The impact of a student-led anti-racism programme on medical students' perceptions and awareness of racial bias in medicine and confidence to advocate against racism.

INTRODUCTION: Systemic racism impacts personal and community health; however, education regarding its role in perpetuating healthcare inequity remains limited in medical curricula. This study implemented and evaluated the impact of a student-led anti-racism programme on medical students' perceptions of racial bias in medicine, awareness of, and confidence to advocate against racism in medicine. METHOD: A total of 543 early stage medical students were invited to participate in the programme. Participants were assigned readings and videos exploring racial injustice in medicine and attended a virtual small-group discussion facilitated by faculty and students. Online surveys were used to collect pre- and post-programme data using Likert scales for response items. Open-ended questions were independently reviewed by three authors using reflexive thematic analysis. RESULTS: Sixty-three early-stage medical students enrolled in the programme, of which 42 completed the pre-programme survey. There was a 76% (n = 32) response rate for the post-programme survey. The majority of students (60%, n = 25) had no previous education about racism in medicine. From pre- to post-programme, there was a significant change in students' perceived definition of race from genetic, biological, geographical, and cultural factors to socio-political factors (P < 0.0001). Significant increases in almost all factors assessing student awareness of racism and confidence to advocate against racism were observed. Student-identified barriers to discussing racism included lack of education and lived experience, fear of starting conflict and offending others. All survey respondents would recommend this programme to peers and 69% (n = 32) engaged in further topical self-directed education. CONCLUSION: This simple and reproducible programme improved awareness and confidence to advocate against racism in medicine and resulted in a change in opinion regarding race-based medical practice. These findings are in line with best practice towards addressing racial bias in medicine, decolonizing medical curricula and strengthening anti-racism teaching of future physicians.

Allantodapsone is a Pan-Inhibitor of Staphylococcus aureus Adhesion to Fibrinogen, Loricrin, and Cytokeratin 10.

Staphylococcus aureus infections have become a major challenge in health care due to increasing antibiotic resistance. We aimed to design small molecule inhibitors of S. aureus surface proteins to be developed as colonization inhibitors. We identified allantodapsone in an initial screen searching for inhibitors of clumping factors A and B (ClfA and ClfB). We used microbial adhesion assays to investigate the effect of allantodapsone on extracellular matrix protein interactions. Allantodapsone inhibited S. aureus Newman adhesion to fibrinogen with an IC50 of 21.3 µM (95% CI 4.5-102 µM), minimum adhesion inhibitory concentration (MAIC) of 100 µM (40.2 µg/mL). Additionally, allantodapsone inhibited adhesion of Lactococcus lactis strains exogenously expressing the clumping factors to fibrinogen (L. lactis ClfA, IC50 of 3.8 µM [95% CI 1.0-14.3 µM], MAIC 10 µM, 4.0 µg/mL; and L. lactis ClfB, IC50 of 11.0 µM [95% CI 0.9-13.6 µM], MAIC 33 µM, 13.3 µg/mL), indicating specific inhibition. Furthermore, the dapsone and alloxan fragments of allantodapsone did not have any inhibitory effect. Adhesion of S. aureus Newman to L2v loricrin is dependent on the expression of ClfB. Allantodapsone caused a dose dependent inhibition of S. aureus adhesion to the L2v loricrin fragment, with full inhibition at 40 µM (OD600 0.11 ± 0.01). Furthermore, recombinant ClfB protein binding to L2v loricrin was inhibited by allantodapsone (P < 0.0001). Allantodapsone also demonstrated dose dependent inhibition of S. aureus Newman adhesion to cytokeratin 10 (CK10). Allantodapsone is the first small molecule inhibitor of the S. aureus clumping factors with potential for development as a colonization inhibitor. IMPORTANCE S. aureus colonization of the nares and the skin provide a reservoir of bacteria that can be transferred to wounds that can ultimately result in systemic infections. Antibiotic resistance can make these infections difficult to treat with significant associated morbidity and mortality. We have identified and characterized a first-in-class small molecule inhibitor of the S. aureus clumping factors A and B, which has the potential to be developed further as a colonization inhibitor.

