A swallowable X-ray dosimeter for the real-time monitoring of radiotherapy.

Monitoring X-ray radiation in the gastrointestinal tract can enhance the precision of radiotherapy in patients with gastrointestinal cancer. Here we report the design and performance, in the gastrointestinal tract of rabbits, of a swallowable X-ray dosimeter for the simultaneous real-time monitoring of absolute absorbed radiation dose and of changes in pH and temperature. The dosimeter consists of a biocompatible optoelectronic capsule containing an optical fibre, lanthanide-doped persistent nanoscintillators, a pH-sensitive polyaniline film and a miniaturized system for the wireless readout of luminescence. The persistent luminescence of the nanoscintillators after irradiation can be used to continuously monitor pH without the need for external excitation. By using a neural-network-based regression model, we estimated the radiation dose from radioluminescence and afterglow intensity and temperature, and show that the dosimeter was approximately five times more accurate than standard methods for dose determination. Swallowable dosimeters may help to improve radiotherapy and to understand how radiotherapy affects tumour pH and temperature.

Vascular smooth muscle cells in low SYNTAX scores coronary artery disease exhibit proinflammatory transcripts and proteins correlated with IL1B activation.

BACKGROUND AND AIMS: The SYNTAX score is clinically validated to stratify number of lesions and pattern of CAD. A better understanding of the underlying molecular mechanisms influencing the pattern and complexity of coronary arteries lesions among CAD patients is needed. METHODS: Human arterial biopsies from 49 patients (16 low-SYNTAX-score (LSS, <23), 16 intermediate-SYNTAX-score (ISS, 23 to 32) and 17 high-SYNTAX-score (HSS, >32)) were evaluated using Affymetrix GeneChip® Human Genome U133 Plus 2.0 microarray. The data were validated by Next-Generation Sequencing (NGS). Primary VSMC from patients with low and high SYNTAX scores were isolated and compared using immunohistochemistry, qPCR and immunoblotting to confirm mRNA and proteomic results. RESULTS: The IL1B was verified as the top upstream regulator of 47 inflammatory DEGs in LSS patients and validated by another sets of patient samples using NGS analysis. The upregulated expression of IL1B was translated to increased level of IL1ß protein in the LSS tissue based on immunohistochemical quantitative analysis. Plausibility of idea that IL1B in the arterial wall could be originated from VSMC was checked by exposing culture to proinflammatory conditions where IL1B came out as the top DEG (logFC = 7.083, FDR = 1.38 × 10-114). The LSS patient-derived primary VSMCs confirmed higher levels of IL1B mRNA and protein. CONCLUSIONS: LSS patients could represent a group of patients where IL1B could play a substantial role in disease pathogenesis. The LSS group could represent a plausible cohort of patients for whom anti-inflammatory therapy could be considered.

The Gut-Skin Microbiota Axis and Its Role in Diabetic Wound Healing-A Review Based on Current Literature.

Diabetic foot ulcers (DFU) are a growing concern worldwide as they pose complications in routine clinical practices such as diagnosis and management. Bacterial interactions on the skin surface are vital to the pathophysiology of DFU and may control delayed wound healing. The microbiota from our skin directly regulates cutaneous health and disease by interacting with the numerous cells involved in the wound healing mechanism. Commensal microbiota, in particular, interact with wound-repairing skin cells to enhance barrier regeneration. The observed microbes in DFU include Staphylococcus, Streptococcus, Corynebacterium, Pseudomonas, and several anaerobes. Skin commensal microbes, namely S. epidermidis, can regulate the gamma delta T cells and induce Perforin-2 expression. The increased expression of Perforin-2 by skin cells destroyed S. aureus within the cells, facilitating wound healing. Possible crosstalk between the human commensal microbiome and different cell types involved in cutaneous wound healing promotes the immune response and helps to maintain the barrier function in humans. Wound healing is a highly well-coordinated, complex mechanism; it can be devastating if interrupted. Skin microbiomes are being studied in relation to the gut-skin axis along with their effects on dermatologic conditions. The gut-skin axis illustrates the connection wherein the gut can impact skin health due to its immunological and metabolic properties. The precise mechanism underlying gut-skin microbial interactions is still unidentified, but the immune and endocrine systems are likely to be involved. Next-generation sequencing and the development of bioinformatics pipelines may considerably improve the understanding of the microbiome-skin axis involved in diabetic wound healing in a much more sophisticated way. We endeavor to shed light on the importance of these pathways in the pathomechanisms of the most prevalent inflammatory conditions including the diabetes wound healing, as well as how probiotics may intervene in the gut-skin axis.

