Search

Background: The vast diversity of peptide sequences may hinder the effectiveness of screening for potential peptide therapeutics as if searching for a needle in a haystack. This study aims to develop a new self-evolving peptide algorithm (SEPA), for easy virtual screening of small linear peptides (three to six amino acids) as potential therapeutic agents with the collaborative use of freely available software that can be run on any operating system equipped with a Bash scripting terminal. Mitogen-Inducible Gene 6 (Mig6) protein, a cytoplasmic protein responsible for inhibi-tion and regulation of epidermal growth factor receptor tyrosine kinase, was used to demonstrate the algorithm. Objective: The objective is to propose a new method to discover potential novel peptide inhibitors via an automated peptide generation, docking and post-docking analysis algorithm that ranks short peptides by using essential hydrogen bond interaction between peptides and the target receptor. Method: A library of dockable dipeptides were first created using PyMOL, Open Babel and Au-toDockTools, and docked into the target receptor using AutoDock Vina, automatically via a Bash script. The docked peptides were then ranked by hydrogen bond interaction-based thorough inter-action analysis, where the top-ranked peptides were then elongated, docked, and ranked again. The process repeats until the user-defined peptide length is achieved. Results: In the tested example, SEPA bash script was able to identify the tripeptide YYH ranked within top 20 based on the essential hydrogen bond interaction towards the essential amino acid residue ASP837 in the EGFR-TK receptor. Conclusions: SEPA could be an alternative approach for the virtual screening of peptide sequences against drug targets.

Background There remains uncertainty regarding optimal definitive management for malignant posterior circulation infarcts (MPCI). While guidelines recommend neurosurgery for malignant cerebellar infarcts that are refractory to medical therapy, concerns exist about functional outcome and quality of life after decompressive surgery. Objective This study aims to evaluate the outcomes of surgical intervention compared to medical therapy in MPCI. Methods In this systematic review, MEDLINE, Embase and Cochrane databases were searched from inception until 2nd April 2021. Studies were included if they involved posterior circulation strokes treated with neurosurgical intervention, and reported mortality and functional outcome data. Data were collected according to PRISMA guidelines. Results The search yielded 6,677 studies of which 31 studies (comprising 723 patients) were included for analysis. From the included studies, we found that surgical therapy led to significant differences in mortality and functional outcomes in patients with severe disease. Neurological decline and radiological criteria was often used to decide the timing for surgical intervention, as there is currently limited evidence for preventative neurosurgery. There is also limited evidence for the superiority of one surgical modality over another. Conclusion For patients with MPCI, in terms of mortality and functional outcome, surgical therapy appears to be equivocal to medical therapy, except in patients with severe disease. Reliable evidence is lacking and further prospective studies are rendered.

Previous intracerebral hemorrhage (ICH) is labelled as a contraindication for the use of intravenous tissue plasminogen activator (IV-tPA) in acute ischemic stroke (AIS) based on expert opinion. However, there is a paucity of data available regarding the benefits and risks of IV-tPA in this population. Recent small retrospective cohort studies reporting its off-label use suggest it may be beneficial. This study aims to investigate the safety and efficacy of IV-tPA in AIS patients with previous ICH. We performed a systematic review and meta-analysis of studies reporting on IV-tPA use in AIS patients with and without previous ICH. We searched Embase, PubMed and Cochrane Library from inception to 20 April 2021. Outcomes measured included symptomatic ICH (sICH), 3-month modified Rankin Scale (mRS) score, and 3-month mortality. We included seven retrospective cohort studies comprising 5760 AIS patients who had received IV-tPA, of which 134 had previous ICH. There was no significant difference in the odds of sICH (OR 1.57, 95% CI 0.78–3.15, p = 0.21) and 3-month mRS (mRS 0–1: OR 0.78, 95% CI 0.37–1.65, p = 0.52; mRS 0–2: OR 1.07, 95% CI 0.36–3.15, p = 0.90) between patients with and without previous ICH. There was a trend towards higher 3-month mortality in patients with previous ICH (OR 1.69, 95% CI 0.98–2.91, p = 0.06), although this did not reach statistical significance. The use of IV-tPA in AIS patients with previous ICH was not associated with an increased risk of sICH or disability at 3 months. Further larger studies are needed to establish the safety and efficacy of IV-tPA use in this population.

