ATP1A1/BCL2L1 predicts the response of myelomonocytic and monocytic acute myeloid leukemia to cardiac glycosides.

Myelomonocytic and monocytic acute myeloid leukemia (AML) subtypes are intrinsically resistant to venetoclax-based regimens. Identifying targetable vulnerabilities would limit resistance and relapse. We previously documented the synergism of venetoclax and cardiac glycoside (CG) combination in AML. Despite preclinical evidence, the repurposing of cardiac glycosides (CGs) in cancer therapy remained unsuccessful due to a lack of predictive biomarkers. We report that the ex vivo response of AML patient blasts and the in vitro sensitivity of established cell lines to the hemi-synthetic CG UNBS1450 correlates with the ATPase Na+/K+ transporting subunit alpha 1 (ATP1A1)/BCL2 like 1 (BCL2L1) expression ratio. Publicly available AML datasets identify myelomonocytic/monocytic differentiation as the most robust prognostic feature, along with core-binding factor subunit beta (CBFB), lysine methyltransferase 2A (KMT2A) rearrangements, and missense Fms-related receptor tyrosine kinase 3 (FLT3) mutations. Mechanistically, BCL2L1 protects from cell death commitment induced by the CG-mediated stepwise triggering of ionic perturbation, protein synthesis inhibition, and MCL1 downregulation. In vivo, CGs showed an overall tolerable profile while impacting tumor growth with an effect ranging from tumor growth inhibition to regression. These findings suggest a predictive marker for CG repurposing in specific AML subtypes.

A Case of Intramural Gastric Wall Abscess, a Rare Disease Successfully Treated with Endoscopic Incision and Drainage.

Gastric wall abscess is a rare condition characterized by a purulent inflammatory process resulting in the formation of a pocket of pus in the stomach. As the mucosa is usually intact, it requires various tools such as endoscopic ultrasonography or computed tomography for the differential diagnosis to rule out more common subepithelial tumors. Even after the diagnosis, the treatment for gastric wall abscess was previously restricted to surgical resection in combination with antibiotics. Currently, in order to avoid unnecessary surgery, the alternative method of initial treatment with an endoscopic approach is recommended. It also helps to choose appropriate antibiotics with confirmation of the pathogen by drainage. There are few reports that describe the detailed processing of the endoscopic drainage, and there is no consensus on the treatment. The pathogens that cause gastric wall abscess are usually Streptococci, Staphylococci, and Escherichia coli. There is only one case reported to be caused by Candida albicans. This is the first report of Elizabethkingia anopheles as the pathogen of the gastric wall abscess. Here, we report a case of gastric wall abscess in a 75-year-old man, safely treated by endoscopic drainage and antibiotics, confirmed by isolating the contents of the abscess.

Force uniformity control for large-area roll-to-roll process.

Demand for high throughput manufacturing has recently increased in various fields, such as electronics, photonics, optical devices, and energy. Moreover, flexible electronic devices are indispensable in applications such as touch screens, transparent conductive electrodes, transparent film heaters, organic photovoltaics, organic light-emitting diodes, and battery. For these applications, a large-area roll-to-roll (R2R) process is a promising method for producing with high throughput. However, bending deformation of rollers is unavoidable in a large-scale R2R system, which produces non-uniformity in force distribution during processing and reduces the sample quality. In this study, we propose a new R2R imprinting module to mitigate the deformation by using an additional backup roller to achieve uniform force distribution. From numerical simulations, we found that there exists an optimal imprinting force for each backup roller length to obtain the best uniformity. Experimental results using a large-area pressure sensor verified the effectiveness of the proposed method. Finally, the R2R nanoimprint lithography process showed that the proposed method produces patterns of 100 nm width with uniform residual layer thickness, which are distributed across the substrate of 1.2 m width.

A multiple negative differential resistance heterojunction device and its circuit application to ternary static random access memory.