Circulating Antibodies to Skin Bacteria Detected by Serological Lateral Flow Immunoassays Differentially Correlated With Bacterial Abundance.

The serological lateral flow immunoassay (LFIA) was used to detect circulating antibodies to skin bacteria. Next-generation sequencing analysis of the skin microbiome revealed a high relative abundance of Cutibacterium acnes but low abundance of Staphylococcus aureus and Corynebacterium aurimucosum on human facial samples. Yet, results from both LFIA and antibody titer quantification in 96-well microplates illustrated antibody titers that were not correspondent, and instead negatively correlated, to their respective abundance with human blood containing higher concentrations of antibodies to both S. aureus and C. aurimucosum than C. acnes. Acne vulgaris develops several unique microbial and cellular features, but its correlation with circulating antibodies to bacteria in the pilosebaceous unit remains unknown. Results here revealed that antibodies to C. acnes and S. aureus were approximately 3-fold higher and 1.5-fold lower, respectively, in acne patients than in healthy subjects. Although the results can be further validated by larger sample sizes, the proof-of-concept study demonstrates a newfound discrepancy between the abundance of skin bacteria and amounts of their corresponding antibodies. And in light of acne-correlated amplified titers of specific anticommensal antibodies, we highlight that profiling these antibodies in the pilosebaceous unit by LFIAs may provide a unique signature for monitoring acne vulgaris.

Comparison of extended reality and conventional methods of basic life support training: protocol for a multinational, pragmatic, noninferiority, randomised clinical trial (XR BLS trial).

BACKGROUND: Conventional cardiopulmonary resuscitation (CPR) training for the general public involves the use of a manikin and a training video, which has limitations related to a lack of realism and immersion. To overcome these limitations, virtual reality and extended reality technologies are being used in the field of medical education. The aim of this study is to explore the efficacy and safety of extended reality (XR)-based basic life support (BLS) training. METHODS: This study is a prospective, multinational, multicentre, randomised controlled study. Four institutions in 4 countries will participate in the study. A total of 154 participants will be randomly assigned to either the XR group or the conventional group stratified by institution and sex (1:1 ratio). Each participant who is allocated to either group will be sent to a separate room to receive training with an XR BLS module or conventional CPR training video. All participants will perform a test on a CPR manikin after the training. The primary outcome will be mean compression depth. The secondary outcome will be overall BLS performance, including compression rate, correct hand position, compression, and full release and hands-off time. DISCUSSION: Using virtual reality (VR) to establish a virtual educational environment can give trainees a sense of realism. In the XR environment, which combines the virtual world with the real world, trainees can more effectively learn various skills. This trial will provide evidence of the usefulness of XR in CPR education. TRIAL REGISTRATION: ClinicalTrials.gov NCT04736888. Registered on 29 January 2021.

Milk-derived extracellular vesicles alleviate ulcerative colitis by regulating the gut immunity and reshaping the gut microbiota.

