Effects of cilengitide derivatives on TGF-ß1-induced epithelial-to-mesenchymal transition and invasion in gefitinib-resistant non-small cell lung cancer cells.

Long-term administration of tyrosine kinase inhibitors (TKIs) used for the treatment of non-small cell lung cancer (NSCLC) induces TKI resistance in cells. The appearance of resistant cells requires the combined administration of another therapeutic agent and may cause side effects in the gastrointestinal and central nervous system. In previous studies, we found that derivatives of cilengitide, a cyclic Arg-Gly-Asp (RGD) peptide, exert NSCLC apoptotic and anti-epithelial-mesenchymal transition (EMT) effects. In particular, cRGDwV and cRGDyV, which are cyclic peptides containing aromatic amino acids, were found to inhibit NSCLC cell growth, TGF-ß1-induced EMT, and invasion. In this study, we confirmed the effects of cRGDwV and cRGDyV on proliferation, TGF-ß1-induced EMT marker expression, migration, and invasion in gefitinib-resistant NSCLC A549 (A549GR) cells. In A549GR cells, cRGDwV and cRGDyV showed inhibitory effects on the expression of mesenchymal marker expression, migration, and invasion. These results indicate that cyclic RGD peptides containing aromatic amino acids can be used to inhibit mesenchymal marker expression as well as migration and invasion in gefitinib-resistant cells.

Advanced Laparoscopic Adenomyomectomy Technique for Focal Uterine Adenomyosis by Three-step Approach.

Background and Objective: Owing to the increasing trend of preserving fertility in adenomyomectomy, the need for laparoscopic adenomyomectomy has increased. This study aimed to introduce a new surgical technique, an advanced laparoscopic adenomyomectomy technique, and to evaluate its efficacy, benefits, and safety in focal uterine adenomyosis. Methods: From February 1, 2019 to February 29, 2020, 47 patients who underwent laparoscopic adenomyomectomy using the new surgical technique were enrolled in the study. The inclusion criteria were: (1) Focal-type adenomyosis, diagnosed by ultrasound or magnetic resonance imaging that was refractory to medical treatments. (2) A strong desire to preserve the uterus. All the operations were performed by a single surgeon with a uniform technique. Results: The mean patient age was 40.53 ± 5.93 years (median 38.5, range 32-47). The mean diameter of the adenomyoma lesions was 4.57 ± 1.21 cm and the mean weight of the excised lesions was 40.53 ± 35.65g (range, 15-209 g). The mean total operation time was 70.11 ± 15.05 minutes. The mean estimated blood loss was 88.88 ± 20.0 mL (20 - 500 ml). There was no conversion to laparotomy or major complications requiring reoperation. At the seven-month follow-up, there was complete remission of dysmenorrhea and menorrhagia in 97.4% and 88.9% of the patients, respectively. Conclusions: The new advanced laparoscopic adenomyomectomy technique with a three-step approach could be a safe and effective therapeutic method.

Online information analysis on pancreatic cancer in Korea using structural topic model.

Inappropriate information on a deadly and rare disease can make people vulnerable to problematic decisions, leading to irreversible bad outcomes. This study explored online information exchanges on pancreatic cancer. We collected 35,596 questions and 83,888 answers related to pancreatic cancer from January 1, 2003 to May 31, 2020, from Naver, the most popular Korean web portal. We also collected 8495 news articles related to pancreatic cancer during the same period. The study methods employed were structural topic modeling, keyword frequency analysis, and qualitative coding of medical professionals. The number of questions and news articles increased over time. In Naver's questions, topics on symptoms and diagnostic tests regarding pancreatic cancer increased in proportion. The news topics on new technologies related to pancreatic cancer from various companies increased as well. The use of words related to back pain-which is not an important early symptom in pancreatic cancer-and biomarker tests using blood increased over time in Naver's questions. Based on 100 question samples related to symptoms and diagnostic tests and an analysis of the threaded answers' appropriateness, there was considerable misinformation and commercialized information in both categories.