For increasing the restricted bit-density in the conventional binary logic system, extensive research efforts have been directed toward implementing single devices with a two threshold voltage (VTH) characteristic via the single negative differential resistance (NDR) phenomenon. In particular, recent advances in forming van der Waals (vdW) heterostructures with two-dimensional crystals have opened up new possibilities for realizing such NDR-based tunneling devices. However, it has been challenging to exhibit three VTH through the multiple-NDR (m-NDR) phenomenon in a single device even by using vdW heterostructures. Here, we show the m-NDR device formed on a BP/(ReS2 + HfS2) type-III double-heterostructure. This m-NDR device is then integrated with a vdW transistor to demonstrate a ternary vdW latch circuit capable of storing three logic states. Finally, the ternary latch is extended toward ternary SRAM, and its high-speed write and read operations are theoretically verified.

Structural and Biophysical Analyses of Human N-Myc Downstream-Regulated Gene 3 (NDRG3) Protein.

The N-Myc downstream-regulated gene (NDRG) family belongs to the α/ß-hydrolase fold and is known to exert various physiologic functions in cell proliferation, differentiation, and hypoxia-induced cancer metabolism. In particular, NDRG3 is closely related to proliferation and migration of prostate cancer cells, and recent studies reported its implication in lactate-triggered hypoxia responses or tumorigenesis. However, the underlying mechanism for the functions of NDRG3 remains unclear. Here, we report the crystal structure of human NDRG3 at 2.2 Å resolution, with six molecules in an asymmetric unit. While NDRG3 adopts the α/ß-hydrolase fold, complete substitution of the canonical catalytic triad residues to non-reactive residues and steric hindrance around the pseudo-active site seem to disable the α/ß-hydrolase activity. While NDRG3 shares a high similarity to NDRG2 in terms of amino acid sequence and structure, NDRG3 exhibited remarkable structural differences in a flexible loop corresponding to helix α6 of NDRG2 that is responsible for tumor suppression. Thus, this flexible loop region seems to play a distinct role in oncogenic progression induced by NDRG3. Collectively, our studies could provide structural and biophysical insights into the molecular characteristics of NDRG3.

Structural and Functional Analyses of Human ChaC2 in Glutathione Metabolism.

Glutathione (GSH) degradation plays an essential role in GSH homeostasis, which regulates cell survival, especially in cancer cells. Among human GSH degradation enzymes, the ChaC2 enzyme acts on GSH to form 5-l-oxoproline and Cys-Gly specifically in the cytosol. Here, we report the crystal structures of ChaC2 in two different conformations and compare the structural features with other known γ-glutamylcyclotransferase enzymes. The unique flexible loop of ChaC2 seems to function as a gate to achieve specificity for GSH binding and regulate the constant GSH degradation rate. Structural and biochemical analyses of ChaC2 revealed that Glu74 and Glu83 play crucial roles in directing the conformation of the enzyme and in modulating the enzyme activity. Based on a docking study of GSH to ChaC2 and binding assays, we propose a substrate-binding mode and catalytic mechanism. We also found that overexpression of ChaC2, but not mutants that inhibit activity of ChaC2, significantly promoted breast cancer cell proliferation, suggesting that the GSH degradation by ChaC2 affects the growth of breast cancer cells. Our structural and functional analyses of ChaC2 will contribute to the development of inhibitors for the ChaC family, which could effectively regulate the progression of GSH degradation-related cancers.

Effect of thoracic and pelvic anteroposterior diameters on spinal sagittal alignment.