Rationale: Bovine milk constitutes an essential part of human diet, especially for children, due to its enrichment of various nutrients. We recently developed an effective protocol for the isolation of extracellular vesicles from milk (mEVs) and discovered that mEVs contained large amounts of immune-active proteins and modulated the gut immunity and microbiota in healthy mice. Here, we aimed to explore the therapeutic effects of mEVs on inflammatory bowel disease. Methods: MicroRNAs and protein content in mEVs were analyzed by RNA sequencing and proteomics, respectively, followed by functional annotation. Ulcerative colitis (UC) was induced by feeding mice with dextran sulfate sodium. Intestinal immune cell populations were phenotyped by flow cytometry, and the gut microbiota was analyzed via 16S rRNA sequencing. Results: We showed that abundant proteins and microRNAs in mEVs were involved in the regulation of immune and inflammatory pathways and that oral administration of mEVs prevented colon shortening, reduced intestinal epithelium disruption, inhibited infiltration of inflammatory cells and tissue fibrosis in a mouse UC model. Mechanistically, mEVs attenuated inflammatory response via inhibiting TLR4-NF-κB signaling pathway and NLRP3 inflammasome activation. Furthermore, mEVs were able to correct cytokine production disorder and restore the balance between T helper type 17 (Th17) cells and interleukin-10+Foxp3+ regulatory T (Treg) cells in the inflamed colon. The disturbed gut microbiota in UC was also partially recovered upon treatment with mEVs. The correlation between the gut microbiota and cytokines suggests that mEVs may modulate intestinal immunity via influencing the gut microbiota. Conclusions: These findings reveal that mEVs alleviate colitis by regulating intestinal immune homeostasis via inhibiting TLR4-NF-κB and NLRP3 signaling pathways, restoring Treg/Th17 cell balance, and reshaping the gut microbiota.

Gut Microbiome of a Multiethnic Community Possessed No Predominant Microbiota.

With increasing globalisation, various diets from around the world are readily available in global cities. This study aimed to verify if multiethnic dietary habits destabilised the gut microbiome in response to frequent changes, leading to readily colonisation of exogenous microbes. This may have health implications. We profiled Singapore young adults of different ethnicities for dietary habits, faecal type, gut microbiome and cytokine levels. Subjects were challenged with Lactobacillus casei, and corresponding changes in microbiome and cytokines were evaluated. Here, we found that the majority of young adults had normal stool types (73% Bristol Scale Types 3 and 4) and faecal microbiome categorised into three clusters, irrespective of race and gender. Cluster 1 was dominated by Bacteroides, Cluster 2 by Prevotella, while Cluster 3 showed a marginal increase in Blautia, Ruminococaceae and Ruminococcus, without a predominant microbiota. These youngsters in the three faecal microbiome clusters preferred Western high sugary beverages, Southeast Asian plant-rich diet and Asian/Western diets in rotation, respectively. Multiethnic dietary habits (Cluster 3) led to a gut microbiome without predominant microbiota yet demonstrated colonisation resistance to Lactobacillus. Although Bacteroides and Prevotella are reported to be health-promoting but also risk factors for some illnesses, Singapore-style dietary rotation habits may alleviate Bacteroides and Prevotella associated ill effects. Different immunological outcome was observed during consumption of the lactobacilli among the three microbiome clusters.

Gut Microbiota Dysbiosis as a Target for Improved Post-Surgical Outcomes and Improved Patient Care: A Review of Current Literature.

ABSTRACT: Critical illness results in significant changes in the human gut microbiota, leading to the breakdown of the intestinal barrier function, which plays a role in the pathogenesis of multiple organ dysfunction. Patients with sepsis/acute respiratory distress syndrome (ARDS) have a profoundly distorted intestinal microbiota rhythm, which plays a considerable role in the development of gut-derived infections and intestinal dysbiosis. Despite recent medical developments, postsurgical complications are associated with a high morbidity and mortality rate. Bacterial translocation, which is the movement of bacteria and bacterial products across the intestinal barrier, was shown to be a mechanism behind sepsis. Current research is focusing on a solution by addressing significant factors that contribute to intestinal dysbiosis, which subsequently leads to multiple organ failure and, thus, mortality. It may, however, be challenging to manipulate the microbiota in critically ill patients for enhanced therapeutic gain. Probiotic manipulation is advantageous for maintaining the gut-barrier defense and for modulating the immune response. Based on available published research, this review aims to address the application of potential strategies in the intensive care unit, supplemented with current therapeutics by the administration of probiotics, prebiotics, and fecal microbiota transplant, to reduce post-surgical complications of sepsis/ARDS in critically ill patients.

The interaction between 30b-5p miRNA and MBNL1 mRNA is involved in vascular smooth muscle cell differentiation in patients with coronary atherosclerosis.

