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Yuan Wei Liau,1 Celine Cheow,1 Kenneth Tin Yau Leung,2 Hejing Tan,3 Suat Fern Low,4 Hua Heng McVin Cheen,5 Woan Chyi Lim,6 Li Ling Tan,6 Joyce Zhen Yin Tan,7 Eng Sing Lee,8 Sandra Jialun Xu,9 Corrinne Yong Koon Tan,10 Jie Wen Phang,11 Jie Kie Phang,12 Miao Hui Lam,2 Dan V Blalock,13,14 Corrine I Voils,15,16 Kai Zhen Yap,1 Yu Heng Kwan2,171Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore; 2Department of Pharmacy, Khoo Teck Puat Hospital, Singapore, Singapore; 3Department of Pharmacy, Woodlands Health Campus, Singapore, Singapore; 4Department of Pharmacy, Yishun Community Hospital, Singapore, Singapore; 5Department of Pharmacy, Singapore General Hospital, Singapore, Singapore; 6Department of Pharmacy, Tan Tock Seng Hospital, Singapore, Singapore; 7Department of Pharmacy, Admiralty Medical Centre, Singapore, Singapore; 8Clinical Research Unit, Family Medicine Development Division, National Healthcare Group Polyclinics, Singapore, Singapore; 9Department of Pharmacy, National Healthcare Group Polyclinics (Hougang), Singapore, Singapore; 10Pharmacy Transformation Office, National Healthcare Group Pharmacy, Singapore, Singapore; 11Department of Pharmacy, Ng Teng Fong General Hospital, Singapore, Singapore; 12Department of Rheumatology and Immunology, Singapore General Hospital, Singapore, Singapore; 13Center of Innovation to Accelerate Discovery and Practice Transformation (ADAPT), Durham Veterans Affairs Health Care System, Durham, NC, USA; 14Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, USA; 15Department of Surgery, University of Wisconsin School of Medicine and Public Health, Wisconsin, WI, USA; 16William S Middleton Memorial Veterans Hospital, Wisconsin, WI, USA; 17Program in Health Services and Systems Research, Duke-NUS Medical School, Singapore, SingaporeBackground: This self-report measure is a new instrument to measure the extent of and reasons for medication adherence separately. However, few studies have assessed its psychometric properties in diabetic patients and also in Asian populations.Objectives: To validate this self-report measure in diabetic patients in Singapore.Methods: We collected data prospectively using a questionnaire among 393 diabetic patients from hospitals in Singapore from July 2018 to January 2019. Using the COnsensus-based Standards for the selection of health Measurement INstruments framework, we assessed face validity, internal consistency, test–retest reliability, structural validity, and measurement error. We tested four a priori hypotheses on correlation of extent score with patient-reported outcome measures to assess construct validity. We examined cross-cultural validity via measurement invariance across gender, age groups, and languages.Results: We performed cognitive interviews with 30 consenting English-literate, Chinese-literate, and Malay-literate (10 patients per language) diabetic patients (age range 48–76 years, 53% male, disease duration range 1–30 years) and face validity was supported. Among 393 patients (mean age: 59.4±12.2 years, 50.9% female, 52.4% Chinese), we showed moderate internal consistency (Cronbach’s alpha =0.67) and test–retest reliability (intra-class coefficient=0.56 [95% CI 0.37–0.70]). We calculated smallest detectable change as 0.80. We established construct validity by meeting all four hypotheses. We showed structural validity as confirmatory factor analysis confirmed a one-factor model, with excellent fit statistics (Comparative Fit Index=1.0; Tucker-Lewis Index=1.0; Root Mean Square Error of Approximation

The transcriptional regulation of p53-dependent genes in response to DNA damage is critical for effective DNA repair and cell survival. We previously established that RSF1 (remodeling and spacing factor 1) is necessary for p53-dependent gene transcription in response to DNA strand breaks. Here, we further elucidate that the role of RSF1 in p53 regulation by demonstrating that its depletion results in a reduction in the acetylated-Lys(K)382 level of p53, which governs its transcriptional activity. RSF1 was co-precipitated with p300 acetyltransferase upon etoposide treatment. Chromatin immunoprecipitation assays on the upstream region of CDKN1A gene revealed reduced p300 and TBP accumulation, which were accompanied with low H3H27ac and H3K4me1 levels in RSF1 knockout cells. Moreover, RSF1 depletion led to a reduced accumulation of SSRP1 and SPT16, subunits of FACT complex at the promoter of CDKN1A gene. These findings suggest that RSF1 promotes p53-dependent p21 gene transcription by facilitating the accumulation of p300 acetyltransferase at the enhancer and FACT at the promoter region of CDKN1A gene, respectively., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/aims: Growing evidence suggests histologic healing (HH) improves clinical outcomes in ulcerative colitis (UC) patients beyond endoscopic healing (EH). We hypothesize that HH is associated with better clinical outcomes in Asian UC patients, for whom data is lacking., Methods: We performed a retrospective study of UC patients in clinical remission (CR) with a follow-up colonoscopy and minimum 1-year follow-up post-colonoscopy. Primary outcome was clinical relapse (CRL), defined as either a Simple Clinical Colitis Activity Index score of > 2, medication escalation, hospitalization or colectomy. Predictors of CRL and HH were assessed., Results: One hundred patients were included with a median follow-up of 22 months. At index colonoscopy, 80 patients were in EH. On follow-up, 41 patients experienced CRL. Of 80 patients in EH, 34 (42.5%) had persistent histologic activity (Nancy Index ≥ 2) and 29 (36.3%) relapsed during the follow-up period. Amongst patients in CR and EH, those with HH had lower CRL rate (26.1% vs. 50.0%, P= 0.028) and longer CRL-free survival (mean 46.1 months vs. 31.5 months, P= 0.015) than those with persistent histologic activity. On bivariable analysis of 100 patients in CR, HH, and Mayo endoscopic score (MES) of 0 were significantly associated with lower risk of CRL. On multivariable analysis, only MES 0 remained predictive of lower CRL risk., Conclusions: Above and beyond CR and EH, achieving HH improves clinical outcomes in Asian UC patients. However, HH may not confer incremental benefit if MES 0 has been achieved. Further prospective studies evaluating the benefit of histologically guided therapeutic decisions are needed.

Competing Interests: The authors declare no conflicts of interest.

Alzheimer's disease (AD) is an important geriatric disease that creates challenges in health policy planning. There is no previous attempt to quantify the actual direct healthcare cost of AD among older adults in Malaysia. This retrospective observational study with bottom-up micro-costing approach aimed to evaluate the direct healthcare expenditure on AD along with its potential predictors from healthcare providers' perspective, conducted across six tertiary hospitals in Malaysia. AD patients aged 65 and above who received AD treatment between 1 January 2016 and 31 December 2021 were included. Direct healthcare cost (DHC) of AD was estimated by extracting one-year follow-up information from patient medical records. As a result, 333 AD patients were included in the study. The mean DHC of AD was estimated RM2641.30 (USD 572.45) per patient per year (PPPY) from the healthcare payer's perspective. Laboratory investigations accounted for 37.2% of total DHC, followed by clinic care (31.5%) and prescription medicine (24.9%). As disease severity increases, annual DHC increases from RM2459.04 (mild), RM 2642.27 (moderate), to RM3087.61 (severe) PPPY. Patients aged 81 and above recorded significantly higher annual DHC (p = 0.003). Such real-world estimates are important in assisting the process of formulating healthcare policies in geriatric care., (© 2024. The Author(s).)