Functional Antagonism of Junctional Adhesion Molecule-A (JAM-A), Overexpressed in Breast Ductal Carcinoma In Situ (DCIS), Reduces HER2-Positive Tumor Progression.

Breast ductal carcinoma in situ (DCIS) is clinically challenging, featuring high diagnosis rates and few targeted therapies. Expression/signaling from junctional adhesion molecule-A (JAM-A) has been linked to poor prognosis in invasive breast cancers, but its role in DCIS is unknown. Since progression from DCIS to invasive cancer has been linked with overexpression of the human epidermal growth factor receptor-2 (HER2), and JAM-A regulates HER2 expression, we evaluated JAM-A as a therapeutic target in DCIS. JAM-A expression was immunohistochemically assessed in patient DCIS tissues. A novel JAM-A antagonist (JBS2) was designed and tested alone/in combination with the HER2 kinase inhibitor lapatinib, using SUM-225 cells in vitro and in vivo as validated DCIS models. Murine tumors were proteomically analyzed. JAM-A expression was moderate/high in 96% of DCIS patient tissues, versus 23% of normal adjacent tissues. JBS2 bound to recombinant JAM-A, inhibiting cell viability in SUM-225 cells and a primary DCIS culture in vitro and in a chick embryo xenograft model. JBS2 reduced tumor progression in in vivo models of SUM-225 cells engrafted into mammary fat pads or directly injected into the mammary ducts of NOD-SCID mice. Preliminary proteomic analysis revealed alterations in angiogenic and apoptotic pathways. High JAM-A expression in aggressive DCIS lesions and their sensitivity to treatment by a novel JAM-A antagonist support the viability of testing JAM-A as a novel therapeutic target in DCIS.

Acceptability of Self-Management Group Education to Reduce Fear of Hypoglycemia as a Barrier to Physical Activity in Adults With Type 1 Diabetes: A Mixed Methods Approach.

OBJECTIVES: Mixed methods were used to evaluate a group self-management education intervention to address type 1 diabetes (T1D)-specific barriers to physical activity (PA). We evaluated the acceptability of study resources and procedures. METHODS: Consenting participants from a quantitative evaluation (n=70) were invited to participate in 1 of 5 focus groups. Interviews explored the acceptability of procedures across the randomized controlled trial schedule, acceptability of the intervention/control workshops and resources and the perceived effectiveness of the intervention/control on participant outcomes. The use and helpfulness of intervention take-home resources, Facebook data and fidelity coding were also examined to inform other aspects of intervention acceptability. RESULTS: Twenty-one focus group participants from control or intervention arms participated in 1 of the 5 focus groups. Participants were 46±10 years of age; about half were female and had been living with T1D for 23±16 years. Study procedures were widely accepted; however, randomization and some aspects of the questionnaire were of concern to a small number of participants. Group education was acceptable and preferred, but participants expressed ambivalence toward the private Facebook group. Control participants indicated that basic information on PA guidelines and hypoglycemia risk are not currently being provided in standard care. Fidelity assessment confirmed the intervention was delivered consistently and was facilitated using behaviours and communication skills based on social cognitive theory. CONCLUSIONS: Future definitive evaluation of this promising intervention should utilize a blinded randomized controlled trial study design. Alterations to the control workshop are required to better reflect standard care in Australia. Our qualitative findings suggest that group education can be an acceptable and preferred method of education in T1D management for PA.

Exploring medical students' perceptions of the challenges and benefits of volunteering in the intensive care unit during the COVID-19 pandemic: a qualitative study.