Background and Purpose: In patients with acute ischemic stroke with large vessel occlusion, the role of intra-arterial adjunctive medications (IAMs), such as urokinase, tPA (tissue-type plasminogen activator), or glycoprotein IIb/IIIa inhibitors, during mechanical thrombectomy (MT) has not been clearly established. We aim to evaluate the efficacy and safety of concomitant or rescue IAM for acute ischemic stroke with large vessel occlusion patients undergoing MT. Methods: We searched Medline, Embase, and Cochrane Stroke Group Trials Register databases from inception until March 13, 2020. We analyzed all studies with patients diagnosed with acute ischemic stroke with large vessel occlusion in the anterior or posterior circulation that provided data for the two treatment arms, (1) MT+IAM and (2) MT only, and also reported on at least one of the following efficacy outcomes, recanalization and 90-day modified Rankin Scale, or safety outcomes, symptomatic intracranial hemorrhage and 90-day mortality. Data were collated in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: Sixteen nonrandomized observational studies with a total of 4581 patients were analyzed. MT only was performed in 3233 (70.6%) patients, while 1348 (29.4%) patients were treated with both MT and IAM. As compared with patients treated with MT alone, patients treated with combination therapy (MT+IAM) had a higher likelihood of achieving good functional outcome (risk ratio, 1.13 [95% CI, 1.03–1.24]) and a lower risk of 90-day mortality (risk ratio, 0.82 [95% CI, 0.72–0.94]). There was no significant difference in successful recanalization (risk ratio, 1.02 [95% CI, 0.99–1.06]) and symptomatic intracranial hemorrhage between the two groups (risk ratio, 1.13 [95% CI, 0.87–1.46]). Conclusions: In acute ischemic stroke with large vessel occlusion, the use of IAM together with MT may achieve better functional outcomes and lower mortality rates. Randomized controlled trials are warranted to establish the safety and efficacy of IAM as adjunctive treatment to MT.

Background: There remains uncertainty regarding optimal definitive management for malignant posterior circulation infarcts (MPCI). While guidelines recommend neurosurgery for malignant cerebellar infarcts that are refractory to medical therapy, concerns exist about the functional outcome and quality of life after decompressive surgery. Objective: This study aims to evaluate the outcomes of surgical intervention compared to medical therapy in MPCI. Methods: In this systematic review, MEDLINE, Embase and Cochrane databases were searched from inception until 2 April 2021. Studies were included if they involved posterior circulation strokes treated with neurosurgical intervention and reported mortality and functional outcome data. Data were collected according to PRISMA guidelines. Results: The search yielded 6677 studies, of which 31 studies (comprising 723 patients) were included for analysis. From the included studies, we found that surgical therapy led to significant differences in mortality and functional outcomes in patients with severe disease. Neurological decline and radiological criteria were often used to decide the timing for surgical intervention, as there is currently limited evidence for preventative neurosurgery. There is also limited evidence for the superiority of one surgical modality over another. Conclusion: For patients with MPCI who are clinically stable at the time of presentation, in terms of mortality and functional outcome, surgical therapy appears to be equivocal to medical therapy. Reliable evidence is lacking, and further prospective studies are rendered.

A series of anilinoquinazoline derivatives with modification on the 2nd carbon of the aniline ring has been synthesized and characterized. The compounds have been tested for their in vitro antiproliferative activity against three NSCLC cell lines, including A549, H1650 and H1975. One of the products has demonstrated the highest IC50 value against A549 (17.60 ± 1.70 µM), surpassing the standard drug, gefitinib (34.32 ± 1.30 µM), another one has exhibited IC50 value against H1975 (9.75 ± 1.06 µM), surpassing gefitinib (31.12 ± 0.38 µM). The best performing derivatives in the antiproliferative assay have been selected for further in silico study for investigating their plausible binding mode in different EGFR kinases through molecular docking and molecular dynamics simulations.