Introduction: Gastrointestinal stromal tumours (GISTs) are an important, though uncommon, cause of obscure gastrointestinal bleeding and may rarely be associated with genodermatoses such as neurofibromatosis type 1 (NF1). NF1-related GISTs have unique phenotypic features compared with sporadic GISTs and may elude diagnosis due to their predilection for the small bowel., Case Presentation: We report a case of a 45-year-old Singaporean woman with café-au-lait macules and cutaneous neurofibromas who presented with occult obscure gastrointestinal bleeding and was eventually discovered to have a bleeding jejunal GIST. This finding, considered together with her cutaneous signs, eventually led to the diagnosis of NF1., Conclusion: Genodermatoses and their gastrointestinal complications are likely under-reported in adult Southeast Asian populations and deserve greater awareness from gastroenterologists practising in this region., Competing Interests: The authors have no conflict of interest to declare., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Peripheral T cell lymphomas are typically aggressive with a poor prognosis. Unlike other hematologic malignancies, the lack of target antigens to discriminate healthy from malignant cells limits the efficacy of immunotherapeutic approaches. The T cell receptor expresses one of two highly homologous chains [T cell receptor β-chain constant (TRBC) domains 1 and 2] in a mutually exclusive manner, making it a promising target. Here we demonstrate specificity redirection by rational design using structure-guided computational biology to generate a TRBC2-specific antibody (KFN), complementing the antibody previously described by our laboratory with unique TRBC1 specificity (Jovi-1) in targeting broader spectrum of T cell malignancies clonally expressing either of the two chains. This permits generation of paired reagents (chimeric antigen receptor-T cells) specific for TRBC1 and TRBC2, with preclinical evidence to support their efficacy in T cell malignancies., (© 2024. The Author(s).)

The human leukocyte antigen (HLA) system is a major factor controlling cancer immunosurveillance and response to immunotherapy, yet its status in pediatric cancers remains fragmentary. We determined high-confidence HLA genotypes in 576 children, adolescents and young adults with recurrent/refractory solid tumors from the MOSCATO-01 and MAPPYACTS trials, using normal and tumor whole exome and RNA sequencing data and benchmarked algorithms. There was no evidence for narrowed HLA allelic diversity but discordant homozygosity and allele frequencies across tumor types and subtypes, such as in embryonal and alveolar rhabdomyosarcoma, neuroblastoma MYCN and 11q subtypes, and high-grade glioma, and several alleles may represent protective or susceptibility factors to specific pediatric solid cancers. There was a paucity of somatic mutations in HLA and antigen processing and presentation (APP) genes in most tumors, except in cases with mismatch repair deficiency or genetic instability. The prevalence of loss-of-heterozygosity (LOH) ranged from 5.9 to 7.7% in HLA class I and 8.0 to 16.7% in HLA class II genes, but was widely increased in osteosarcoma and glioblastoma (~15-25%), and for DRB1-DQA1-DQB1 in Ewing sarcoma (~23-28%) and low-grade glioma (~33-50%). HLA class I and HLA-DR antigen expression was assessed in 194 tumors and 44 patient-derived xenografts (PDXs) by immunochemistry, and class I and APP transcript levels quantified in PDXs by RT-qPCR. We confirmed that HLA class I antigen expression is heterogeneous in advanced pediatric solid tumors, with class I loss commonly associated with the transcriptional downregulation of HLA-B and transporter associated with antigen processing ( TAP ) genes, whereas class II antigen expression is scarce on tumor cells and occurs on immune infiltrating cells. Patients with tumors expressing sufficient HLA class I and TAP levels such as some glioma, osteosarcoma, Ewing sarcoma and non-rhabdomyosarcoma soft-tissue sarcoma cases may more likely benefit from T cell-based approaches, whereas strategies to upregulate HLA expression, to expand the immunopeptidome, and to target TAP-independent epitopes or possibly LOH might provide novel therapeutic opportunities in others. The consequences of HLA class II expression by immune cells remain to be established. Immunogenetic profiling should be implemented in routine to inform immunotherapy trials for precision medicine of pediatric cancers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Lim, Marques Da Costa, Godefroy, Jacquet, Gragert, Rondof, Marchais, Nhiri, Dalfovo, Viard, Labaied, Khan, Dessen, Romanel, Pasqualini, Schleiermacher, Carrington, Zitvogel, Scoazec, Geoerger and Salmon.)

Background: Complex challenges face clinicians managing critically ill patients with burns, particularly in the context of enhancing outcomes after a stay in ICU. Compounding this, a dearth of research explores the specific and modifiable factors that impact early mobilization in the ICU environment., Aim: To explore the barriers and enablers of early functional mobilization for patients with burns in the ICU from a multidisciplinary perspective., Design: A qualitative phenomenological study., Methods: Semi-structured interviews supplemented by online questionnaires conducted with 12 multidisciplinary clinicians (four doctors, three nurses and five physical therapists) who previously managed burn patients at a quaternary level ICU. Data were thematically analysed., Results: Four main themes: patient, ICU clinicians, the workplace and the physical therapist were identified as impacting on early mobilization. Subthemes identified barriers or enablers to mobilization but all were strongly influenced by overarching theme of the clinician's "emotional filter." Barriers included high levels of pain, heavy sedation and low levels of clinician exposure to treating patients with burns. Enablers included higher levels of clinician's experience and knowledge about burn management and benefits of early mobilization; increased coordinated staff resources when undertaking mobilization; and, open communication and positive culture towards early mobilization across the multidisciplinary team., Conclusion: Patient, clinician and workplace barriers and enablers were identified to influencing the likelihood of achieving early mobilization of patients with burns in the ICU. Emotional support for staff through multidisciplinary collaboration and development of structured burns training program were key recommendations to address barriers and strengthen enablers to early mobilization of patients with burns in the ICU., Competing Interests: Competing interests Not applicable., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

Pediatric patients with recurrent and refractory cancers are in most need for new treatments. This study developed patient-derived-xenograft (PDX) models within the European MAPPYACTS cancer precision medicine trial (NCT02613962). To date, 131 PDX models were established following heterotopical and/or orthotopical implantation in immunocompromised mice: 76 sarcomas, 25 other solid tumors, 12 central nervous system tumors, 15 acute leukemias, and 3 lymphomas. PDX establishment rate was 43%. Histology, whole exome and RNA sequencing revealed a high concordance with the primary patient's tumor profile, human leukocyte-antigen characteristics and specific metabolic pathway signatures. A detailed patient molecular characterization, including specific mutations prioritized in the clinical molecular tumor boards are provided. Ninety models were shared with the IMI2 ITCC Pediatric Preclinical Proof-of-concept Platform (IMI2 ITCC-P4) for further exploitation. This PDX biobank of unique recurrent childhood cancers provides an essential support for basic and translational research and treatments development in advanced pediatric malignancies., (© 2023. Springer Nature Limited.)