Bap1/SMN axis in Dpp4+ skeletal muscle mesenchymal cells regulates the neuromuscular system.

The survival of motor neuron (SMN) protein is a major component of the pre-mRNA splicing machinery and is required for RNA metabolism. Although SMN has been considered a fundamental gene for the central nervous system, due to its relationship with neuromuscular diseases, such as spinal muscular atrophy, recent studies have also revealed the requirement of SMN in non-neuronal cells in the peripheral regions. Here, we report that the fibro-adipogenic progenitor subpopulation expressing Dpp4 (Dpp4+ FAPs) is required for the neuromuscular system. Furthermore, we also reveal that BRCA1-associated protein-1 (Bap1) is crucial for the stabilization of SMN in FAPs by preventing its ubiquitination-dependent degradation. Inactivation of Bap1 in FAPs decreased SMN levels and accompanied degeneration of the neuromuscular junction, leading to loss of motor neurons and muscle atrophy. Overexpression of the ubiquitination-resistant SMN variant, SMNK186R, in Bap1-null FAPs completely prevented neuromuscular degeneration. In addition, transplantation of Dpp4+ FAPs, but not Dpp4- FAPs, completely rescued neuromuscular defects. Our data reveal the crucial role of Bap1-mediated SMN stabilization in Dpp4+ FAPs for the neuromuscular system and provide the possibility of cell-based therapeutics to treat neuromuscular diseases.

PSMD14 Targeting Triggers Paraptosis in Breast Cancer Cells by Inducing Proteasome Inhibition and Ca2+ Imbalance.

PSMD14, a subunit of the 19S regulatory particles of the 26S proteasome, was recently identified as a potential prognostic marker and therapeutic target in diverse human cancers. Here, we show that the silencing and pharmacological blockade of PSMD14 in MDA-MB 435S breast cancer cells induce paraptosis, a non-apoptotic cell death mode characterized by extensive vacuolation derived from the endoplasmic reticulum (ER) and mitochondria. The PSMD14 inhibitor, capzimin (CZM), inhibits proteasome activity but differs from the 20S proteasome subunit-inhibiting bortezomib (Bz) in that it does not induce aggresome formation or Nrf1 upregulation, which underlie Bz resistance in cancer cells. In addition to proteasome inhibition, the release of Ca2+ from the ER into the cytosol critically contributes to CZM-induced paraptosis. Induction of paraptosis by targeting PSMD14 may provide an attractive therapeutic strategy against cancer cells resistant to proteasome inhibitors or pro-apoptotic drugs.

Ordered Microdomain Structures in Saccharide-Polystyrene-Saccharide Hybrid Conjugates.

Hybrid conjugates consist of synthetic polymers and naturally occurring saccharides, and are capable of microphase separation at small molecular weights to form ordered domain structures. In this study, we synthesize ABA triblock-like conjugates with polystyrene as the synthetic mid-segment and either trisaccharide maltotriose (MT) or disaccharide maltose (Mal) as the end unit. Hybrid conjugates of varying compositions are prepared by a combination of atom transfer radical polymerization and a click reaction, and their morphologies are examined by small-angle X-ray scattering and transmission electron microscopy. The MT-containing conjugates are found to form well-ordered domain structures with a sub-10 nm periodicity, and morphology transition from cylinders to spheres to disordered spheres is observed with decreasing saccharide weight fraction. The Mal-containing conjugates also show microphase separation. However, the observed domain morphologies lack regular packing due to the close proximity of polymer glass transition temperature and order-disorder transition temperature. The saccharide-containing conjugates are also found to undergo an irreversible morphology change at high temperatures, attributed to saccharide dehydration-induced pentablock-like structure formation.

Reflux esophagitis in patients with chronic obstructive pulmonary disease.