Cerebral venous thrombosis (CVT) causes significant disability and mortality. Current guidelines for CVT management support the initial use of unfractionated heparin or low molecular weight heparin followed by longer-term oral vitamin K antagonist (VKA). There has been increasing, albeit limited, evidence for the use of direct oral anticoagulants (DOAC) as an alternative to VKA. We performed a systematic review and meta-analysis of studies that compared the safety and efficacy of DOACs to VKA in treating CVT. A comprehensive literature search was carried out in Medline, Embase and Cochrane Stroke Group Trials Register using a suitable keyword/MeSH term search strategy. All studies published in English comparing outcomes of patients with CVT treated with DOAC or VKA were included. In total, 6 studies (5 observational studies and 1 randomized clinical trial) comprising 412 patients (age range 16–83 years) were analyzed. DOAC was used in 151 patients, while 261 received VKA. The follow-up period was 3–11 months. The efficacy of DOACs was comparable with VKA in terms of partial or full thrombus recanalization (RR 1.02, 95% CI 0.89–1.16) and excellent functional recovery with modified Rankin scale

Introduction: Whilst surgical decompression in malignant middle cerebral artery infarction is well established, its role in malignant posterior circulation infarction (MPCI) is unclear. Recent small cohort studies suggest that neurosurgery in this group may be beneficial. This systematic review and meta-analysis aims to compare outcomes of MPCI patients undergoing surgical intervention versus medical therapy. Methods: Medline, Embase and Cochrane were searched from inception until 2 April 2021. Studies were included if they evaluated patients with posterior circulation stroke treated with neurosurgical intervention. Observational cohort studies and case series with death and functional outcome data were included. Death was defined as Glasgow Outcome Scale (GOS) 1 and modified Rankin scale (mRS) 6, or extracted from the text. Favourable functional outcome was defined as mRS 0-2, GOS 4-5, Barthel Index 91-100 or extracted from text at the latest follow-up period. 6673 studies were filtered, with 31 studies included for data extraction, of which 8 studies included both a surgical and medical therapy group. Random effects meta-analysis, analysis of proportions and meta-regression were performed. Results: The medical therapy cohort (n=235) had significantly better odds of good functional outcome (GFO) than the surgical cohort. There was no significant difference in odds of death between the two groups (Figure 1). Amongst surgical patients (n=184), 18% died and 55% had GFO. On meta-regression, the proportion of patients with atrial fibrillation and hydrocephalus was negatively associated with odds of death and GFO respectively (both p Conclusion: In patients with MPCI, neurosurgery did not improve functional outcome or mortality in comparison with medical therapy. Larger cohort studies are warranted to resolve this clinical equipoise.

The vast diversity of peptide sequences may hinder the effectiveness of screening for potential peptide therapeutics as if searching for a needle in a haystack. This study aims to develop a new self-evolving peptide algorithm (SEPA), for easy virtual screening of small linear peptides (three to six amino acids) as potential therapeutic agents with the collaborative use of freely available software that can be run on any operating system equipped with a Bash scripting terminal. Mitogen-inducible Gene 6 (Mig6) protein, a cytoplasmic protein responsible for inhibition and regulation of epidermal growth factor receptor tyrosine kinase, was used to demonstrate the algorithm.The objective is to propose a new method to discover potential novel peptide inhibitors via an automated peptide generation, docking and post-docking analysis algorithm that ranks short peptides by using essential hydrogen bond interaction between peptides and the target receptor.A library of dockable dipeptides were first created using PyMOL, Open Babel and AutoDockTools, and docked into the target receptor using AutoDock Vina, automatically via a Bash script. The docked peptides were then ranked by hydrogen bond interaction-based thorough interaction analysis, where the top-ranked peptides were then elongated, docked, and ranked again. The process repeats until the user-defined peptide length is achieved.In the tested example, SEPA bash script was able to identify the tripeptide YYH ranked within top 20 based on the essential hydrogen bond interaction towards the essential amino acid residue ASP837 in the EGFR-TK receptor.SEPA could be an alternative approach for the virtual screening of peptide sequences against drug targets.