SHP1 and SHP2 are SH2 domain-containing proteins which have inhibitory phosphatase activity when recruited to phosphorylated ITIMs and ITSMs on inhibitory immune receptors. Consequently, SHP1 and SHP2 are key proteins in the transmission of inhibitory signals within T cells, constituting an important point of convergence for diverse inhibitory receptors. Therefore, SHP1 and SHP2 inhibition may represent a strategy for preventing immunosuppression of T cells mediated by cancers hence improving immunotherapies directed against these malignancies. Both SHP1 and SHP2 contain dual SH2 domains responsible for localization to the endodomain of inhibitory receptors and a protein tyrosine phosphatase domain which dephosphorylates and thus inhibits key mediators of T cell activation. We explored the interaction of the isolated SH2 domains of SHP1 and SHP2 to inhibitory motifs from PD1 and identified strong binding of both SH2 domains from SHP2 and more moderate binding in the case of SHP1. We next explored whether a truncated form of SHP1/2 comprising only of SH2 domains (dSHP1/2) could act in a dominant negative fashion by preventing docking of the wild type proteins. When co-expressed with CARs we found that dSHP2 but not dSHP1 could alleviate immunosuppression mediated by PD1. We next explored the capacity of dSHP2 to bind with other inhibitory receptors and observed several potential interactions. In vivo we observed that the expression of PDL1 on tumor cells impaired the ability of CAR T cells to mediate tumor rejection and this effect was partially reversed by the co-expression of dSHP2 albeit at the cost of reduced CAR T cell proliferation. Modulation of SHP1 and SHP2 activity in engineered T cells through the expression of these truncated variants may enhance T cell activity and hence efficacy in the context of cancer immunotherapy., Competing Interests: Authors JT, AB, IG, MR, MS, EK, TG, CM, ME-K, CT-W, WCL, PP, SS, VB, JS, MF, ST, MP were employed by Autolus Limited. All authors have Autolus shares., (Copyright © 2023 Taylor, Bulek, Gannon, Robson, Kokalaki, Grothier, McKenzie, El-Kholy, Stavrou, Traynor-White, Lim, Panagiotou, Srivastava, Baldan, Sillibourne, Ferrari, Pule and Thomas.)

Background: We used a proliferating ligand (APRIL) to construct a ligand-based third generation chimeric antigen receptor (CAR) able to target two myeloma antigens, B-cell maturation antigen (BCMA) and transmembrane activator and CAML interactor., Methods: The APRIL CAR was evaluated in a Phase 1 clinical trial (NCT03287804, AUTO2) in patients with relapsed, refractory multiple myeloma. Eleven patients received 13 doses, the first 15×10 6 CARs, and subsequent patients received 75,225,600 and 900×10 6 CARs in a 3+3 escalation design., Results: The APRIL CAR was well tolerated. Five (45.5%) patients developed Grade 1 cytokine release syndrome and there was no neurotoxicity. However, responses were only observed in 45.5% patients (1×very good partial response, 3×partial response, 1×minimal response). Exploring the mechanistic basis for poor responses, we then compared the APRIL CAR to two other BCMA CARs in a series of in vitro assays, observing reduced interleukin-2 secretion and lack of sustained tumor control by APRIL CAR regardless of transduction method or co-stimulatory domain. There was also impaired interferon signaling of APRIL CAR and no evidence of autoactivation. Thus focusing on APRIL itself, we confirmed similar affinity to BCMA and protein stability in comparison to BCMA CAR binders but reduced binding by cell-expressed APRIL to soluble BCMA and reduced avidity to tumor cells. This indicated either suboptimal folding or stability of membrane-bound APRIL attenuating CAR activation., Conclusions: The APRIL CAR was well tolerated, but the clinical responses observed in AUTO2 were disappointing. Subsequently, when comparing the APRIL CAR to other BCMA CARs, we observed in vitro functional deficiencies due to reduced target binding by cell-expressed ligand., Competing Interests: Competing interests: LSHL, KY and MP are inventors on patents relevant to this paper filed by UCL and are entitled to share of royalties there from. KY and MP owns equity in Autolus Therapeutics. WCL, JT, ZA, WD, VC, MF, ST, SC, SO, NK, VP, MA-H and MP are either current present or former employees of Autolus Therapeutics. LSHL and KY receive research funding from Autolus Therapeutics., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Introduction: In the National University Cancer Institute, Singapore (NCIS), 2 pilot programs providing (i) surgical prehabilitation before cancer surgery and (ii) geriatric oncology support for older adults planned for chemotherapy and/or radiotherapy were merged to form the Geriatric Oncology Longitudinal End to eNd (GOLDEN) program in 2019 to support patients from the time of their cancer diagnosis, through their treatment process, to cancer survivorship., Methods and Materials: Older adults aged ≥65 years were enrolled in either surgical prehabilitation, the geriatric medical oncology (GO) arm, or both. All patients undergo a geriatric assessment. We assessed if patients had a change in treatment plans based on GOLDEN recommendations, and the impact on patient related outcomes., Results: There were 777 patients enrolled in the GOLDEN program over 2 years; 569 (73%) were enrolled in surgical prehabilitation, 308 (40%) were enrolled in the GO arm, with 100 (12.8%) enrolled in both. 56.9% were females. Median age was 73. Lower gastrointestinal (51.2%) and hepatobiliary cancers (24.1%) were the most common cancer types. 43.4% were pre-frail and 11.7% were frail. Of the 308 patients in the GO arm, 86.0% had geriatric syndromes, while 60.7% had a change in their treatment plans based on GOLDEN recommendations. 31.5% reported an improved global health status, while 38.3% maintained their global health status. 226 (73%) responded that they had benefited from the GOLDEN., Conclusion: More than half of the population was either pre-frail or frail. Amongst those in the GO arm, the majority had geriatric syndromes and had a change in their treatment plans based on GOLDEN recommendations. Majority reported either improvement or maintenance in global health status, with most feeling they have benefited from the program. Further evaluation of the longitudinal geriatric hematology-oncology program for cancer-related outcomes and sustainability should be carried out., (© The Author(s) 2023. Published by Oxford University Press.)

Competing Interests: None

Herein, we systematically studied the effect of various excitation processes on the structural, optical, and magnetic properties of ZnO films implanted with 80 keV Ar + , 110 keV Mn + , and 190 keV Ag + ions. Four different doses of 1 × 10 13 , 1 × 10 14 , 1 × 10 15 , and 2 × 10 16 ions per cm 2 were used for implantation. It was observed that the structural, optical, and magnetic properties of the implanted samples were dominantly affected at the highest dose of 2 × 10 16 ions per cm 2 . For lower doses, insignificant changes in these properties were observed. A comparison of various processes involved in the implantation process shows that both the electronic excitation and nuclear excitation processes are responsible for the changes in the structural, optical, and magnetic properties of the implanted ZnO films., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Purpose: The emergency department (ED) plays an important role in initiating early treatment for hip fractures and ensuring prompt transfer to orthopaedic wards. This study reported on the care delivered in a tertiary centre ED in Malaysia and the association between time spent in ED with hospital outcomes., Methods: Patients aged ≥ 65 years with fragility hip fractures and seen by the geriatric team were recruited. Data were collected on patient characteristics, key time points for treatment and hospital outcomes. Median time in ED was used to dichotomise long and short waiting time., Results: 447 patients were recruited. The mean (SD) age was 80.5 (7.0) years and 69.8% were women. 74.9% were prescribed analgesia within 30 min. Median (Q1,Q3) time to diagnostic imaging was 27.0 (24.0-43.0) minutes, clinician confirmation of fracture was 83.0 (49.0-129.0) minutes, and time in ED was 4.8 (3.5-6.9) h. A weekday, weekend, in-hour or out-of-hour admission did not demonstrate a difference in the time important care was delivered. Patients who spent ≥ 5 h in ED had more cardiac events (4.6 vs 10.1%, p = 0.023) and more spent ≥ 14 days in hospital (17.5 vs 29.0%, p = 0.004) compared to those < 5 h. No significant increase in inpatient complications (43.5 vs 34.6%, p = 0.054), length of stay (median, 8 vs 7 days, p = 0.119), care home discharge (5.3 vs 4.6%, p = 0.772), or in-hospital death (6.3 vs 4.2%, p = 0.313) were observed., Conclusion: Time to early hip fracture pain relief and diagnosis was adequate in this ED. Time ≥ 5 h in ED was associated with cardiac events and 2 weeks or more inpatient stay., (© 2022. The Author(s), under exclusive licence to European Geriatric Medicine Society.)