Vascular smooth muscle cells (VSMCs) in the arterial wall have diverse functions. In pathological states, the interplay between transcripts and microRNAs (miRNAs) leads to phenotypic changes. Understanding the regulatory role of miRNAs and their target genes may reveal how VSMCs modulate the pathogenesis of coronary artery disease. Laser capture microdissection was performed on aortic wall tissues obtained from coronary artery bypass graft patients with and without recent acute myocardial infarction (MI). The mSMRT-qPCR miRNA assay platform (MiRXES, Singapore) was used to profile miRNA. The miRNA data were co-analyzed with significant mRNA transcripts. TargetScan 7.1 was applied to evaluate miRNA-mRNA interactions. The miRNA profiles of 29 patients (16 MI and 13 non-MI) were evaluated. Thirteen VSMC-related miRNAs were differentially expressed between the MI and non-MI groups. Analysis revealed seven miRNA-targeted mRNAs related to muscular tissue differentiation and proliferation. TargetScan revealed that among the VSMC-related transcripts, MBNL1 had a recognition site that matched the hsa-miR-30b-5p target seed sequence. In addition to predicted analysis, our experiment in vitro with human VSMC culture confirmed that hsa-miR-30b-5p negatively correlated with MBNL1. Our data showed that overexpression of hsa-miR-30b-5p led to downregulation of MBNL1 in VSMCs. This process influences VSMC proliferation and might be involved in VSMC differentiation.

Ambient and supplemental magnetic fields promote myogenesis via a TRPC1-mitochondrial axis: evidence of a magnetic mitohormetic mechanism.

We show that both supplemental and ambient magnetic fields modulate myogenesis. A lone 10 min exposure of myoblasts to 1.5 mT amplitude supplemental pulsed magnetic fields (PEMFs) accentuated in vitro myogenesis by stimulating transient receptor potential (TRP)-C1-mediated calcium entry and downstream nuclear factor of activated T cells (NFAT)-transcriptional and P300/CBP-associated factor (PCAF)-epigenetic cascades, whereas depriving myoblasts of ambient magnetic fields slowed myogenesis, reduced TRPC1 expression, and silenced NFAT-transcriptional and PCAF-epigenetic cascades. The expression levels of peroxisome proliferator-activated receptor γ coactivator 1α, the master regulator of mitochondriogenesis, was also enhanced by brief PEMF exposure. Accordingly, mitochondriogenesis and respiratory capacity were both enhanced with PEMF exposure, paralleling TRPC1 expression and pharmacological sensitivity. Clustered regularly interspaced short palindromic repeats-Cas9 knockdown of TRPC1 precluded proliferative and mitochondrial responses to supplemental PEMFs, whereas small interfering RNA gene silencing of TRPM7 did not, coinciding with data that magnetoreception did not coincide with the expression or function of other TRP channels. The aminoglycoside antibiotics antagonized and down-regulated TRPC1 expression and, when applied concomitantly with PEMF exposure, attenuated PEMF-stimulated calcium entry, mitochondrial respiration, proliferation, differentiation, and epigenetic directive in myoblasts, elucidating why the developmental potential of magnetic fields may have previously escaped detection. Mitochondrial-based survival adaptations were also activated upon PEMF stimulation. Magnetism thus deploys an authentic myogenic directive that relies on an interplay between mitochondria and TRPC1 to reach fruition.-Yap, J. L. Y., Tai, Y. K., Fröhlich, J., Fong, C. H. H., Yin, J. N., Foo, Z. L., Ramanan, S., Beyer, C., Toh, S. J., Casarosa, M., Bharathy, N., Kala, M. P., Egli, M., Taneja, R., Lee, C. N., Franco-Obregón, A. Ambient and supplemental magnetic fields promote myogenesis via a TRPC1-mitochondrial axis: evidence of a magnetic mitohormetic mechanism.

Comprehensive and Integrative Experimentation Setup for Large Animal Hybrid Valvular Heart Surgery.