ABSTRACT: The relationship between chronic obstructive pulmonary disease (COPD) and reflux esophagitis (RE) was controversial. We investigated the factors influencing RE development in patients with COPD and evaluated the association between RE and AECOPD.Patients with COPD who underwent esophagogastroduodenoscopy from January 2003 to December 2013 in St. Paul's Hospital, the Catholic University of Korea (Seoul, Korea) were enrolled retrospectively. The grade of RE was based on the Los Angeles classification and minimal change esophagitis. Body mass index, smoking history, medical history, AECOPD, pulmonary function test data, endoscopic findings, and comorbidities were reviewed.Of a total of 218 patients with COPD, 111 (50.9%) were diagnosed with RE. None of age, sex, smoking history, or the severity of airflow limitation was associated with RE. AECOPD was not related to either the presence or severity of RE. There was no significant correlation between RE grade by Los Angeles classification and severity of airflow limitation (P = .625). Those who had RE used theophylline (P = .003) and long-acting muscarinic antagonists (P = .026) significantly more often than did controls. The use of theophylline (OR 2.05; 95% CI, 1.16-3.65, P = .014) was associated with an increased incidence of RE.The use of theophylline might increase the risk of RE in COPD patients. RE may not be associated with airflow limitation or AECOPD.

Ta2 Ni3 Se8 : 1D van der Waals Material with Ambipolar Behavior.

In this study, high-purity and centimeter-scale bulk Ta2 Ni3 Se8 crystals are obtained by controlling the growth temperature and stoichiometric ratio between tantalum, nickel, and selenium. It is demonstrated that the bulk Ta2 Ni3 Se8 crystals could be effectively exfoliated into a few chain-scale nanowires through simple mechanical exfoliation and liquid-phase exfoliation. Also, the calculation of electronic band structures confirms that Ta2 Ni3 Se8 is a semiconducting material with a small bandgap. A field-effect transistor is successfully fabricated on the mechanically exfoliated Ta2 Ni3 Se8 nanowires. Transport measurements at room temperature reveal that Ta2 Ni3 Se8 nanowires exhibit ambipolar semiconducting behavior with maximum mobilities of 20.3 and 3.52 cm2 V-1 s-1 for electrons and holes, respectively. The temperature-dependent transport measurement (from 90 to 295 K) confirms the carrier transport mechanism of Ta2 Ni3 Se8 nanowires. Based on these characteristics, the obtained 1D vdW material is expected to be a potential candidate for additional 1D materials as channel materials.

Does enhanced environmental cleaning reduce carbapenem-resistant Acinetobacter baumannii colonization in the intensive care unit?

OBJECTIVE: To evaluate the impact of enhanced environmental cleaning (two times per day) compared with conventional cleaning on the acquisition of carbapenem-resistant Acinetobacter baumannii (CRAB) in a highly endemic intensive care unit (ICU). METHODS: The intervention consisted of alternating environmental cleaning and conventional cleaning every 3 months during the study period from July 2018 to June 2019. CRAB acquisition was assessed using incidence and prevalence rates, and colonization pressure. RESULTS: The incidence rates of CRAB with and without enhanced cleaning were 16.3 and 13.9 cases per 1000 population, respectively; and the prevalence rates were 66.9 and 61.7 cases per 1000 population, respectively. Colonization pressure was 53.3% with enhanced cleaning and 51.3% without enhanced cleaning. No association was found between enhanced environmental cleaning and the incidence (P=0.156), prevalence (P=0.888) and colonization pressure (P=0.825) of CRAB acquisition. The ventilator utilization ratio increased the colonization pressure of CRAB acquisition (P=0.010, ß coefficient=0.37). The proportion of new nurses with <3 years of clinical practice experience was positively correlated with the incidence and prevalence of CRAB acquisition. CONCLUSION: Enhanced environmental cleaning alone failed to reduce CRAB acquisition in a highly endemic ICU. The ventilator utilization ratio may be of more importance than environmental cleaning. Inexperienced nurses may need to be monitored regarding infection control activities in addition to hand hygiene adherence.

Dissection of Functional Modules of AT-HOOK MOTIF NUCLEAR LOCALIZED PROTEIN 4 in the Development of the Root Xylem.

