembly, while containing a vinylnitrile group for photoinduced cis-trans isomerization. We demonstrate spontaneous self-assembly of the vinylnitrile-containing AA in water to form nanoribbons. Upon UV irradiation, trans-to-cis isomerizations occur concomitantly with a morphological transition from nanoribbons to nanotubes. The nanotube structure persists in water for over six months, stabilized by strong and collective intermolecular interactions. We demonstrate that the nanoribbon-to-nanotube transition is reversible upon heating and that switching between states can be achieved repeatedly. Finally, we use electron microscopy to capture the transition and propose mechanisms for nanoribbon-to-nanotube rearrangement and vice versa. The stability and switchability of photoresponsive AA nanostructures make them viable for a range of future applications.

Self-assembly of aramid amphiphiles into ultra-stable nanoribbons and aligned nanoribbon threads.

Small-molecule self-assembly is an established route for producing high-surface-area nanostructures with readily customizable chemistries and precise molecular organization. However, these structures are fragile, exhibiting molecular exchange, migration and rearrangement-among other dynamic instabilities-and are prone to dissociation upon drying. Here we show a small-molecule platform, the aramid amphiphile, that overcomes these dynamic instabilities by incorporating a Kevlar-inspired domain into the molecular structure. Strong, anisotropic interactions between aramid amphiphiles suppress molecular exchange and elicit spontaneous self-assembly in water to form nanoribbons with lengths of up to 20 micrometres. Individual nanoribbons have a Young's modulus of 1.7 GPa and tensile strength of 1.9 GPa. We exploit this stability to extend small-molecule self-assembly to hierarchically ordered macroscopic materials outside of solvated environments. Through an aqueous shear alignment process, we organize aramid amphiphile nanoribbons into arbitrarily long, flexible threads that support 200 times their weight when dried. Tensile tests of the dry threads provide a benchmark for Young's moduli (between ~400 and 600 MPa) and extensibilities (between ~0.6 and 1.1%) that depend on the counterion chemistry. This bottom-up approach to macroscopic materials could benefit solid-state applications historically inaccessible by self-assembled nanomaterials.

Regulatory role of insulin-like growth factor-binding proteins in odontogenic mineralization in rats.

Much information is currently available for molecules in early odontogenesis, but there is limited knowledge regarding terminal cytodifferentiation of ameloblasts and odontoblasts for the determination of normal crown morphology. The present differential display PCR (DD-PCR) revealed that insulin-like growth factor-binding protein 5 (IGFBP5) was differentially expressed in molar tooth germs between the cap (before crown mineralization) and root formation (after crown mineralization) stages. Real-time PCR confirmed that the expression levels of IGFBP1-4 were not significantly changed but those of IGFBP5-7 were upregulated in a time-dependent manner. Immunoreactivities for IGFBP5-7 were hardly seen in molar germs at the cap/early bell stage and protective-stage ameloblasts at the root formation stage. However, the reactivity was strong in odontoblasts and maturation-stage ameloblasts, which are morphologically and functionally characterized by wide intercellular space and active enamel matrix mineralization. The localization of each IGFBP was temporospatial. IGFBP5 was localized in the nuclei of fully differentiated odontoblasts and ameloblasts, while IGFBP6 was localized in the apical cytoplasm of ameloblasts and odontoblasts with dentinal tubules, and IGFBP7 was mainly found in the whole cytoplasm of odontoblasts and the intercellular space of ameloblasts. IGFBP silencing using specific siRNAs upregulated representative genes for dentinogenesis and amelogenesis, such as DMP1 and amelogenin, respectively, and augmented the differentiation media-induced mineralization, which was confirmed by alizarin red s and alkaline phosphatase staining. These results suggest that IGFBP5-7 may play independent and redundant regulatory roles in late-stage odontogenesis by modulating the functional differentiation of ameloblasts and odontoblasts.

Single-cell analysis of AIMP2 splice variants informs on drug sensitivity and prognosis in hematologic cancer.

Aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) is a non-enzymatic component required for the multi-tRNA synthetase complex. While exon 2 skipping alternatively spliced variant of AIMP2 (AIMP2-DX2) compromises AIMP2 activity and is associated with carcinogenesis, its clinical potential awaits further validation. Here, we found that AIMP2-DX2/AIMP2 expression ratio is strongly correlated with major cancer signaling pathways and poor prognosis, particularly in acute myeloid leukemia (AML). Analysis of a clinical patient cohort revealed that AIMP2-DX2 positive AML patients show decreased overall survival and progression-free survival. We also developed targeted RNA-sequencing and single-molecule RNA-FISH tools to quantitatively analyze AIMP2-DX2/AIMP2 ratios at the single-cell level. By subclassifying hematologic cancer cells based on their AIMP2-DX2/AIMP2 ratios, we found that downregulating AIMP2-DX2 sensitizes cells to anticancer drugs only for a subgroup of cells while it has adverse effects on others. Collectively, our study establishes AIMP2-DX2 as a potential biomarker and a therapeutic target for hematologic cancer.

Understanding of the Mechanism for Laser Ablation-Assisted Patterning of Graphene/ITO Double Layers: Role of Effective Thermal Energy Transfer.

Demand for the fabrication of high-performance, transparent electronic devices with improved electronic and mechanical properties is significantly increasing for various applications. In this context, it is essential to develop highly transparent and conductive electrodes for the realization of such devices. To this end, in this work, a chemical vapor deposition (CVD)-grown graphene was transferred to both glass and polyethylene terephthalate (PET) substrates that had been pre-coated with an indium tin oxide (ITO) layer and then subsequently patterned by using a laser-ablation method for a low-cost, simple, and high-throughput process. A comparison of the results of the laser ablation of such a graphene/ITO double layer with those of the ITO single-layered films reveals that a larger amount of effective thermal energy of the laser used is transferred in the lateral direction along the graphene upper layer in the graphene/ITO double-layered structure, attributable to the high thermal conductivity of graphene. The transferred thermal energy is expected to melt and evaporate the lower ITO layer at a relatively lower threshold energy of laser ablation. The transient analysis of the temperature profiles indicates that the graphene layers can act as both an effective thermal diffuser and converter for the planar heat transfer. Raman spectroscopy was used to investigate the graphite peak on the ITO layer where the graphene upper layer was selectively removed because of the incomplete heating and removal process for the ITO layer by the laterally transferred effective thermal energy of the laser beam. Our approach could have broad implications for designing highly transparent and conductive electrodes as well as a new way of nanoscale patterning for other optoelectronic-device applications using laser-ablation methods.

Diacetylene-Functionalized Dendrons: Self-Assembled and Photopolymerized Three-Dimensional Networks for Advanced Self-Healing and Wringing Soft Materials.

The physical properties of supramolecular soft materials strongly depend on the molecular packing structures constructed by thermodynamically and kinetically controlled molecular self-assembly. To investigate the relationship between molecular function and self-assembled molecular packing structure, a series of diacetylene (DA)-based supramolecules was synthesized by chemically connecting flexible dendrons to DA with amide (aDA-D) or ester (eDA-D) functions. The three-dimensional (3D) organogel network of amide-functionalized aDA-D was prepared in both polar and nonpolar solvents due to the intermolecular hydrogen bonding. 3D networks of aDA-D can be further stabilized by topochemical photopolymerization. The self-healing behavior of aDA-D was observed in the sheet-like structure formed in n-dodecane by the hydrophobic interaction between the gelator and solvent. The wringing behavior of aDA-D was also demonstrated using the dynamic interaction of amide function with n-butanol solvent. Kinetically controlled and photostabilized 3D networks can be a key component from biomedical devices to soft robotic applications.

MED-TMA: A clinical decision support tool for differential diagnosis of TMA with enhanced accuracy using an ensemble method.