Cells are constantly challenged by genotoxic stresses that can lead to genome instability. The integrity of the nuclear genome is preserved by the DNA damage response (DDR) and repair. Additionally, these stresses can induce mitochondria to transiently hyperfuse; however, it remains unclear whether canonical DDR is linked to these mitochondrial morphological changes. Here, we report that the abolition of mitochondrial fusion causes a substantial defect in the ATM-mediated DDR signaling. This deficiency is overcome by the restoration of mitochondria fusion. In cells with fragmented mitochondria, genotoxic stress-induced activation of JNK and its translocation to DNA lesion are lost. Importantly, the mitochondrial fusion machinery of MFN1/MFN2 associates with Sab (SH3BP5) and JNK, and these interactions are indispensable for the Sab-mediated activation of JNK and the ATM-mediated DDR signaling. Accordingly, the formation of BRCA1 and 53BP1 foci, as well as homology and end-joining repair are impaired in cells with fragmented mitochondria. Together, these data show that mitochondrial fusion-dependent JNK signaling is essential for the DDR, providing vital insight into the integration of nuclear and cytoplasmic stress signals., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Ginsenoside Rf (G-Rf) is a saponin of the protopanaxatriol family and a bioactive component of Korean ginseng. Several ginsenosides are known to have a positive effect on exercise endurance, but there is not yet a report on that of G-Rf. Forced swimming tests were performed on G-Rf-treated mice to evaluate the effect of G-Rf on exercise endurance. Subsequently, the expression of markers related to myoblast differentiation and mitochondrial biogenesis in murine skeletal C2C12 myotubes and tibialis anterior muscle tissue was determined using Western blotting, quantitative real-time polymerase chain reaction, and immunofluorescence staining to elucidate the mechanism of action of G-Rf. The swimming duration of the experimental animal was increased by oral gavage administration of G-Rf. Moreover, G-Rf significantly upregulated the myoblast differentiation markers, mitochondrial biogenesis markers, and its upstream regulators. In particular, the mitochondrial biogenesis marker increased by G-Rf was decreased by each inhibitor of the upstream regulators. G-Rf enhances exercise endurance in mice, which may be mediated by myoblast differentiation and enhanced mitochondrial biogenesis through AMPK and p38 MAPK signaling pathways, suggesting that it increases energy production to satisfy additional needs of exercising muscle cells. Therefore, G-Rf is an active ingredient in Korean ginseng responsible for improving exercise performance.

One of the main purposes of smart and multifunctional coatings is to have the versatility to be applied in a wide range of applications. However, the functions of smart materials are often highly limited. In particular, the stimuli-responsive lateral expansion of coatings based on 2D materials has not been reported before. This manuscript describes small two-dimensional graphene oxide (GO) flakes ( e.g. , thin sheets with a thickness of a few nanometers and much larger lateral dimensions) that act as elementary agents for the formation of smart and multifunctional coatings. The coating can be self-assembled from the GO flakes and disassembled flexibly when required. The coating is stimuli-responsive: upon localized contact with water, it expands and forms wrinkling patterns throughout its whole surface. Evaporating the water allows the wrinkles to disappear; hence, the process is reversible. This stimuli-responsiveness can be controlled to be reduced or completely switched off by temperature or pressure. These features are fundamentally due to the reversible intermolecular interactions among the flakes and favorable packing structure of the coating. The smart coating is shown to be useful for patterned fluidic systems of the desired shapes and the development of channels between fluidic reservoirs via the shortest path. Importantly, these results showed that a simple collection of uniquely 2D elementary agents with small nanoscale thickness can self-assemble into macroscopic materials that perform interactive and multifunctional operations.

Objective: To investigate the incidence of gastric cancer (GC) attributed to gastric intestinal metaplasia (IM), and validate the Operative Link on Gastric Intestinal Metaplasia (OLGIM) for targeted endoscopic surveillance in regions with low-intermediate incidence of GC., Methods: A prospective, longitudinal and multicentre study was carried out in Singapore. The study participants comprised 2980 patients undergoing screening gastroscopy with standardised gastric mucosal sampling, from January 2004 and December 2010, with scheduled surveillance endoscopies at year 3 and 5. Participants were also matched against the National Registry of Diseases Office for missed diagnoses of early gastric neoplasia (EGN)., Results: There were 21 participants diagnosed with EGN. IM was a significant risk factor for EGN (adjusted-HR 5.36; 95% CI 1.51 to 19.0; p<0.01). The age-adjusted EGN incidence rates for patients with and without IM were 133.9 and 12.5 per 100 000 person-years. Participants with OLGIM stages III-IV were at greatest risk (adjusted-HR 20.7; 95% CI 5.04 to 85.6; p<0.01). More than half of the EGNs (n=4/7) attributed to baseline OLGIM III-IV developed within 2 years (range: 12.7-44.8 months). Serum trefoil factor 3 distinguishes (Area Under the Receiver Operating Characteristics 0.749) patients with OLGIM III-IV if they are negative for H. pylori . Participants with OLGIM II were also at significant risk of EGN (adjusted-HR 7.34; 95% CI 1.60 to 33.7; p=0.02). A significant smoking history further increases the risk of EGN among patients with OLGIM stages II-IV., Conclusions: We suggest a risk-stratified approach and recommend that high-risk patients (OLGIM III-IV) have endoscopic surveillance in 2 years, intermediate-risk patients (OLGIM II) in 5 years., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We surveyed primary care physicians in Malaysia for their knowledge, attitude and practice in screening and managing osteoporosis. We found a low level of screening and active management of osteoporosis in the primary care setting despite positive attitudes towards them. We advocate for the active management of osteoporosis at the primary care level., Introduction: Prevention of osteoporotic fracture is important in primary healthcare for healthy ageing. Little is known about the knowledge, attitude, practice and barriers in the screening and managing osteoporosis among primary care doctors., Methods: A cross-sectional study, using an online pre-tested questionnaire after face and content validation, was conducted for primary care doctors from 1 June to 30 July 2021 across Malaysia. Pearson's chi-square test and logistic regression were employed., Results: A total of 350 primary care doctors in Malaysia, consisting of 113 (32.3%) family medicine specialists (FMS) and 237 (67.7%) medical officers, participated in this study. The mean ± SD score of osteoporosis knowledge was 50.46 ± 15.09 with minimum and maximum values of 0 and 83.64%, respectively. One hundred and ten (31.4%) respondents achieved a satisfactory overall knowledge score of ≥ 60%, 156 (44.6%) were confident in advising patients for initiation of anti-osteoporotic medication, and 243 (69.4%) perceived that bisphosphonate should be made available in health clinics. Only 97 (27.7%) practised osteoporosis screening. Inaccessibility of bone mineral densitometry (BMD) (90.6%), inadequate knowledge (87.7%) and inaccessibility of pharmacotherapy (87.1%) are perceived modifiable barriers to osteoporosis screening and management. Factors associated with a satisfactory knowledge of osteoporosis are designation as a family medicine specialist (AOR 3.034, p = 0.002), attendance at an osteoporosis management update course (AOR 2.095, p = 0.034) and the practice of osteoporosis screening for the elderly (AOR 2.767, p = 0.001)., Conclusion: Given the insufficient knowledge and low level of osteoporosis screening, there is a need for a national structured health programme to address the knowledge gap, increase screening practices and enhance accessibility to BMD and anti-osteoporosis medication in primary care., (© 2022. International Osteoporosis Foundation and National Osteoporosis Foundation.)