BACKGROUND: Experimental surgical procedures for atrioventricular valves present promising translational capabilities, and preclinical studies are necessary to assess their applicability and to train young enthusiastic heart teams. Here, we present a synopsis of experimental surgical procedures on porcine models for mitral valvular (MV) and tricuspid valvular (TV) interventions; mitral valve-in-valve implantation (MViV), transapical cardioscopic (TAC) MV replacement (MVR), TAC-MV annuloplasty, and tricuspid valve-in-a-ring (TViR) procedures. METHODS: Twenty-five (n = 25) female Yorkshire pigs of 55-65 kg is the total number used in the four approaches; seven animals underwent MViV, six TAC-MVR, six TAC-MV annuloplasty, and six TViR, respectively. All were subjected to a first conventional valvular surgery (bioprosthetic valve replacement and/or prosthetic ring repair). Then, after 4 wk, a less-invasive second surgery was performed using the transcatheter approaches under investigation. Except for the TAC-MVR and annuloplasty procedures, all animals were followed up for additional 4 wk. RESULTS: (1) MViV (n = 7): Standard MVR was successfully performed in all animals. Transvalvular pressure gradients and flow velocities were (Pmax 3.77 ± 0.8 mmHg; Pmean 2.1 ± 0.6 mmHg, Vmax 97 ± 13 cm/s; Vmean 68 ± 21 cm/s). Effective MViV followed (Pmax 16.7 ± 1.8 mmHg; Pmean 6.2 ± 1.2 mmHg, Vmax 216 ± 32 cm/s; Vmean 110 ± 24 cm/s). (2) TAC-MVR (n = 6): The overall bypass time was 177.2 ± 44.2 min. Transprosthetic Pmean was 4.6 ± 2.4 mmHg; no paravalvular leaks in all animals. (3) TAC-MV annuloplasty (n = 6): The implantation time was 47 ± 6 min. MV was competent, left ventricular ejection fraction (LV-EF%) was 63 ± 4%. (4) TViR (n = 6): Conventional TV ring repair was performed in all animals (Pmax 2.42 ± 0.7 mmHg; Pmean 1.3 ± 0.6 mmHg, Vmax 82 ± 10.4 cm/s; Vmean 65.4 ± 21 cm/s). All TViRs were implanted efficiently (Pmax 4.7 ± 1.6 mmHg; Pmean 2.7 ± 0.8 mmHg, Vmax 105 ± 31 cm/s; Vmean 81 ± 16 cm/s). A mild paravalvular leak was observed in one animal (16%). CONCLUSIONS: All studied experimental valvular interventions are feasible, within the context of well-trained cardiac surgery specialists, and all possibilities should be considered when treating a patient to determine which one suits best his individual challenges and scope.

Transcriptome alterations of vascular smooth muscle cells in aortic wall of myocardial infarction patients.

This article contains further data and information from our published manuscript [1]. We aim to identify significant transcriptome alterations of vascular smooth muscle cells (VSMCs) in the aortic wall of myocardial infarction (MI) patients. Microarray gene analysis was applied to evaluate VSMCs of MI and non-MI patients. Prediction Analysis of Microarray (PAM) identified genes that significantly discriminated the two groups of samples. Incorporation of gene ontology (GO) identified a VSMCs-associated classifier that discriminated between the two groups of samples. Mass spectrometry-based iTRAQ analysis revealed proteins significantly differentiating these two groups of samples. Ingenuity Pathway Analysis (IPA) revealed top pathways associated with hypoxia signaling in cardiovascular system. Enrichment analysis of these proteins suggested an activated pathway, and an integrated transcriptome-proteome pathway analysis revealed that it is the most implicated pathway. The intersection of the top candidate molecules from the transcriptome and proteome highlighted overexpression.

Gene expression profile analysis of aortic vascular smooth muscle cells reveals upregulation of cadherin genes in myocardial infarction patients.