Xylem development in the Arabidopsis root apical meristem requires a complex cross talk between plant hormone signaling and transcriptional factors (TFs). The key processes involve fine-tuning between neighboring cells, mediated via the intercellular movement of signaling molecules. As an example, we previously reported that AT-HOOK MOTIF NUCLEAR LOCALIZED PROTEIN (AHL) 4 (AHL4), a member of the 29 AT-hook family TFs in Arabidopsis, moves into xylem precursors from their neighbors to determine xylem differentiation. As part of the effort to understand the molecular functions of AHL4, we performed domain swapping analyses using AHL1 as a counterpart, finding that AHL4 has three functionally distinctive protein modules. The plant and prokaryotes conserved (PPC) domain of AHL4 acts as a mediator of protein-protein interactions with AHL members. The N-terminus of AHL4 is required for the regulation of xylem development likely via its unique DNA-binding activity. The C-terminus of AHL4 confers intercellular mobility. Our characterization of modules in the AHL4 protein will augment our understanding of the complexity of regulation and the evolution of intercellular mobility in AHL4 and its relatives.

Tacky-Free Polyurethanes Pressure-Sensitive Adhesives by Molecular-Weight and HDI Trimer Design.

Polyurethane pressure-sensitive adhesives (PU-PSAs) with satisfactory tack, cohesion, and removability were newly developed through the synthetic process by reacting methylene diisocyanate, poly(ethylene glycol) (PEG), and a 1,4-butanediol chain extender based on the different HDI/HDI trimer ratios. The sticking properties of PU-PSAs depended on both the HDI/HDI trimer ratio and crosslinking-agent composition in the formulation. The molecular weight (MW) dependence of adhesion in PU-PSA was observed in the range of 1000 < Mn < 3000, suggesting that the increase in MW limits the pressure-sensitive adhesion of these samples. The differences in the crosslinking-density significantly affected the cohesion, adhesion, and tack in PU-PSA. The formulation of 50 wt.% 600PEG and 50 wt.% crosslinking-agent and an HDI/HDI trimer ratio of 1.0 led to the optimal balance between the adhesion and cohesion properties owing to the sufficient tack, high 180-peel strength, and good cohesion.

Fusing Visual Attention CNN and Bag of Visual Words for Cross-Corpus Speech Emotion Recognition.

Speech emotion recognition (SER) classifies emotions using low-level features or a spectrogram of an utterance. When SER methods are trained and tested using different datasets, they have shown performance reduction. Cross-corpus SER research identifies speech emotion using different corpora and languages. Recent cross-corpus SER research has been conducted to improve generalization. To improve the cross-corpus SER performance, we pretrained the log-mel spectrograms of the source dataset using our designed visual attention convolutional neural network (VACNN), which has a 2D CNN base model with channel- and spatial-wise visual attention modules. To train the target dataset, we extracted the feature vector using a bag of visual words (BOVW) to assist the fine-tuned model. Because visual words represent local features in the image, the BOVW helps VACNN to learn global and local features in the log-mel spectrogram by constructing a frequency histogram of visual words. The proposed method shows an overall accuracy of 83.33%, 86.92%, and 75.00% in the Ryerson Audio-Visual Database of Emotional Speech and Song (RAVDESS), the Berlin Database of Emotional Speech (EmoDB), and Surrey Audio-Visual Expressed Emotion (SAVEE), respectively. Experimental results on RAVDESS, EmoDB, SAVEE demonstrate improvements of 7.73%, 15.12%, and 2.34% compared to existing state-of-the-art cross-corpus SER approaches.

Correction to: Biologic Drug Quality Assurance to Optimize HER2+ Breast Cancer Treatment: Insights from Development of the Trastuzumab Biosimilar SB3.

The article Biologic Drug Quality Assurance to Optimize HER2+ Breast Cancer Treatment: Insights from Development of the Trastuzumab Biosimilar SB3.

Information on the move: vascular tissue development in space and time during postembryonic root growth.