The energy balance approach is one of the design approaches approved in fall protection standards Z359.6, Z259.16 and SS 607 to ensure that horizontal lifeline systems (HLLSs) are adequately designed. However, this study found that theoretical calculations predicting the total fall distance ( h TFD ) and maximum arrest load (MAL) using an energy balance approach need to be corrected before they can be used safely. Based on the data from 48 drop tests, the authors determined that energy balance calculations differ significantly from the empirical h TFD and MAL values of HLLSs. As a result, further correction factors are introduced into the theoretical calculations to estimate h TFD and MAL conservatively. These correction factors are estimated from a regression equation derived based on experimental results and theoretical calculations.

Objective: To examine the effectiveness and safety of non-pharmacological interventions to reduce bone loss among post-stroke adult patients., Data Sources: Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database for Systematic Reviews, MEDLINE, CINAHL, ScienceDirect, Scopus, PubMed and PeDRO databases were searched from inception up to 31st August 2021., Methods: A systematic review of randomized controlled trials, experimental studies without randomization and prospective cohort studies with concurrent control of non-pharmacological interventions for adult stroke patients compared with placebo or other stroke care. The review outcomes were bone loss, fall and fracture. The Cochrane Risk of Bias Tools were used to assess methodological quality, and Grading of Recommendations, Assessment, Development and Evaluations Framework to assess outcome quality. Synthesis Without Meta-Analysis (SWiM) was used for result synthesis., Results: Seven studies (n = 453) were included. The methodological and outcome qualities varied from low to moderate. There were statistically significant changes between the intervention and parallel/placebo group in bone mineral density, bone mineral content, cortical thickness and bone turnover markers with specific physical and vibration therapies (p<0.05). Falls were higher in the intervention group, but no fracture was reported., Conclusion: There was low to moderate evidence that physical and vibration therapies significantly reduced bone loss in post-stroke patients at the expense of a higher falls rate. The sample size was small, and the interventions were highly heterogeneous with different duration, intensities and frequencies. Despite osteoporosis occurring with ageing and accelerated by stroke, there were no studies on vitamin D or protein supplementation to curb the ongoing loss. Effective, high-quality non-pharmacological intervention to improve post-stroke bone health is required., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Prehabilitation may benefit older patients undergoing major surgeries. Currently, its efficacy has not been conclusively proven. This is a retrospective review of a multimodal prehabilitation programme., Methods: Patients aged 65 years and above undergoing major abdominal surgery between May 2015 and December 2019 in the National University Hospital were included in our institutional programme that incorporated aspects of multimodal prehabilitation and Enhanced Recovery After Surgery concepts as 1 holistic perioperative pathway to deal with issues specific to older patients. Physical therapy, nutritional advice and psychosocial support were provided as part of prehabilitation., Results: There were 335 patients in the prehabilitation cohort and 256 patients whose records were reviewed as control. No difference in postoperative length of stay ( P =0.150) or major complications ( P =0.690) were noted. Patients in the prehabilitation group were observed to ambulate a longer distance and participate more actively with their physiotherapists from postoperative day 1 until 4. In the subgroup of patients with cancer, more patients had undergone neoadjuvant therapy in the prehabilitation group compared to the control group (21.7% versus 12.6%, P =0.009). Prehabilitation patients were more likely to proceed to adjuvant chemotherapy (prehabilitation 87.2% vs control 65.6%, P <0.001) if it had been recommended., Conclusion: The current study found no differences in traditional surgical outcome measures with and without prehabilitation. An increase in patient mobility in the immediate postoperative period was noted with prehabilitation, as well as an association between prehabilitation and increased adherence to postoperative adjuvant therapy. Larger prospective studies will be needed to validate the findings of this retrospective review.

Rosa gallica is a widely used Rosa species for medicinal and culinary purposes. Rosa gallica has been reported to display antioxidant, anti-inflammatory, and antibacterial activities. However, the effect of Rosa gallica against skin aging in vivo is unknown and its active components have not been fully understood. Oral administration of Rosa gallica prevented UVB-mediated skin wrinkle formation and loss of collagen/keratin fibers in the dorsal skin of mice. Examination of biomarkers at the molecular level showed that Rosa gallica downregulates UVB-induced COX-2 and MMP-1 expression in the skin. Through a direct comparison of major compounds identified using the UHPLC-MS/MS system, we discovered gallic acid as the primary component contributing to the anti-skin aging effect exhibited by Rosa gallica . Examination of the molecular mechanism revealed that gallic acid can potently and selectively target the c-Raf/MEK/ERK/c-Fos signaling axis. In addition, both gallic acid and MEK inhibitor blocked UVB-induced MMP-1 expression and restored collagen levels in a reconstructed 3D human skin model. Collectively, Rosa gallica could be used as a functional ingredient in the development of nutraceuticals against skin aging.

To ensure that vertical lifeline systems (VLLSs) are well designed, calculation methods are required to estimate the extension of a personal energy absorber (PEA) ( x PEA ) and the total fall distance ( h TFD ). Thus, the authors conducted 28 tests to validate the accuracy of the energy balance approach for estimating x PEA and h TFD of VLLSs and propose suitable correction factors to improve the accuracy and safety of the estimated x PEA and h TFD . For 9 out of 19 tests with a PEA, the difference between the theorical x PEA and empirical x PEA was 25% or higher, indicating that the energy balance approach is not accurate for estimation of x PEA . In contrast, theoretical values of h TFD are more accurate. Linear regression equations for estimating x PEA ( R 2  = 0.81) and h TFD ( R 2  = 0.99) were developed. The regression equations can be used to improve the accuracy and conservativeness of estimations of x PEA and h TFD during the design of VLLSs.

Materials (e.g., brick or wood) are generally perceived as unintelligent. Even the highly researched "smart" materials are only capable of extremely primitive analytical functions (e.g., simple logical operations). Here, a material is shown to have the ability to perform (i.e., without a computer), an advanced mathematical operation in calculus: the temporal derivative. It consists of a stimuli-responsive material coated asymmetrically with an adaptive impermeable layer. Its ability to analyze the derivative is shown by experiments, numerical modeling, and theory (i.e., scaling between derivative and response). This class of freestanding stimuli-responsive materials is demonstrated to serve effectively as a derivative controller for controlled delivery and self-regulation. Its fast response realizes the same designed functionality and efficiency as complex industrial derivative controllers widely used in manufacturing. These results illustrate the possibility to associate specifically designed materials directly with higher concepts of mathematics for the development of "intelligent" material-based systems., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

(1) Background: Older people with COVID-19 infection report worse clinical outcomes. There is a paucity of local data and this study aimed to describe the clinical progression of older people admitted to a university hospital in Malaysia with COVID-19 infection. (2) Methods: Older people (≥60 years) admitted with COVID-19 infection confirmed with RT-PCR from 27 February 2020-25 May 2020 were included in this study. Data on patient characteristics, hospital treatment, and inpatient outcomes were collected via hospital-held electronic medical records. Analysis was done to describe the cohort and identify factors associated with inpatient mortality. (3) Results: 26 participants were included (mean age 76.2 years, female 57.7%). All had at least one comorbid condition and half were frail. About 19.2% had non-respiratory (atypical) symptoms; 23.1% had a severe disease that required intensive care unit monitoring; 46.2% were given COVID-19 targeted therapy. Inpatient mortality and overall complication rates were 23.1% and 42.3%, respectively. Delirium on presentation and lower Ct-value were associated with mortality. (4) Conclusions: Older people with COVID-19 infection have severe infection and poor hospital outcomes. Vigilant hospital care is necessary to address their multimorbidity and frailty, along with appropriate treatment for their infection.