Previous intracerebral hemorrhage (ICH) is labelled as a contraindication for the use of intravenous tissue plasminogen activator (IV-tPA) in acute ischemic stroke (AIS) based on expert opinion. However, there is a paucity of data available regarding the benefits and risks of IV-tPA in this population. Recent small retrospective cohort studies reporting its off-label use suggest it may be beneficial. This study aims to investigate the safety and efficacy of IV-tPA in AIS patients with previous ICH. We performed a systematic review and meta-analysis of studies reporting on IV-tPA use in AIS patients with and without previous ICH. We searched Embase, PubMed and Cochrane Library from inception to 20 April 2021. Outcomes measured included symptomatic ICH (sICH), 3-month modified Rankin Scale (mRS) score, and 3-month mortality. We included seven retrospective cohort studies comprising 5760 AIS patients who had received IV-tPA, of which 134 had previous ICH. There was no significant difference in the odds of sICH (OR 1.57, 95% CI 0.78-3.15, p = 0.21) and 3-month mRS (mRS 0-1: OR 0.78, 95% CI 0.37-1.65, p = 0.52; mRS 0-2: OR 1.07, 95% CI 0.36-3.15, p = 0.90) between patients with and without previous ICH. There was a trend towards higher 3-month mortality in patients with previous ICH (OR 1.69, 95% CI 0.98-2.91, p = 0.06), although this did not reach statistical significance. The use of IV-tPA in AIS patients with previous ICH was not associated with an increased risk of sICH or disability at 3 months. Further larger studies are needed to establish the safety and efficacy of IV-tPA use in this population.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the cells through the binding of its spike protein (S-protein) to the cell surface-expressing angiotensin-converting enzyme 2 (ACE2). Thus, inhibition of S-protein-ACE2 binding may impede SARS-CoV-2 cell entry and attenuate the progression of Coronavirus disease 2019 (COVID-19). In this study, an electrochemical impedance spectroscopy-based biosensing platform consisting of a recombinant ACE2-coated palladium nano-thin-film electrode as the core sensing element was fabricated for the screening of potential inhibitors against S-protein-ACE2 binding. The platform could detect interference of small analytes against S-protein-ACE2 binding at low analyte concentration and small volume (0.1 μg/ml and ∼1 μl, estimated total analyte consumption < 4 pg) within 21 minutes. Thus, a few potential inhibitors of S-protein-ACE2 binding were identified. This includes (2S,3aS,6aS)-1-((S)-N-((S)-1-Carboxy-3-phenylpropyl)alanyl)tetrahydrocyclopenta[b] pyrrole-2-carboxylic acid (ramiprilat) and (2S,3aS,7aS)-1-[(2S)-2-[[(2S)-1-Carboxybutyl]amino]propanoyl]-2,3,3a,4,5,6,7,7a-octahydroindole-2-carboxylic acid (perindoprilat) that reduced the binding affinity of S-protein to ACE2 by 72% and 67%; and SARS-CoV-2 in vitro infectivity to the ACE2-expressing human oral cavity squamous carcinoma cells (OEC-M1) by 36.4 and 20.1%, respectively, compared to the PBS control. These findings demonstrated the usefulness of the developed biosensing platform for the rapid screening of modulators for S-protein-ACE2 binding.

Introduction and hypothesis: In patients with acute ischemic stroke with large vessel occlusion (AIS-LVO), the role of intra-arterial adjunctive medications (IAM) like urokinase, tPA or glycoprotein IIb/IIIa inhibitors, during mechanical thrombectomy (MT) has not been clearly established. We hypothesize that AIS-LVO patients treated with both MT + IAM (rescue or concurrent) achieve better safety and efficacy outcomes than patients treated with MT alone and aim to determine the efficacy and safety of concomitant or rescue IAM for AIS-LVO patients undergoing MT. Methods: We searched Medline, Embase and Cochrane Stroke Group Trials Register databases from inception until 13th March 2020. We analysed all studies with patients diagnosed with AIS-LVO in the anterior or posterior circulation, that provided data for the two treatment arms: 1)MT+IAM and 2)MT-only, and also reported on at least one of the following outcomes: reperfusion, 90-days modified Rankin Scale (mRS), symptomatic intracranial hemorrhage (sICH) and 90-days mortality. Data were collated in accordance with the PRISMA guidelines. Results: Sixteen non-randomized observational studies with a total of 4581 patients were analysed. MT-only was performed in 3233 (70.6%) patients, while 1348 (29.4%) patients were treated with both MT+IAM. As compared to patients treated with MT alone, patients treated with combination therapy (MT +IAM) had a higher likelihood of achieving good functional outcome (risk ratio=1.13, 95% CI 1.03-1.24) and a lower risk of 90-day mortality (risk ratio=0.82, 95% CI 0.72-0.94). There was no significant difference in successful reperfusion (risk ratio=1.02, 95% CI 0.99-1.06) and sICH between the two groups (risk ratio = 1.13, 95% CI 0.87-1.46) (Figure 1). Conclusions: In AIS-LVO, use of IAM together with MT may achieve better functional outcomes and lower mortality rates. Randomized controlled trials are warranted to confirm the safety and efficacy of IAM as adjunctive treatment of MT.