PURPOSE: This study aimed to analyze the effect of the thoracic anteroposterior diameter (TAPD) and pelvic anteroposterior diameter (PAPD) on global sagittal alignment in asymptomatic patients with normal sagittal alignment. PATIENT SAMPLE: The study investigated 2042 adult patients who initially presented at our hospital with a hip and knee problem without history of symptoms related to the entire spine. Only 57 patients with normal global sagittal alignment (C2-7 sagittal vertical axis (SVA) and C7-S1 SVA of <10 mm) were considered. METHODS: The whole-spine standing lateral radiographs were obtained to analyze the following parameters: pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), lumbar lordosis (LL), thoracic inlet angle (TIA), T1 slope, cervical spinal parameters (angle of C0-2, C2-7, and C0-7), TAPD, and PAPD. Statistical analysis was performed using Pearson correlation coefficients and multiple regression analyses. RESULTS: All the parameters showed a normal distribution. TAPD had a significant relationship with thoracic kyphosis (TK; r = 0.458), TIA (r = 0.677), and C0-2 angle (r = 0.294) but no significant relationship with T1 slope and other cervical parameters. PAPD had a significant relationship with PI (r = 0.309) and PT (r = 0.463) but no significant relationship with LL, SS, and TK. The multiple regression analysis showed that TIA = 21.974 + 0.405 (TK) + 0.188 (TAPD) (p < 0.0001). CONCLUSIONS: TAPD and PAPD are associated with TIA, TK, C0-2 angle, PI, and PT, all of which act as key factors in spinal sagittal alignment. Although they did not directly correlate with other cervical parameters, T1 slope, and LL, TAPD and PAPD might have indirect effects on cervical and lumbar spinal sagittal alignment through their relationships with TIA, TK, and PI.

ZnO composite nanolayer with mobility edge quantization for multi-value logic transistors.

A quantum confined transport based on a zinc oxide composite nanolayer that has conducting states with mobility edge quantization is proposed and was applied to develop multi-value logic transistors with stable intermediate states. A composite nanolayer with zinc oxide quantum dots embedded in amorphous zinc oxide domains generated quantized conducting states at the mobility edge, which we refer to as "mobility edge quantization". The unique quantized conducting state effectively restricted the occupied number of carriers due to its low density of states, which enable current saturation. Multi-value logic transistors were realized by applying a hybrid superlattice consisting of zinc oxide composite nanolayers and organic barriers as channels in the transistor. The superlattice channels produced multiple states due to current saturation of the quantized conducting state in the composite nanolayers. Our multi-value transistors exhibited excellent performance characteristics, stable and reliable operation with no current fluctuation, and adjustable multi-level states.

Synergistic AML Cell Death Induction by Marine Cytotoxin (+)-1(R), 6(S), 1'(R), 6'(S), 11(R), 17(S)-Fistularin-3 and Bcl-2 Inhibitor Venetoclax.

Treatment of acute myeloid leukemia (AML) patients is still hindered by resistance and relapse, resulting in an overall poor survival rate. Recently, combining specific B-cell lymphoma (Bcl)-2 inhibitors with compounds downregulating myeloid cell leukemia (Mcl)-1 has been proposed as a new effective strategy to eradicate resistant AML cells. We show here that 1(R), 6(S), 1'(R), 6'(S), 11(R), 17(S)-fistularin-3, a bromotyrosine compound of the fistularin family, isolated from the marine sponge Suberea clavata, synergizes with Bcl-2 inhibitor ABT-199 to efficiently kill Mcl-1/Bcl-2-positive AML cell lines, associated with Mcl-1 downregulation and endoplasmic reticulum stress induction. The absolute configuration of carbons 11 and 17 of the fistularin-3 stereoisomer was fully resolved in this study for the first time, showing that the fistularin we isolated from the marine sponge Subarea clavata is in fact the (+)-11(R), 17(S)-fistularin-3 stereoisomer keeping the known configuration 1(R), 6(S), 1'(R), and 6'(S) for the verongidoic acid part. Docking studies and in vitro assays confirm the potential of this family of molecules to inhibit DNA methyltransferase 1 activity.

Cardiac Glycoside Glucoevatromonoside Induces Cancer Type-Specific Cell Death.