Background: Lung cancer has a high incidence worldwide, and most lung cancer-associated deaths are attributable to cancer metastasis. Although several medicinal properties of Panax ginseng Meyer have been reported, the effect of ginsenosides Rk1 and Rg5 on epithelial-mesenchymal transition (EMT) stimulated by transforming growth factor beta 1 (TGF- β1) and self-renewal in A549 cells is relatively unknown., Methods: We treated TGF-β1 or alternatively Rk1 and Rg5 in A549 cells. We used western blot analysis, real-time polymerase chain reaction (qPCR), wound healing assay, Matrigel invasion assay, and anoikis assays to determine the effect of Rk1 and Rg5 on TGF-mediated EMT in lung cancer cell. In addition, we performed tumorsphere formation assays and real-time PCR to evaluate the stem-like properties., Results: EMT is induced by TGF-β1 in A549 cells causing the development of cancer stem-like features. Expression of E-cadherin, an epithelial marker, decreased and an increase in vimentin expression was noted. Cell mobility, invasiveness, and anoikis resistance were enhanced with TGF-β1 treatment. In addition, the expression of stem cell markers, CD44, and CD133, was also increased. Treatment with Rk1 and Rg5 suppressed EMT by TGF-β1 and the development of stemness in a dose-dependent manner. Additionally, Rk1 and Rg5 markedly suppressed TGF-β1-induced metalloproteinase-2/9 (MMP2/9) activity, and activation of Smad2/3 and nuclear factor kappa B/extra-cellular signal regulated kinases (NF-kB/ERK) pathways in lung cancer cells., Conclusions: Rk1 and Rg5 regulate the EMT inducing TGF-β1 by suppressing the Smad and NF-κB/ERK pathways (non-Smad pathway)., Competing Interests: The authors have no conflicts of interests to disclose., (© 2020 The Korean Society of Ginseng. Publishing services by Elsevier B.V.)

Aqueous liquids can be charged effectively by a number of methods for many important applications. Organic liquids, however, cannot be charged effectively by existing methods due to their low conductivities, especially the insulating nonpolar organic liquids; hence, there has not been any significant application developed based on charged organic liquids. This study describes an effective fundamental strategy for charging organic liquids, including nonpolar organic liquids: static charge is simply mixed into the liquid. Analyses suggested that the charged species are molecular ions that reside in the bulk of the liquid after charging. This method is simple and general, and the amount and polarity of charge can be flexibly tunable. The effectiveness of this method gives rise to opportunities for the development of novel applications. Charged organic droplets are manipulated for the first time by an electric field for controlling organic reactions. Particles with charge embedded in their bulk matrices are fabricated for the first time (i.e., via polymerizing the liquid monomers mixed with static charge). The charge in this novel class of bulk-charged particles is stable and permanent, especially when compared to the typical surface-charged particles. Simultaneous bulk-charged and bulk-magnetic particles are fabricated for the first time via simply mixing both the static charge and magnetic nanoparticles into the liquid monomers. These highly versatile particles are responsive to both electric and magnetic fields for practical applications.

Herein, sputtering duration and annealing temperature effects on the structure and local electronic structure of MgO thin films were studied using synchrotron radiation based X-ray diffraction and X-ray absorption spectroscopic investigations. These films were grown at substrate temperature of 350 °C by varying sputtering duration from 25 min to 324 min in radio frequency (RF) sputtering method followed by post-deposition annealing at 400, 600 and 700 °C for 3 h. These films were amorphous upto certain sputtering durations, typically upto 144 min and attains crystallization thereafter. This kind of behavior was observed at all annealing temperature. The textured coefficient of crystalline films envisaged that the orientation was affected by annealing temperature. Coordination of Mg 2+ ions was more distorted in amorphous films compared to crystalline films. Moreover, onset of molecular oxygen are absorbed at low annealing temperature on these films.

In the present study, to verify the effect of polysaccharides derived from persimmon leaves (PLE) at epithelial-to-mesenchymal transition (EMT), A549 cells were treated with TGF-β1 alone or co-treated with TGF-β1 and PLE (50 and 75 μg/mL). PLE-treated cells showed higher expression of E-cadherin and lower expression of N-cadherin and vimentin compared to TGF-β1-treated cells by inhibiting the levels of transcription factors, including Snail, Slug, and ZEB1, all associated with EMT. PLE also significantly decreased migration, invasion, and anoikis resistance through TGF-β1 mediated EMT suppression, whereby PLE inhibited the levels of MMP-2 and MMP-9 while cleaving PARP. These inhibitory effects of PLE against EMT, migration, invasion, and anoikis resistance were determined by activating the canonical SMAD2/3 and non-canonical ERK/p38 signaling pathways. Therefore, these results suggest that PLE could be used as a potential chemical therapeutic agent for early metastasis of lung cancer in vitro., Competing Interests: Declaration of competing interest All the authors confirm that there is not any potential conflict of interest regarding this publication., (Copyright © 2020. Published by Elsevier B.V.)

We sought to investigate the effect of rose petal extract (RPE) on the proliferation, migration, and invasion of cancer cells. RPE significantly inhibited the growth of lung and colorectal cancer cell lines, with rapid suppression of A549 lung cancer cells at low concentrations. These effects occurred concomitantly with downregulation of the cell proliferation mediators PCNA, cyclin D1, and c-myc. In addition, RPE suppressed the migration and invasion of A549 cells by inhibiting the expression and activity of matrix metalloproteinase-2 and matrix metalloproteinase-9 (MMP-2 and -9). We hypothesize that the suppressive activity of RPE against lung cancer cell proliferation and early metastasis occurs via the EGFR-MAPK and mTOR-Akt signaling pathways. These early results highlight the significant potency of RPE, particularly for lung cancer cells, and warrant further investigation.

We sought to investigate the effect of extracts from Rosa gallica petals (RPE) on skin whitening and anti-wrinkle activity. Tyrosinase activity was attenuated by RPE treatment, concomitant with the reduction of melanin accumulation in human B16F10 melanoma. Treatment of the facial skin of volunteers in a clinical trial with an RPE-containing formulation enhanced skin brightness (L* value) significantly. The underlying mechanism responsible was determined to be associated with mitogen-activated protein kinase (MAPK) activation. In addition, RPE exhibited anti-wrinkle formation activity of human dermal fibroblasts by suppressing matrix metalloproteinase (MMP)-1 level. In vivo study, RPE also inhibited solar ultraviolet-stimulated MMP-1 level by c-Jun regulation. Overall, our findings indicate that RPE evokes skin whitening and anti-wrinkle formation activity by regulating intracellular signaling, supporting its utility as an ingredient for skin whitening and anti-wrinkle cosmetic products.