Myocardial infarction (MI) induced by acute coronary arterial occlusion is usually secondary to atherosclerotic plaque rupture. Dysregulated response of vascular smooth muscle cells (VSMCs) in atherosclerotic plaques may promote plaque rupture. Cadherins (CDHs) form adherens junctions and are known stabilizers of atherosclerotic plaques. To date, the expression patterns of cadherin have not been well investigated in MI aortic VSMCs. We aimed to investigate the expression of cadherin genes in the aortic wall of patients with and without MI. Laser capture microdissected VSMCs were obtained from aortic tissue samples of patients undergoing coronary artery bypass graft surgery. Integrative bioinformatic analysis of the microarray profiles of the VSMCs revealed that MI is discriminated at the whole transcriptome level by hundreds of differentially expressed genes, including genes involved in cell adhesion, of which the cadherin superfamily genes were among the top structural category. Eleven significantly deregulated candidates of the cadherin superfamily were chosen and formed a new classifier that collectively discriminated MI vs. non-MI with ~95% accuracy. Significance validation was performed with an independent cohort by quantitative RT-quantitative PCR, confirming overexpression of CDH2, CDH12, PCDH17, and PCDH18 in MI VSMCs. The dysregulation of these cadherin superfamily genes might be related to an MI-induced remote effect on aortic wall VSMCs and to imbalances in signaling pathways and myocardial repair mechanisms. Although pathophysiological significance of our findings requires functional studies, mRNA upregulation of the identified cadherin superfamily members in VSMCs might be associated with the progression of atherosclerosis and angiogenesis activation in MI.

Distinctive molecular signature and activated signaling pathways in aortic smooth muscle cells of patients with myocardial infarction.

BACKGROUND AND AIMS: We aim to identify significant transcriptome alterations of vascular smooth muscle cells (VSMCs) in the aortic wall of myocardial infarction (MI) patients. Providing a robust transcriptomic signature, we aim to highlight the most likely aberrant pathway(s) in MI VSMCs. METHODS AND RESULTS: Laser-captured microdissection (LCM) was used to obtain VSMCs from aortic wall tissues harvested during coronary artery bypass surgery. Microarray gene analysis was applied to analyse VSMCs from 17 MI and 19 non-MI patients. Prediction Analysis of Microarray (PAM) identified 370 genes that significantly discriminated MI and non-MI samples and were enriched in genes responsible for muscle development, differentiation and phenotype regulation. Incorporation of gene ontology (GO) led to the identification of a 21-gene VSMCs-associated classifier that discriminated between MI and non-MI patients with 92% accuracy. The mass spectrometry-based iTRAQ analysis of the MI and non-MI samples revealed 94 proteins significantly differentiating these tissues. Ingenuity Pathway Analysis (IPA) of 370 genes revealed top pathways associated with hypoxia signaling in the cardiovascular system. Enrichment analysis of these proteins suggested an activation of the superoxide radical degradation pathway. An integrated transcriptome-proteome pathway analysis revealed that superoxide radical degradation pathway remained the most implicated pathway. The intersection of the top candidate molecules from the transcriptome and proteome highlighted superoxide dismutase (SOD1) overexpression. CONCLUSIONS: We provided a novel 21-gene VSMCs-associated MI classifier in reference to significant VSMCs transcriptome alterations that, in combination with proteomics data, suggests the activation of superoxide radical degradation pathway in VSMCs of MI patients.

Myocardial Injury Is Distinguished from Stable Angina by a Set of Candidate Plasma Biomarkers Identified Using iTRAQ/MRM-Based Approach.

The lack of precise biomarkers that identify patients at risk for myocardial injury and stable angina delays administration of optimal therapy. Hence, the search for noninvasive biomarkers that could accurately stratify patients with impending heart attack, from patients with stable coronary artery disease (CAD), is urgently needed in the clinic. Herein, we performed comparative quantitative proteomics on whole plasma sampled from patients with stable angina (NMI), acute myocardial infarction (MI), and healthy control subjects (Ctrl). We detected a total of 371 proteins with high confidence (FDR < 1%, p < 0.05) including 53 preliminary biomarkers that displayed ≥2-fold modulated expression in patients with CAD (27 associated with atherosclerotic stable angina, 26 with myocardial injury). In the verification phase, we used label-free LC-MRM-MS-based targeted method to verify the preliminary biomarkers in pooled plasma, excluded peptides that were poorly distinguished from background, and performed further validation of the remaining candidates in 49 individual plasma samples. Using this approach, we identified a final panel of eight novel candidate biomarkers that were significantly modulated in CAD (p < 0.05) including proteins associated with atherosclerotic stable angina that were implicated in endothelial dysfunction (F10 and MST1), proteins associated with myocardial injury reportedly involved in plaque destabilization (SERPINA3, CPN2, LUM), and in tissue protection/repair mechanisms (ORM2, ACTG1, NAGLU). Taken together, our data showed that candidate biomarkers with potential diagnostic values can be successfully detected in nondepleted human plasma using an iTRAQ/MRM-based discovery-validation approach and demonstrated the plausible clinical utility of the proposed panel in discriminating atherosclerotic stable angina from myocardial injury in the studied cohort.