Considering difficulties in on-site ADAMTS13 testing and the performance instability of PLASMIC score according to ethnicity, we developed a prediction tool, MED-TMA (machine learning (ML) method for differential diagnosis (DDx) of thrombotic microangiopathy (TMA)) to support clinical decision. Data from 319 patients visiting 31 hospitals in Korea clinically diagnosed with primary TMA was randomly separated by 2:1 into two groups - the development dataset (D-set, n = 212), the validation dataset (V-set, n = 107). Feature elimination was conducted to select optimal clinical predictors. We developed the model with the selected features using ML methods, verifying using V-set. After the feature elimination using 19 clinical variables, five variables were selected with high importance value. Among nine ML methods, four ML methods were chosen considering the Area Under the Curves (AUC) and the correlation between the methods using D-set. We developed MED-TMA based on an optimized ensemble model with the selected four ML methods resulting in AUC values of 0.945 and 0.924 in D-set and V-set, respectively. In addition to the binary outcome, MED-TMA was capable of providing a probability for DDx of TMA. The ensemble approach driven MED-TMA showed comparable accurate and intuitive decision support for DDx of TMA to that of the existing models based on a single ML method. We provide a web-based nomogram for the appropriate use of effective but costly therapeutics to treat TMA patients (http://hematology.snu.ac.kr/medtma/).

Making Nonconjugated Small-Molecule Organic Radicals Conduct.

Charge neutral, nonconjugated organic radicals have emerged as extremely useful active materials for solid-state electronic applications. This previous achievement confirmed the potential of radical-based macromolecules in organic electronic devices; however, charge transport in radical molecules has not been studied in great detail from a fundamental perspective. Here we demonstrate the charge transport in a nonconjugated organic small radical, 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (h-TEMPO). The chemical component of this radical molecule allows us to form a single crystal via physical vapor deposition (PVD). While the charge transport of this macroscopic open-shell single crystal is rather low, thermal annealing of the well-defined single crystal enables the molecule to have a rapid charge transfer reaction due to the electronic communication of open-shell sites with each other, which results in electrical conductivities greater than 0.05 S m-1. This effort demonstrates a drastically different model than the commonly accepted conjugated polymers or molecules for the creation of next-generation conductors.

Truncation of MYH8 tail in AML: a novel prognostic marker with increase cell migration and epithelial-mesenchymal transition utilizing RAF/MAPK pathway.

MYH8 is an actin-based motor protin involved in integrin-mediated cell adhesion and migration. Heretofore, the association of MYH8 mutation and cancer is unclear. In this study, we investigated the biologic significance of novel MYH8 tail truncation mutation, R1292X, in acute myeloid leukemia (AML) which was discovered by whole-exome sequencing and targeted re-sequencing of 209 AML patients. The patients harboring the mutation all relapsed within 3.8-20.9 months. To explore the functional consequence of the mutation in AML progress, we established knock-in cell lines using CRISPR-Cas9 genome editing. Using the established mutant model, we assessed traits of cancer progress. The mutant cells had improved motility, which was confirmed by immunofluorescence staining, wound healing, transwell migration and adhesion assay. The cell morphology and cell cycle were altered to be accessible to migration and epithelial-to-mesenchymal transition (EMT) transcription factors were also increased. The Raf and p44/42 MAPK pathway was a major regulator of these characteristics proved by a screening of signal transduction and inhibitor assay. Further, a public cancer genome database (cBioPortal) shows that MYH8 tail truncation mutations occurring near the R1292 position of the genome may have a significant function in cancer. In conclusion, truncation of MYH8 could be a novel prognostic marker related to poor prognosis by inducing cell migration and EMT features, and inhibition of the Raf/MAPK pathway would be a therapeutic strategy for AML patients with MYH8 tail truncation.

The Temporal Sequence and the Differences in Somatic Mutation Acquisition Determines Clinical Behaviors of JAK2-Positive Myeloproliferative Neoplasms.

BACKGROUND/AIM: We have yet to understand why JAK2-positive myeloproliferative neoplasms (MPN) patients manifest different phenotypes despite harboring JAK2 mutations and what drives secondary transformations. PATIENTS AND METHODS: Using targeted sequencing, we analyzed mutational status of 17 polycythemia vera (PV), 16 essential thrombocythemia (ET), 8 primary myelofibrosis (PMF) patients who tested positive for JAK by polymerase chain reaction. RESULTS: The somatic mutations in JAK2 influence the clinical behavior of the disease. We found that ASXL1 or EZH2 mutation acquisition after JAK2 leads to PV, while ASXL1 mutation acquisition before JAK2 leads to ET or PMF. Mutations in TP53, ASXL1, and splicing genes are associated with the prognosis of MPN. PMF was more frequently associated with splicing mutations, while PV was more closely related to mutations in chromatin modifiers. The presence of these mutations influenced hemogram at MPN diagnosis. CONCLUSION: Each subtype of MPN harbors distinct patterns of somatic mutations and acquisition order, while mutations in TP53, ASXL1, and splicing genes may be associated with the prognosis of MPN.