Polysaccharides isolated from various plants are considered precious bioactive materials owing to their potent biological activities. Previously, we prepared a polysaccharide fraction (BLE0) isolated from young barley leaves ( Hordeum vulgare L.), demonstrating its anti-osteoporotic and immunostimulatory activities. However, data regarding BLE0 toxicity is lacking. To establish its safety, in vitro genotoxicity (chromosomal aberration and bacterial reverse mutation assays) and acute oral toxicity assays were conducted. In the in vitro genotoxicity assays, bacterial reverse mutation and chromosomal aberration assays showed that BLE0 possessed no mutagenicity or clastogenicity. Furthermore, the median lethal dose (LD 50 ) of BLE0 was higher than 5000 mg/kg in female and male Sprague-Dawley (SD) rats and no adverse effects were observed in terms of mortality and abnormal changes in clinical signs (body weight and necropsy). Based on these results, BLE0 was found to be safe with regards to genotoxicity under our test conditions, demonstrating no acute oral toxicity up to 5000 mg/kg in SD rats.

Herein, the size dependent behavior of cobalt ferrite nanoparticles was investigated using synchrotron radiation based techniques. Scanning electron micrographs revealed the enhancement of particle/crystallite size with increase of annealing temperature. Moreover, the shape of these particles also changed with increase of crystallite size. Saturation magnetization increased with increase of crystallite size. The higher saturation magnetization for larger crystallite size nanoparticles was attributed to a cation distribution similar to that of bulk CoFe 2 O 4 . The optical band-gap of these nanoparticles decreased from 1.9 eV to 1.7 eV with increase of crystallite size. The enhancement of the optical band-gap for smaller crystallites was due to phenomena of optical confinement occurring in the nanoparticles. Fe L Co L-edge near edge extended X-ray absorption fine structure (NEXAFS) measurements showed that Fe and Co ions remain in the 3+ and 2+ state in these nanoparticles. The results obtained from Fe & Co K-edge X-ray absorption near edge structure (XANES)-imaging experiments further revealed that this oxidation state was possessed by even the crystallites. Extended X-ray absorption fine structure (EXAFS) measurements revealed distribution of Fe and Co ions among tetrahedral (A) and octahedral (B) sites of the spinel structure which corroborates the results obtained from Rietveld refinement of X-ray diffraction patterns (XRD). X-ray magnetic circular di-chroism (XMCD) measurements revealed negative exchange interaction among the ions situated in tetrahedral (A) and octahedral (B) sites. Theoretical and experimental calculated magnetic moments revealed the dominancy of size effects rather than the cation redistribution in the spinel lattice of CoFe 2 O 4 nanoparticles., Competing Interests: Authors declare no conflicts of interests., (This journal is © The Royal Society of Chemistry.)

Thiopurines are used in the treatment of inflammatory bowel disease (IBD) but remain clinically challenging to manage due to wide interpatient variability in clinical outcomes and adverse events. Apart from genetic variants in thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) genes, polymorphisms in FTO alpha-ketoglutarate dependent dioxygenase (FTO) were found predictive of thiopurine-induced leukopenia, albeit with conflicting results. To clarify the role of FTO variants in a multiethnic Asian IBD cohort, we recruited 149 patients on thiopurine-based therapy and genotyped two FTO variants p.Ala134Thr (rs79206939) and rs16952570 T > C using Sanger sequencing. FTO p.Ala134Thr (rs79206939) was non-polymorphic and absent whereas intronic rs16952570 T > C was equally prevalent in Chinese (22%) and Indians (18%) and higher in Malays (28%). Higher nadir white blood cell (WBC) and absolute neutrophil count (ANC) levels were observed in patients harboring FTO rs16952570 CC genotypes compared with TT carriers at 4, 8, and 12 weeks after start of thiopurine therapy (P < 0.05). A similar trend was observed in patients carrying the previously well-characterized NUDT15 rs116855232 wild-type CC genotypes. Further in silico analysis suggests that FTO variants linked to rs16952570, particularly rs74018601, may play a regulatory role in altering the FTO expression. The findings from this study indicate a novel protective association with the FTO variant rs16952570 CC genotype and hematological parameters.

Epithelial-mesenchymal transition (EMT) is a major cellular process in which epithelial cells lose cell polarity and cell-cell adhesion and become motility and invasiveness by transforming into mesenchymal cells. Catechol is one of the natural compounds present in fruits and vegetables and has various pharmacological and physiological activities including anti-carcinogenic effects. However, the effects of catechol on EMT has not been reported. Epidermal growth factor (EGF) is one of the growth factors and is known to play a role in inducing EMT. The present study showed that catechol suppressed not only the morphological changes to the mesenchymal phenotype of epithelial HCC cells, but also the reduction of E-cadherin and the increment of Vimentin, which are typical hallmark of EMT. In addition, catechol suppressed EMT-related steps such as migration, invasion, anoikis resistance acquisition, and stem cell-like characterization through the EGFR-AKT-ERK signaling pathway during liver cancer metastasis. Therefore, these results suggest that catechol may be able to regulate the early metastasis of liver cancer in vitro.

Delamination is one of the detrimental defects in laminated composite materials that often arose due to manufacturing defects or in-service loadings (e.g., low/high velocity impacts). Most of the contemporary research efforts are dedicated to high-frequency guided wave and mode shape-based methods for the assessment (i.e., detection, quantification, localization) of delamination. This paper presents a deep learning framework for structural vibration-based assessment of delamination in smart composite laminates. A number of small-sized (4.5% of total area) inner and edge delaminations are simulated using an electromechanically coupled model of the piezo-bonded laminated composite. Healthy and delaminated structures are stimulated with random loads and the corresponding transient responses are transformed into spectrograms using optimal values of window size, overlapping rate, window type, and fast Fourier transform (FFT) resolution. A convolutional neural network (CNN) is designed to automatically extract discriminative features from the vibration-based spectrograms and use those to distinguish the intact and delaminated cases of the smart composite laminate. The proposed architecture of the convolutional neural network showed a training accuracy of 99.9%, validation accuracy of 97.1%, and test accuracy of 94.5% on an unseen data set. The testing confusion chart of the pre-trained convolutional neural network revealed interesting results regarding the severity and detectability for the in-plane and through the thickness scenarios of delamination.

Red ginseng has been reported to elicit various therapeutic effects relevant to cancer, diabetes, neurodegenerative diseases, and inflammatory diseases. However, the effect of red ginseng on exercise endurance and skeletal muscle function remains unclear. Herein, we sought to investigate whether red ginseng could affect exercise endurance and examined its molecular mechanism. Mice were fed with red ginseng extract (RG) and undertook swimming exercises to determine the time to exhaustion. Animals fed with RG had significantly longer swimming endurance. RG treatment was also observed to enhance ATP production levels in myoblasts. RG increased mRNA expressions of mitochondrial biogenesis regulators, NRF-1 , TFAM , and PGC-1α , which was accompanied by an elevation in mitochondrial DNA, suggesting an enhancement in mitochondrial energy-generating capacity. Importantly, RG treatment induced phosphorylation of p38 and AMPK and upregulated PGC1α expression in both myoblasts and in vivo muscle tissue. In addition, RG treatment also stimulated C2C12 myogenic differentiation. Our findings show that red ginseng improves exercise endurance, suggesting that it may have applications in supporting skeletal muscle function and exercise performance.