Peptide-Functionalized Polyurethane Coatings Prepared via Grafting-To Strategy to Selectively Promote Endothelialization.

Endothelialization, formation of endothelial cells (ECs) layer on cardiovascular implant surface, is considered an ideal approach to prevent restenosis (renarrowing of blood vessel mainly due to the accumulation of proliferated vascular smooth muscle cells, SMCs) and thrombosis. In this study, the possibility of using polyurethane (PU) as a coating platform for functionalization with peptide to enhance endothelialization on implants is explored. PUs are synthesized through metal-free organocatalytic polymerization followed by chemical conjugation with an EC-specific REDV peptide through thiol-ene reaction. Meanwhile, the free isocyanate groups of PU allow for covalent grafting of REDV-functionalized PU (PU/REDV) to silanize implant materials (nitinol and PET). PU/REDV coating with peptide grafting density of ≈2 nmol cm-2 selectively accommodates primary human umbilical vein ECs (HUVECs) and retards spreading of primary human umbilical artery SMCs (HUASMCs). In addition, a layer of HUVECs is formed within 3 d on PU/REDV-coated surfaces, while proliferation of HUASMCs is inhibited. The selectivity is further confirmed by coculture of HUVECs and HUASMCs. Moreover, the PU/REDV-coated surfaces are less thrombogenic as evidenced by reduced number and activity of adhered platelets. Therefore, PU/REDV can be potentially used as a coating of cardiovascular implants to prevent restenosis and thrombosis by promoting endothelialization.

Monocyte adhesion to atherosclerotic matrix proteins is enhanced by Asn-Gly-Arg deamidation.

Atherosclerosis arises from leukocyte infiltration and thickening of the artery walls and constitutes a major component of vascular disease pathology, but the molecular events underpinning this process are not fully understood. Proteins containing an Asn-Gly-Arg (NGR) motif readily undergo deamidation of asparagine to generate isoDGR structures that bind to integrin αvß3 on circulating leukocytes. Here we report the identification of isoDGR motifs in human atherosclerotic plaque components including extracellular matrix (ECM) proteins fibronectin and tenascin C, which have been strongly implicated in human atherosclerosis. We further demonstrate that deamidation of NGR motifs in fibronectin and tenascin C leads to increased adhesion of the monocytic cell line U937 and enhanced binding of primary human monocytes, except in the presence of a αvß3-blocking antibody or the αv-selective inhibitor cilengitide. In contrast, under the same deamidating conditions monocyte-macrophages displayed only weak binding to the alternative ECM component vitronectin which lacks NGR motifs. Together, these findings confirm a critical role for isoDGR motifs in mediating leukocyte adhesion to the ECM via integrin αvß3 and suggest that protein deamidation may promote the pathological progression of human atherosclerosis by enhancing monocyte recruitment to developing plaques.

Establishment of a minimally invasive cardiac surgery programme in Singapore.

Although minimally invasive cardiac surgery is available in Singapore, it is not widely practised. Local surgeons have pioneered and introduced technologies in Singapore that were launched in the West to address various heart pathologies. However, in spite of the possibilities, the unique position and function of Singapore in the region, the structure and dynamics of cardiothoracic surgery practice in government centres and private practice, and the overall small volume of patients in the country may pose limitations in the thriving and sharing of such new technologies. Herein, we give an account of our progress and accomplishments with regard to minimally invasive cardiac surgery in Singapore and indicate areas of improvement that have further potential for synergy and growth.