Oncogenic effects of germline variants in lysosomal storage disease genes.

PURPOSE: Clinical and experimental evidence has suggested pathobiological crosstalk between lysosomal storage diseases (LSDs) and cancer. We aimed to elucidate the association between germline variants in LSD genes and cancer. METHODS: We performed aggregate rare variant association analysis of potentially pathogenic variants (PPVs) in 42 LSD genes and >30 histological types of cancer using genome sequencing data from 2567 cancer patients (Pan-Cancer cohort) and 2504 healthy individuals (1000 Genomes cohort) and exome sequencing data from 53,105 individuals without cancer (ExAC cohort). RESULTS: PPVs were significantly enriched in the Pan-Cancer cohort compared with the 1000 Genomes cohort (PPV prevalence, 20.7% vs. 13.5%; P = 8.7 × 10-12). Cancer risk was higher in individuals with a greater number of PPVs (P = 7.3 × 10-12). Population structure-adjusted optimal sequence kernel association test (SKAT-O) revealed 37 significantly associated cancer type-LSD gene pairs. These results were supported by the consistent tendency toward enrichment of PPVs in cancer patients compared with the ExAC cohort. Cancer developed earlier in PPV carriers than in wild-type patients. Analysis of tumor transcriptomic data from the pancreatic adenocarcinoma cohort revealed 508 genes differentially expressed according to PPV carrier status, which were highly enriched in the core signaling pathways of pancreatic cancer. CONCLUSION: Carriers of PPVs in LSD genes are at increased risk of cancer.

Combination of Genetic Aberration With International Staging System Classification for Stratification of Asian Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation.

BACKGROUND/AIM: The aim of the study was to contribute to the development of adaptive risk stratification methods specific to Asian multiple myeloma (MM) patients undergoing autologous stem cell transplantation (ASCT). PATIENTS AND METHODS: We conducted this study to evaluate the prognostic impact of genetic abnormalities detected by fluorescent in situ hybridization (FISH) on survival outcomes in combination with the International Staging System (ISS) classification in 161 MM patients. This was a single-center retrospective longitudinal cohort study of newly diagnosed MM patients undergoing ASCT within 12 months from initial diagnosis. A single-center retrospective cohort study of newly diagnosed MM. RESULTS: Patients were divided into 3 groups according to risk stratification: 1) low-risk, patients without del(17p13) nor t(14;16) or t(4;14) and ISS I/II; 2) high-risk, patients with t(4;14), regardless of ISS stage; 3) intermediate-risk, all remaining patients. The median PFS for the low-risk group was 18 months versus 13 months for the intermediate group (p=0.047, HR=1.527, 95%CI=1.006-2.316) versus 10 months for the high-risk group (p<0.001, HR=2.656, 95%CI=1.572-4.490). CONCLUSION: An ISS/FISH-based prognostication strategy was developed that can predict PFS for Asian MM patients undergoing ASCT.

Discovery of donor genotype associated with long-term survival of patients with hematopoietic stem cell transplantation in refractory acute myeloid leukemia.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been the only treatment option for acute myeloid leukemia (AML) refractory to induction chemotherapy, with only 10-20% of patients achieving long-term survival. Certain donor genotypes may confer leukemia-clearing effects after allo-HSCT. We performed whole-exome sequencing of five pairs of the germ lines in AML patients who achieved long-term remission after allo-HSCT and in their donors, and found two significant variants: EGFR c.2982C > T and CDH11 c.945G > A. To validate the protective effects of these leukemia-clearing genotypes (LCGs), AML patients who received allo-HSCT in a complete-remission status were also analyzed. Twenty-two of 96 donors (22.9%) had LCGs in their genomes, and overall survival was significantly longer in patients who received allo-HSCT from donors with germ-line LCGs (hazard ratio=0.47, 95% confidence interval=0.24-0.94, p = .033). These findings indicate that donor germ-line LCGs have phenotypically leukemia-clearing effects and are biomarkers for predicting clinical outcomes in allogeneic transplantation in AML patients.