Cardiac glycosides (CGs) are natural compounds used traditionally to treat congestive heart diseases. Recent investigations repositioned CGs as potential anticancer agents. To discover novel cytotoxic CG scaffolds, we selected the cardenolide glucoevatromonoside (GEV) out of 46 CGs for its low nanomolar anti-lung cancer activity. GEV presented reduced toxicity toward non-cancerous cell types (lung MRC-5 and PBMC) and high-affinity binding to the Na+/K+-ATPase α subunit, assessed by computational docking. GEV-induced cell death was caspase-independent, as investigated by a multiparametric approach, and culminates in severe morphological alterations in A549 cells, monitored by transmission electron microscopy, live cell imaging and flow cytometry. This non-canonical cell death was not preceded or accompanied by exacerbation of autophagy. In the presence of GEV, markers of autophagic flux (e.g. LC3I-II conversion) were impacted, even in presence of bafilomycin A1. Cell death induction remained unaffected by calpain, cathepsin, parthanatos, or necroptosis inhibitors. Interestingly, GEV triggered caspase-dependent apoptosis in U937 acute myeloid leukemia cells, witnessing cancer-type specific cell death induction. Differential cell cycle modulation by this CG led to a G2/M arrest, cyclin B1 and p53 downregulation in A549, but not in U937 cells. We further extended the anti-cancer potential of GEV to 3D cell culture using clonogenic and spheroid formation assays and validated our findings in vivo by zebrafish xenografts. Altogether, GEV shows an interesting anticancer profile with the ability to exert cytotoxic effects via induction of different cell death modalities.

Highly-Sensitive Thin Film THz Detector Based on Edge Metal-Semiconductor-Metal Junction.

Terahertz (THz) detectors have been extensively studied for various applications such as security, wireless communication, and medical imaging. In case of metal-insulator-metal (MIM) tunnel junction THz detector, a small junction area is desirable because the detector response time can be shortened by reducing it. An edge metal-semiconductor-metal (EMSM) junction has been developed with a small junction area controlled precisely by the thicknesses of metal and semiconductor films. The voltage response of the EMSM THz detector shows the clear dependence on the polarization angle of incident THz wave and the responsivity is found to be very high (~2,169 V/W) at 0.4 THz without any antenna and signal amplifier. The EMSM junction structure can be a new and efficient way of fabricating the nonlinear device THz detector with high cut-off frequency relying on extremely small junction area.

The Effect of a CAD/CAM-Guided Template on Formation of the Screw-Access Channel for Fixed Prostheses Supported by Lingually Placed Implants.

PURPOSE: The aim of this study was to evaluate the effect of a computer-aided design/computer-assisted manufacturing (CAD/CAM) guide on drilling the screw-access channel for lingually placed implants. MATERIALS AND METHODS: Screw-channel drilling guides were fabricated on lingually placed implant models using CAD/CAM technology. The screw channels were prepared with guided or freehand drilling by 20 dental graduates. The accuracy of each screw channel was assessed for drilling entry point, channel volume, and angulation (α = .05). RESULTS: The guided drilling group showed smaller deviations than the freehand drilling group, and prosthesis position influenced the guide effect (P < .001). CONCLUSION: The CAD/CAM guide facilitated the screw channel preparation of cement-retained prostheses supported by lingually placed implants.

Non-Radiological Method for Fabrication of a Screw-Channel Drilling Guide in Cement-Retained Implant Restorations Using Intraoral Digital Scanning and Imaging Superimposition: A Clinical Report.

The difficulty of retrieving the abutment screw is a major disadvantage of cement-retained implant restorations. Conventional methods for locating the screw-access hole are based largely on radiography or manual labor, which limits accuracy and clinical feasibility. This clinical report describes a non-radiological method for fabricating an accurate drilling guide for location of the screw channel using intraoral optical scanning, 3D superimposition, and computer-aided design and computer-aided manufacturing (CAD/CAM) technologies. The present technique not only improves the guide fabrication process and the accuracy of screw-channel drilling, but also has wide indications for implant restorations.