The Asia-Pacific Working Group on Inflammatory Bowel Disease was established in Cebu, Philippines, under the auspices of the Asia-Pacific Association of Gastroenterology with the goal of improving inflammatory bowel disease care in Asia. This consensus is carried out in collaboration with Asian Organization for Crohn's and Colitis. With biologic agents and biosimilars becoming more established, it is necessary to conduct a review on existing literature and establish a consensus on when and how to introduce biologic agents and biosimilars in conjunction with conventional treatments for ulcerative colitis and Crohn's disease in Asia. These statements also address how pharmacogenetics influences the treatments of ulcerative colitis and Crohn's disease and provides guidance on response monitoring and strategies to restore loss of response. Finally, the review includes statements on how to manage treatment alongside possible hepatitis B and tuberculosis infections, both common in Asia. These statements have been prepared and voted upon by members of inflammatory bowel disease workgroup employing the modified Delphi process. These statements do not intend to be all-encompassing, and future revisions are likely as new data continue to emerge., (© 2019 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Epithelial-to-mesenchymal transition (EMT), important cellular process in metastasis of primary tumors, is characterized by loss of their cell polarity, disruption of cell-cell adhesion, and gain certain properties of mesenchymal phenotype that enable migration and invasion. Delphinidin is a member of anthocyanidin belong to flavonoid groups, known as having pharmacological and physiological effects including anti-tumorigenic, antioxidative, anti-inflammatory, and antiangiogenic effects. However, the effects of delphinidin on EMT is rarely investigated. Epidermal growth factor (EGF) is known as a crucial inducer of EMT in various cancer including hepatocellular carcinoma (HCC). To determine whether delphinidin inhibits EGF-induced EMT in HCC cells, antiproliferative effect of delphinidin on Huh7 and PLC/PRF/5 cells were measured by Cell Counting Kit-8 assay. As a result, delphinidin inhibited cell proliferation in a dose-dependent manner. Based on the result of proliferation, to measure the effects of delphinidin on EGF-induced EMT, we designated a proper concentration of delphinidin, which is not affected to cell proliferation. We found that delphinidin inhibits morphological changes from epithelial to mesenchymal phenotype by EGF. Moreover, delphinidin increased the messenger RNA and protein expression of E-cadherin and decreased those of Vimentin and Snail in EGF-induced HCC cells. Also, delphinidin prevented motility and invasiveness of EGF-induced HCC cells through suppressing activation of matrix metalloproteinase 2, EGF receptor (EGFR), AKT, and extracellular signal-regulated kinase (ERK). Taken together, our findings demonstrate that delphinidin inhibits EGF-induced EMT by inhibiting EGFR/AKT/ERK signaling pathway in HCC cells., (© 2018 Wiley Periodicals, Inc.)

The occurrence of Leptospirosis and Escherichia coli coinfection in the post-partum period is a novel case. This report illustrated a previously well woman from a suburban area presented with acute neurological deterioration following a two days history of fever during her puerperal period. Early interventions with fluids, broad spectrum antibiotics and intensive supportive care were given. Despite that, she deteriorated rapidly and developed pulmonary hemorrhage, disseminated intravascular coagulopathy, and multi-organ failure. She succumbed within 12 hours of admission. The knowledge about such fatal co-infections should be disseminated to medical practitioners encountering Leptospirosis infection and general public.

Zinc ferrite thin films were deposited using a radio-frequency-sputtering method on glass substrates. As-deposited films were annealed at 200°C for 1, 3 and 5 h, respectively. X-ray diffraction studies revealed the amorphous nature of as-grown and annealed films. Thickness of as-deposited film is 96 nm as determined from Rutherford backscattering spectroscopy which remains almost invariant with annealing. Transmission electron microscopic investigations envisaged a low degree of crystalline order in as-deposited and annealed films. Thicknesses estimated from these measurements were almost 62 nm. Roughness values of these films were almost 1-2 nm as determined from atomic force microscopy. X-ray reflectivity measurements further support the results obtained from TEM and AFM. Near-edge X-ray absorption fine structure measurements envisaged 3+ and 2+ valence states of Fe and Zn ions in these films. UV-Vis spectra of these films were characterized by a sharp absorption in the UV region. All films exhibited almost the same value of optical band gap within experimental error, which is close to 2.86 eV., Competing Interests: The authors have no competing interests.

Research on two-dimensional (2D) metal dichalcogenides is rapidly expanding owing to their unique characteristics that do not exist in bulk materials. The industrially compatible development of these emerging materials is indispensable to facilitate the transition of 2D metal dichalcogenides from the research stage to the practical industrial application stage. However, an industrially relevant method, i.e., the low-temperature synthesis of wafer-scale, continuous, and orientation-controlled 2D metal dichalcogenides, still remains a significant challenge. Here, we report the low-temperature (≤350 °C) synthesis of uniform and continuous n-type SnS2 thin films via the combination of atomic layer deposition (ALD) of tin oxides and subsequent sulfurization. Well-crystallized and aligned SnS2 layers parallel to the substrate are demonstrated through the phase engineering of the ALD-grown tin oxide and the substrate surface. The additional H2S plasma treatment at 300 °C leads to the formation of stoichiometric SnS2. The formation of conformal SnS2 layers over a three-dimensional undulating hole structure is confirmed, which reveals the potential for applications beyond the planar structured architecture. The present results could be a step toward the realization of 2D metal dichalcogenides in industry.

The interactions of energetic ions with multi-cation compounds and their consequences in terms of changes in the local electronic structure, which may facilitate intriguing hybridization between O 2p and metal d orbitals and magnetic ordering, are the subject of debate and require a deep understanding of energy transfer processes and magnetic exchange mechanisms. In this study, nanocrystals of ZnFe2O4 were exposed to O7+ ions with an energy of 100 MeV to understand, qualitatively and quantitatively, the metal-ligand field interactions, cation migration and magnetic exchange interactions by employing X-ray absorption fine structure measurements and X-ray magnetic circular dichroism to get deeper mechanistic insights. Nanosized zinc ferrite nanoparticles (NPs) with a size of ∼16 nm synthesized in the cubic spinel phase exhibited deterioration of the crystalline phase when 100 MeV O7+ ions passed through them. However, the size of these NPs remained almost the same. The behaviour of crystal deterioration is associated with the confinement of heat in this interaction. The energy confined inside the nanoparticles promotes cation redistribution as well as the modification of the local electronic structure. Prior to this interaction, almost 42% of Zn2+ ions occupied AO4 tetrahedra; however, this value increased to 63% after the interaction. An inverse effect was observed for metal ion occupancies in BO6 octahedra. The L-edge spectra of Fe and Zn reveal that the spin and valence states of the metal ions were not affected by this interaction. This effect is also supported by K-edge measurements for Fe and Zn. The t2g/eg intensity ratio in the O K-edge spectra decreased after this interaction, which is associated with detachment of Zn2+ ions from the lattice. The extent of hybridization, as estimated from the ratio of the post-edge to the pre-edge region of the O K-edge spectra, decreased after this interaction. The metal-oxygen and metal-metal bond lengths were modified as a result of this interaction, as determined from extended X-ray absorption fine structure measurements. These measurements further support the observation of cation migration from AO4 tetrahedra to AO6 octahedra and vice versa. The Fe L-edge magnetic circular dichroism spectra indicate that Fe3+ ions occupying sites in AO4 tetrahedra and BO6 octahedra exhibited antiferromagnetic-like ordering prior to this interaction. The NPs that interacted with energetic O ions displayed a different kind of magnetic ordering.