OBJECTIVES: In March 2020, the WHO declared SARS-CoV-2 a pandemic. Hospitals across the world faced staff, bed and supply shortages, with some European hospitals calling on medical students to fill the staffing gaps. This study aimed to document the impact of volunteering during the COVID-19 pandemic on students' professional development, resilience and future perceived career choices. DESIGN: This is a retrospective, qualitative study of student reflections, using purposive sampling.The Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences recruited 26 medical student volunteers to assist in pronation and supination of ventilated patients affected by SARS-CoV-2. These students were invited to complete an anonymous survey based on their experiences as volunteers. Thematic analysis was performed on these written reflections. RESULTS: The results showed that volunteering during the COVID-19 pandemic developed key skills from RCSI's medical curriculum, significantly fostered medical students' resilience and guided their career choices. Major areas of development included communication, teamwork, compassion and altruism, which are not easily developed through the formal curriculum. A further area that was highlighted was the importance of evidence-based health in a pandemic. Finally, our respondents were early stage medical students with limited clinical exposure. Some found the experience difficult to cope with and therefore supports should be established for students volunteering in such a crisis. CONCLUSION: These results suggest that clinical exposure is an important driver in developing students' resilience and that volunteering during a pandemic has multiple benefits to students' professional development and professional identity formation.

Multi-targeted metallo-ciprofloxacin derivatives rationally designed and developed to overcome antimicrobial resistance.

Antimicrobial resistance is a major global threat to human health due to the rise, spread and persistence of multi-drug-resistant bacteria or 'superbugs'. There is an urgent need to develop novel chemotherapeutics to overcome this overarching challenge. The authors derivatized a clinically used fluoroquinolone antibiotic ciprofloxacin (Cip), and complexed it to a copper phenanthrene framework. This resulted in the development of two novel metallo-antibiotics of general formula [Cu(N,N)(CipHA)]NO3 where N,N represents a phenanthrene ligand and CipHA represents a hydroxamic acid of Cip derivative. Comprehensive studies, including a detailed proteomic study in which Staphylococcus aureus cells were exposed to the complexes, were undertaken to gain an insight into their mode of action. These new complexes possess potent antibacterial activity against S. aureus and methicillin-resistant S. aureus. In addition, they were found to be well tolerated in vivo in Galleria mellonella larvae, which has both functional and structural similarities to the innate immune system of mammals. These findings suggest that proteins involved in virulence, pathogenesis, and the synthesis of nucleotides and DNA repair mechanisms are most affected. In addition, both complexes affected similar cell pathways when compared with clinically used Cip, including cationic antimicrobial peptide resistance. The Cu-DPPZ-CipHA (DPPZ = dipyrido[3,2-a:2',3'-c]phenazine) analogue also induces cell leakage, which leads to an altered proteome indicative of reduced virulence and increased stress.

Self-Management Group Education to Reduce Fear of Hypoglycemia as a Barrier to Physical Activity in Adults Living With Type 1 Diabetes: A Pilot Randomized Controlled Trial.

OBJECTIVES: The aim of this study was to evaluate the feasibility, acceptability and preliminary efficacy of a theory-driven group education intervention designed to reduce fear of hypoglycemia (FoH) as a barrier to physical activity (PA) in adults with type 1 diabetes (T1D). METHODS: This study was a single-blinded, pilot randomized controlled trial of adults aged 18 to 65 years and living with T1D in Western Australia. Participants were randomized (1:1) to standard care or intervention with self-management education. Primary outcomes were feasibility and acceptability of the study procedures, and change to barriers to PA and FoH. Secondary outcomes were change to attitudes and intentions toward PA, self-reported participation in PA, self-efficacy, diabetes distress and well-being. To calculate effect sizes, we used a Bayesian comparison of the between-group difference scores (i.e. [scoret2 - scoret1]TREATMENT vs [scoret2 - scoret1]CONTROL). RESULTS: We randomized 117 participants with T1D, 86 (74%) of whom provided baseline data and attended initial workshops. Of these participants, 81% attended the booster workshop 4 weeks later. They were 45±12 years of age, reported high levels of activity and had been living with T1D for 20±14 years. Small-to-moderate effect sizes [ESs] in favour of the intervention were observed at 12 weeks for overall barriers to PA (ES, -0.38; highest density interval, -0.92 to 0.17), self-efficacy for blood glucose management after PA (ES, 0.45; highest density interval, 0 to 0.91), diabetes distress (ES, -0.29; highest density interval, -0.77 to 0.15) and well-being (ES, 0.36; highest density interval, -0.12 to 0.8). CONCLUSIONS: Quantitative findings indicate study procedures were acceptable to participants and feasible to deliver. A future definitive trial is justified to replicate preliminary efficacy and to determine the utility of the intervention for improving PA participation.