Double-Step Image Superimposition Technique for Fabricating a Drilling Guide to Access the Abutment Screw in Implant Prostheses.

Limited retrievability is a major disadvantage of cement-retained implant restorations. Despite great progress in locating the abutment screw within crowns, the existing techniques are based on prior data or prefabricated devices and require significant work. This study introduces a new procedure for fabricating a guide template to drill a screw access hole using a double-step superimposition technique that incorporates intraoral optical scanning, cone beam computed tomography, and dental design software. The double-step superimposition technique with computer-aided design/computer-assisted manufacturing technology can enhance the convenience and accuracy of drilling the screw-access hole.

Accurate Analysis and Characterization of Silicon Field Effect Transistor-Based Terahertz Wave Detector with Quasi-Plasma Two-Dimensional Electron Gas.

We report the nonresonant plasmonic terahertz (THz) wave detector based on the silicon (Si) field effect transistor (FET) with a technology computer-aided design (TCAD) platform. The plasma wave behavior has been modeled by a quasi-plasma electron box as a two-dimensional electron gas (2DEG) in the channel of the FET. The incoming alternating current (AC) signal as the THz wave radiation can induce the direct-current (DC) voltage difference between the source and drain, which is called the photoresponse. For accurate analysis of the modulation and propagation of the channel electron density as the plasma wave, we have characterized the quasi-plasma 2DEG model with two key parameters, such as quasi-plasma 2DEG length (I(QP)) and density (N(QP)). By using our normalization method, I(QP) and N(QP) is defined exactly as extracting the average point of the electron density. We also investigate the performance enhancement of the plasmonic terahertz wave detector based on Si FET by scaling down the gate oxide thickness (t(ox)), which is a significant parameter of FET-based plasmonic terahertz detector for the channel electron density modulation. According to scaling down t(ox), the responsivity (R(v)) and noise equivalent power (NEP), which are the important performance metrics of the THz wave detector, have been enhanced. The proposed methodologies will provide the advanced physical analysis and structural design platform for developing the plasmonic terahertz detectors operating in nonresonant regime.

Multiple Negative Differential Resistance Device by Using the Ambipolar Behavior of Tunneling Field Effect Transistor with Fast Switching Characteristics.

We propose a novel double-peak negative differential resistance (NDR) characteristic at the conventional single-peak MOS-NDR circuit by employing ambipolar behavior of TFET. The fluctuated voltage transfer curve (VTC) from ambipolar inverter is analyzed with simple model and successfully demonstrated with TFET, as a practical example, on the device simulation. We also verified that the fluctuated VTC generates additional peak and valleys on NDR characteristics by using circuit simulations. Moreover, by adjusting the threshold voltage of conventional MOSFET, ultra-high 1st and 2nd peak-to-valley current ratio (PVCR) over 10(7) is obtained with fully suppressed valley currents. The proposed double-peak NDR circuit expected to apply on faster switching and low power multi-functional applications.

Covalent Self-Assembly and One-Step Photocrosslinking of Tyrosine-Rich Oligopeptides to Form Diverse Nanostructures.

We present covalently self-assembled peptide hollow nanocapsule and peptide lamella. These biomimetic dityrosine peptide nanostructures are synthesized by one-step photopolymerization of a tyrosine-rich short peptide without the aid of a template. This simple approach offers direct synthesis of fluorescent peptide nanocages and free-standing thin films. The simple crosslinked peptide lamella films provide robust mechanical properties with an elastic modulus of approximately 30 GPa and a hardness of 740 MPa. These nanostructures also allow for the design of peptidosomes. The approach taken here represents a rare example of covalent self-assembly of short peptides into nano-objects, which may be useful as microcompartments and separation membranes.

Discovery and characterization of Isofistularin-3, a marine brominated alkaloid, as a new DNA demethylating agent inducing cell cycle arrest and sensitization to TRAIL in cancer cells.