Cascades of temporal and spatial regulation of gene expression play crucial roles in the vascular development in plant roots. Once vascular cell fates are determined, the timing of their differentiation is tightly controlled in a cell-autonomous manner. In contrast, extensive cell-to-cell communication contributes to the positioning and specifying of vascular cell types in the root meristem. Diverse factors moving short distances in a radial direction were found to be key contributors to these processes. Furthermore, signals from differentiated phloem were found to influence the phloem precursor and determine how the corresponding asymmetric cell division proceeded. These findings highlight the potential importance of underexplored types of intercellular communication in relation to vascular tissue development during postembryonic root growth.

Biologic Drug Quality Assurance to Optimize HER2 + Breast Cancer Treatment: Insights from Development of the Trastuzumab Biosimilar SB3.

SB3 is a biosimilar of trastuzumab that has been approved for use in the treatment of human epidermal growth factor 2-positive breast cancer and human epidermal growth factor 2-positive gastric cancer. Antibody-dependent cellular cytotoxicity is one of several critical quality attributes of trastuzumab. Data from the development of SB3 support the hypothesis of a relationship between antibody-dependent cellular cytotoxicity activity and clinical outcomes in terms of the response rate and long-term survival. Current analytic methods utilizing advanced technology allow the detection of small changes in other quality attributes that influence antibody-dependent cellular cytotoxicity, such as glycosylation and FcγRIIIa binding. Use of such methods to monitor batch-to-batch consistency enables production of trastuzumab biosimilars with consistent quality. Trastuzumab biosimilars such as SB3 therefore have the potential to increase accessibility to trastuzumab-based therapy without compromising efficacy or safety.

Granulomatous peritonitis caused by iatrogenic spillage of ovarian dermoid cystectomy: a case report and literature review.

A 39-year-old nulliparous woman experienced continuous mild fever and abdominal pain since undergoing laparoscopic ovarian dermoid cystectomy 3 months previously in a local hospital. Abdominal computed tomography revealed diffuse heterogeneous fat infiltrations with numerous micronodules in the greater and lesser omentum, combined with ascites with thickening of the parietal peritoneum. The patient underwent exploratory laparoscopy, which included partial pelvic peritonectomy, excision of granulomas, and adhesiolysis with massive irrigation. The patient was treated successfully with laparoscopic surgery and all reproductive structures were spared without operative complications. To avoid peritonitis, complete removal of cyst contents and massive irrigation should be performed during ovarian dermoid cystectomy. Conservative surgical treatment may be a good choice for treating granulomatous peritonitis induced by iatrogenic rupture.

Growth Kinetics of Individual Co Particles Ex-solved on SrTi0.75Co0.25O3-δ Polycrystalline Perovskite Thin Films.

A precise control of the size, density, and distribution of metal nanoparticles dispersed on functional oxide supports is critical for promoting catalytic activity and stability in renewable energy and catalysis devices. Here, we measure the growth kinetics of individual Co particles ex-solved on SrTi0.75Co0.25O3-δ polycrystalline thin films under a high vacuum, and at various temperatures and grain sizes using in situ transmission electron microscopy. The ex-solution preferentially occurs at grain boundaries and corners which appear essential for controlling particle density and distribution, and enabling low temperature ex-solution. The particle reaches a saturated size after a few minutes, and the size depends on temperature. Quantitative measurements with a kinetic model determine the rate limiting step, vacancy formation enthalpy, ex-solution enthalpy, and activation energy for particle growth. The ex-solved particles are tightly socketed, preventing interactions among them over 800 °C. Furthermore, we obtain the first direct clarification of the active reaction site for CO oxidation-the Co-oxide interface, agreeing well with density functional theory calculations.

Evaluation of human electroencephalogram change for sensory effects of fragrance.