Systemic delivery of antagomirs during blood-brain barrier disruption is disease-modifying in experimental epilepsy.

Oligonucleotide therapies offer precision treatments for a variety of neurological diseases, including epilepsy, but their deployment is hampered by the blood-brain barrier (BBB). Previous studies showed that intracerebroventricular injection of an antisense oligonucleotide (antagomir) targeting microRNA-134 (Ant-134) reduced evoked and spontaneous seizures in animal models of epilepsy. In this study, we used assays of serum protein and tracer extravasation to determine that BBB disruption occurring after status epilepticus in mice was sufficient to permit passage of systemically injected Ant-134 into the brain parenchyma. Intraperitoneal and intravenous injection of Ant-134 reached the hippocampus and blocked seizure-induced upregulation of miR-134. A single intraperitoneal injection of Ant-134 at 2 h after status epilepticus in mice resulted in potent suppression of spontaneous recurrent seizures, reaching a 99.5% reduction during recordings at 3 months. The duration of spontaneous seizures, when they occurred, was also reduced in Ant-134-treated mice. In vivo knockdown of LIM kinase-1 (Limk-1) increased seizure frequency in Ant-134-treated mice, implicating de-repression of Limk-1 in the antagomir mechanism. These studies indicate that systemic delivery of Ant-134 reaches the brain and produces long-lasting seizure-suppressive effects after systemic injection in mice when timed with BBB disruption and may be a clinically viable approach for this and other disease-modifying microRNA therapies.

Barriers and facilitators of physical activity participation in adults living with type 1 diabetes: a systematic scoping review.

To identify and map barriers and facilitators of physical activity (PA) in adults living with type 1 diabetes (T1D) in any care setting or environment. A scoping review was conducted in accordance with the PRISMA-ScR guidelines to address the aim of this review. Exclusion/inclusion criteria were determined a priori. Articles captured in the search were subject to title and abstract screening before full-text articles were assessed for eligibility against the exclusion/inclusion criteria. Included articles underwent critical appraisal before being charted, mapped, and discussed. Forty-six articles were included in the final synthesis. Most commonly, articles reported cross-sectional survey studies (46%), then qualitative designs (17%), and opinion or text (17%). Experimental studies accounted for 13% of included articles. Hypoglycaemia/fear of hypoglycaemia was the most commonly reported barrier and patient education the most commonly discussed facilitator. Quality appraisal revealed methodological issues among included articles. Higher quality research with theoretically sound behaviour-change interventions combined with targeted patient education is needed to address hypoglycaemia/fear of hypoglycaemia as a barrier to PA. Novelty: Hypoglycaemia and fear of hypoglycaemia were the most commonly reported barriers to PA in adults with T1D. Powered randomised controlled trials are required to establish efficacy of behaviour change interventions targeting these barriers to PA.

Barriers and facilitators to physical activity participation in adults living with type 1 diabetes: a scoping review protocol.