We characterized the brominated alkaloid Isofistularin-3 (Iso-3), from the marine sponge Aplysina aerophoba, as a new DNA methyltransferase (DNMT)1 inhibitor. Docking analysis confirmed our in vitro DNMT inhibition data and revealed binding of Iso-3 within the DNA binding site of DNMT1. Subsequent increased expression of tumor suppressor gene aryl hydrocarbon receptor (AHR) could be correlated to decreased methylation of CpG sites within the essential Sp1 regulatory region of its promoter. Iso-3 induced growth arrest of cancer cells in G0/G1 concomitant with increased p21 and p27 expression and reduced cyclin E1, PCNA and c-myc levels. Reduced proliferation was accompanied by morphological changes typical of autophagy revealed by fluorescent and transmission electron microscopy and validated by LC3I-II conversion. Furthermore, Iso-3 strongly synergized with tumor-necrosis-factor related apoptosis inducing ligand (TRAIL) in RAJI [combination index (CI) = 0.22] and U-937 cells (CI = 0.21) and increased TRAIL-induced apoptosis via a mechanism involving reduction of survivin expression but not of Bcl-2 family proteins nor X-linked inhibitor of apoptosis protein (XIAP). Iso-3 treatment decreased FLIPL expression and triggered activation of endoplasmatic reticulum (ER) stress with increased GRP78 expression, eventually inducing TRAIL receptor death receptor (DR)5 surface expression. Importantly, as a potential candidate for further anticancer drug development, Iso-3 reduced the viability, colony and in vivo tumor forming potential without affecting the viability of PBMCs from healthy donors or zebrafish development.

Subscapular bursitis as a rare manifestation of dermatomyositis: a case report.

Dermatomyositis (DM) is characterized by proximal muscle weakness and characteristic skin rash. Pain is a less common feature and usually indicates inflammation of extramuscular structures such as fascia. Here we report a rare case of subscapular bursitis in a 48-year-old woman with DM. She initially presented with severe, sharp, stabbing pain in her right shoulder that worsened with shoulder movement. Magnetic resonance imaging (MRI) revealed inflammation in the right subscapular bursae. A few months later, the patient developed periungual erythema, Gottron's papules, and shawl sign with muscle pain in her thighs. DM was diagnosed based on the presence of interface dermatitis on skin biopsy and diffuse muscle inflammation on MRI. Bursitis and myalgia responded incompletely to nonsteroidal anti-inflammatory drugs but promptly to corticosteroids. Here we report a case of subscapular bursitis as a rare manifestation of DM. Pain in patients with DM may warrant physicians to evaluate for the presence of additional inflammatory processes in the perimuscular structures.

5-aryl-1,3,4-thiadiazole-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents: synthesis, bioevaluation and docking study.

The search for newer histone deacetylase (HDAC) inhibitors has attracted a great deal of interest of medicinal chemists worldwide, especially after the first HDAC inhibitor (Zolinza(®), widely known as SAHA or Suberoylanilide hydroxamic acid) was approved by the FDA for the treatment of Tcell lymphoma in 2006. As a continuity of our ongoing research in this area, we designed and synthesized a series of 5-aryl-1,3,4-thiadiazole-based hydroxamic acids as analogues of SAHA and evaluated their biological activities. Most of the compounds in this series, e.g. compounds with 5-aryl moiety being 2- furfuryl (5a), 5-bromofuran-2-yl (5b), 5-methylfuran-2-yl (5c), thiophen-2-yl (5d), 5-methylthiophen-2-yl (5f) and pyridyl (5g-i), were found to have potent anticancer cytotoxicity with IC50 values of generally 5- to 10-fold lower than that of SAHA in 4 human cancer cell lines assayed. Those compounds with potent cytotoxicity were also found to have strong HDAC inhibition effects. Docking studies revealed that compounds 5a and 5d displayed high affinities towards HDAC2 and 8.