BACKGROUND: The stabilizing effect of lavender and the arousal effect of peppermint essential oils are acknowledged and used widely in aromatherapy and the cosmetics industry. However, no evaluation method confirms the effects of essential oils through quantitative and objective electroencephalogram (EEG) results; instead, only a psychological and subjective method exists. Therefore, this study aims to create a new emotional cosmetic evaluation paradigm using EEG values. Moreover, it enables quantitative interpretation of the results in addition to the subjective survey outcomes. METHODS: For this study, 12 healthy female Korean participants were recruited and three fragrances were used. The EEG results were collected for 3 minutes (1 minute each before, during, and after inhalation of every fragrance). RESULTS: The quantitative EEG outcomes indicate changes in the participant's brainwaves before and after inhalation. Significant changes in the EEG were observed. Based on the results, the effects of fragrances were confirmed to be stabilizing for lavender, and arousing for peppermint and coffee aroma. Furthermore, the subjective questionnaire results indicate similar tendency as that of the quantitative EEG results. CONCLUSION: In addition to psychological and subjective assessments, our emotional evaluation method can verify the cosmetic fragrance effects through quantitative and objective results.

Two TPL-Binding Motifs of ARF2 Are Involved in Repression of Auxin Responses.

Auxin signaling is finalized by activator auxin response factors (aARFs) that are released from Auxin/Indole-3-Acetic Acid (Aux/IAA) repressors and directly activate auxin-responsive genes. However, it remains to be answered how repressor ARFs (rARFs) exert their repression function. In this study, we assessed the molecular and biological functions of two putative co-repressor-binding motifs (EAR and RLFGI) of ARF2 (a rARF) in Arabidopsis thaliana. In the yeast two-hybrid assay, the EAR mutation moderately and the RLFGI mutation, or both motifs, almost completely disrupted the interaction between the co-repressor TOPLESS (TPL) and the repressive motifs-containing middle domain (MD) of ARF2. The ARF2-MD interacted not only with TPL but also with TPL homologs (TPRs). Root hair-specific overexpression of rARFs (ARF1-4, 9-11, and 16) considerably inhibited root hair growth, suggesting that rARFs generally function as repressors in the auxin-responsive root hair single cell. Individual mutation of the ARF2 EAR or RLFGI motif slightly and both mutations greatly compromised ARF2-mediated inhibition of root hair growth and auxin-responsive gene expression. In addition, flowering time and seed size, two representative arf2 mutant phenotypes, were examined to assess the function of the repressive motifs in mutant-complementation experiments. ARF2-mediated inhibition of flowering and seed growth was suppressed considerably by the individual mutation of EAR or RLFGI and almost completely by both mutations. These results suggest that EAR and RLFGI work together as major repressive motifs for ARF2 to recruit TPL/TPR co-repressors and to exhibit its repressive biological functions.

MAP4-regulated dynein-dependent trafficking of BTN3A1 controls the TBK1-IRF3 signaling axis.

The innate immune system detects viral nucleic acids and induces type I interferon (IFN) responses. The RNA- and DNA-sensing pathways converge on the protein kinase TANK-binding kinase 1 (TBK1) and the transcription factor IFN-regulatory factor 3 (IRF3). Activation of the IFN signaling pathway is known to trigger the redistribution of key signaling molecules to punctate perinuclear structures, but the mediators of this spatiotemporal regulation have yet to be defined. Here we identify butyrophilin 3A1 (BTN3A1) as a positive regulator of nucleic acid-mediated type I IFN signaling. Depletion of BTN3A1 inhibits the cytoplasmic nucleic acid- or virus-triggered activation of IFN-ß production. In the resting state, BTN3A1 is constitutively associated with TBK1. Stimulation with nucleic acids induces the redistribution of the BTN3A1-TBK1 complex to the perinuclear region, where BTN3A1 mediates the interaction between TBK1 and IRF3, leading to the phosphorylation of IRF3. Furthermore, we show that microtubule-associated protein 4 (MAP4) controls the dynein-dependent transport of BTN3A1 in response to nucleic acid stimulation, thereby identifying MAP4 as an upstream regulator of BTN3A1. Thus, the depletion of either MAP4 or BTN3A1 impairs cytosolic DNA- or RNA-mediated type I IFN responses. Our findings demonstrate a critical role for MAP4 and BTN3A1 in the spatiotemporal regulation of TBK1, a central player in the intracellular nucleic acid-sensing pathways involved in antiviral signaling.