OBJECTIVE: The objective of this scoping review is to identify and map barriers to and facilitators of physical activity in adults living with type 1 diabetes. INTRODUCTION: Physical activity is crucial to the day-to-day management of type 1 diabetes and in the prevention of diabetes-related complications. Despite these benefits, people living with type 1 diabetes have higher inactivity rates than those in the general population. Identifying barriers and facilitators to physical activity, specific to the type 1 diabetes population, may help explain this discrepancy. INCLUSION CRITERIA: This scoping review will include articles describing adults aged 18 years or over, living with type 1 diabetes in any care setting. Included literature will focus on the key concepts under review: barriers to or facilitators of physical activity participation. Literature examining efficacy of strategies to manage blood glucose levels for physical activity will not be included. METHODS: All sources of information will be reviewed, including peer-reviewed, published and unpublished literature. Database search limits will be applied to include articles written in English, involving human participants and published between 1996 and February 2019. Once all records are identified, duplicates will be removed. Remaining records will be subject to title and abstract screening where articles will be excluded if they clearly meet at least one exclusion criteria. All remaining full-text articles will be assessed for eligibility against inclusion and exclusion criteria. Included articles will undergo critical appraisal before being synthesized, charted and discussed.

Impact of introduction of xpert flu assay for influenza PCR testing on obstetric patients: a quality improvement project.

OBJECTIVE: The aim of this project was to assess the implementation of a quality improvement project regarding the introduction of on-site influenza PCR testing in a stand-alone obstetric hospital. METHODS: As part of a quality improvement project on the management of influenza in obstetric patients, the Xpert Flu assay (Cepheid Inc., Sunnyvale, CA) was introduced on-site and it replaced the previous method of PCR testing which was off-site. The main outcome measures were duration of antimicrobials, rate of admission and administration of oseltamavir in the emergency department. RESULTS: Twenty-eight patients were included in the pre-intervention period and 45 patients were included in the post-intervention period. Following the introduction of the test, there was a statistically significant reduction seen in commencement of antimicrobials (76% pre- and 33% post-intervention), and also rate of admission (88% pre- and 45% post-intervention) while there was a statistically significant improvement in the commencement of oseltamavir in the emergency department (72% pre-and 95% post-intervention) (p < .01 for all outcomes). CONCLUSION: Introduction of on-site rapid influenza PCR testing can lead to a significant improvement in patient management and should be considered for introduction to other sites.

Molecular interactions and inhibition of the staphylococcal biofilm-forming protein SdrC.

Staphylococcus aureus forms biofilms on indwelling medical devices using a variety of cell-surface proteins. There is growing evidence that specific homophilic interactions between these proteins represent an important mechanism of cell accumulation during biofilm formation, but the underlying molecular mechanisms are still not well-understood. Here we report the direct measurement of homophilic binding forces by the serine-aspartate repeat protein SdrC and their inhibition by a peptide. Using single-cell and single-molecule force measurements, we find that SdrC is engaged in low-affinity homophilic bonds that promote cell-cell adhesion. Low-affinity intercellular adhesion may play a role in favoring biofilm dynamics. We show that SdrC also mediates strong cellular interactions with hydrophobic surfaces, which are likely to be involved in the initial attachment to biomaterials, the first stage of biofilm formation. Furthermore, we demonstrate that a peptide derived from ß-neurexin is a powerful competitive inhibitor capable of efficiently blocking surface attachment, homophilic adhesion, and biofilm accumulation. Molecular modeling suggests that this blocking activity may originate from binding of the peptide to a sequence of SdrC involved in homophilic interactions. Our study opens up avenues for understanding the role of homophilic interactions in staphylococcal adhesion, and for the design of new molecules to prevent biofilm formation during infection.

Novel anti-staphylococcal and anti-biofilm properties of two anti-malarial compounds: MMV665953 {1-(3-chloro-4-fluorophenyl)-3-(3,4-dichlorophenyl)urea} and MMV665807 {5-chloro-2-hydroxy-N-[3-(trifluoromethyl)phenyl]benzamide}.

PURPOSE: The treatment of device-related infections is challenging and current anti-microbial compounds have poor anti-biofilm activity. We aimed to identify and characterize novel compounds effective in the eradication of Staphylococcus aureus biofilms. METHODOLOGY: Two novel compounds, MMV665953 {1-(3-chloro-4-fluorophenyl)-3-(3,4-dichlorophenyl)urea} and MMV665807{5-chloro-2-hydroxy-N-[3-(trifluoromethyl)phenyl]benzamide}, effective in killing S. aureus biofilms, were identified by screening of the open access 'malaria box' chemical library. The minimum bactericidal concentrations, half-maximal inhibition concentration (IC50) values and minimal biofilm killing concentrations effective in the killing of biofilm were determined against meticillin-resistant S. aureus and meticillin-sensitive S. aureus. Fibrin-embedded biofilms were grown under in vivo-relevant conditions, and viability was measured using a resazurin-conversion assay and confocal microscopy. The potential for the development of resistance and cytotoxicity was also assessed. RESULTS: MMV665953 and MMV665807 were bactericidal against S. aureus isolates. The IC50 against S. aureus biofilms was at 0.15-0.58 mg l-1 after 24 h treatment, whereas the concentration required to eradicate all tested biofilms was 4 mg l-1, making the compounds more bactericidal than conventional antibiotics. The cytotoxicity against human keratinocytes and primary endothelial cells was determined as IC50 7.47 and 0.18 mg l-1 for MMV665953, and as 1.895 and 0.076 mg l-1 for MMV665807. Neither compound was haemolytic nor caused platelet activation. MMV665953 and MMV665807 derivatives with reduced cytotoxicity exhibited a concomitant loss in anti-staphylococcal activity. CONCLUSION: MMV665953 and MMV665807 are more bactericidal against S. aureus biofilms than currently used anti-staphylococcal antibiotics and represent a valuable structural basis for further investigation in the treatment of staphylococcal biofilm-related infections.

Impact of genetic variation in the 5-HT transporter and receptor on platelet function in patients with stable CAD taking aspirin.

BACKGROUND: Serotonin (5-HT) induces platelet aggregation by activating its 5-HT2A receptor. Platelet uptake is mediated by the 5-HT transporter (5-HTT). A common 5-HTT promoter (5-HTTLPR) splice variant results in long (L) and short (S) alleles. 5-HTTLPR genotype has been associated with increased platelet activation and risk of MI. Variation within HTR2A gene (C1354T) that encodes the 5-HT2A receptor has also been associated with enhanced platelet aggregation. We hypothesised that 5-HTT and/or HTR2A variation may influence platelet response to aspirin in patients with stable CAD. METHODS: Patients (n=144) with stable cardiovascular disease taking aspirin were genotyped for the 5-HTTLPR and HTR2A variants. Platelet inhibition was assessed by serum thromboxane and arachidonic acid-induced platelet aggregation assay. RESULTS: 5-HTT genotype (LL vs *S) was a significant determinant of serum TX level (8.9±2.6ng/ml vs 6.0±1.6ng/ml respectively; p<0.02) and 5-HTT LL genotype predicted an incomplete aspirin response (serum TXB2>2.2ng/ml) (p=0.04; OR=2.22, CI=1.03-4.79). Odds ratio of the effect of LL genotype on TX elevation was 3.8 (95% CI 1.2-11.6) in younger patients (under 64) compared to 1.0 (95% CI=0.3-3.8) in older subjects. LL genotype did not influence AA aggregation (p=0.83, OR=1.2, CI=0.3-4.1). The HTR2A variant had no effect on TX generation (p=0.70; OR=1.22, CI=0.45-3.26) nor AA aggregation (p=0.99; OR=1.0, CI=0.2-4.9). CONCLUSIONS: In younger patients with stable CAD 5HTT LL genotype carried by almost one third of our cohort is associated with a diminished response to aspirin that may increase cardiovascular risk. Genotypic variation in platelet activation may be a contributing mechanism.

Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond.

A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts.

A novel role for the fibrinogen Asn-Gly-Arg (NGR) motif in platelet function.

The integrin αIIbß3 on resting platelets can bind to immobilised fibrinogen resulting in platelet spreading and activation but requires activation to bind to soluble fibrinogen. αIIbß3 is known to interact with the general integrin-recognition motif RGD (arginine-glycine-aspartate) as well as the fibrinogen-specific γ-chain dodecapeptide; however, it is not known how fibrinogen binding triggers platelet activation. NGR (asparagine-glycine-arginine) is another integrin-recognition sequence present in fibrinogen and this study aims to determine if it plays a role in the interaction between fibrinogen and αIIbß3. NGR-containing peptides inhibited resting platelet adhesion to fibrinogen with an IC50 of 175 µM but failed to inhibit the adhesion of activated platelets to fibrinogen (IC50> 500 µM). Resting platelet adhesion to mutant fibrinogens lacking the NGR sequences was reduced compared to normal fibrinogen under both static and shear conditions (200 s⁻¹). However, pre-activated platelets were able to fully spread on all types of fibrinogen. Thus, the NGR motif in fibrinogen is the site that is primarily responsible for the interaction with resting αIIbß3 and is responsible for triggering platelet activation.

The therapeutic potential of I-domain integrins.

Due to their role in processes central to cancer and autoimmune disease I-domain integrins are an attractive drug target. Both antibodies and small molecule antagonists have been discovered and tested in the clinic. Much of the effort has focused on αLß2 antagonists. Maybe the most successful was the monoclonal antibody efalizumab, which was approved for the treatment of psoriasis but subsequently withdrawn from the market due to the occurrence of a serious adverse effect (progressive multifocal leukoencephalopathy). Other monoclonal antibodies were tested for the treatment of reperfusion injury, post-myocardial infarction, but failed to progress due to lack of efficacy. New potent small molecule inhibitors of αv integrins are promising reagents for treating fibrotic disease. Small molecule inhibitors targeting collagen-binding integrins have been discovered and future work will focus on identifying molecules selectively targeting each of the collagen receptors and identifying appropriate target diseases for future clinical studies.

A novel platinum complex of the histone deacetylase inhibitor belinostat: rational design, development and in vitro cytotoxicity.

The successful design and synthesis of a novel Pt complex of the histone deacteylase inhibitor belinostat are reported. Molecular modelling assisted in the identification of a suitable malonate derivative of belinostat (mal-p-Bel) for complexation to platinum. Reaction of [Pt(NH3)2(H2O)2](NO3)2 with the disodium salt of mal-p-Bel gave cis-[Pt(NH3)2(mal-p-Bel-2H)] (where -2H indicates that mal-p-Bel is doubly deprotonated) in excellent yield. An in vitro cytotoxicity study revealed that cis-[Pt(NH3)2(mal-p-Bel-2H)] possesses (i) considerable cytotoxicity against reported ovarian cancer cell lines, (ii) enhanced cytotoxicity relative to the previously reported Pt histone deacetylase inhibitor conjugate, cis-[Pt(II)(NH3)2(malSAHA-2H)] and (iii) favourable cyto-selective properties as compared to cisplatin and belinostat.

TIN-a combinatorial compound collection of synthetically feasible multicomponent synthesis products.

The synthetic feasibility of any compound library used for virtual screening is critical to the drug discovery process. TIN, a recursive acronym for 'TIN Is Not commercial', is a virtual combinatorial database enumeration of diversity-orientated multicomponent syntheses (MCR). Using a 'one-pot' synthetic technique, 12 unique small molecule scaffolds were developed, predominantly styrylisoxazoles and bis-acetylenic ketones, with extensive derivatization potential. Importantly, the scaffolds were accessible in a single operation from commercially available sources containing R-groups which were then linked combinatorially. This resulted in a combinatorial database of over 28 million product structures, each of which is synthetically feasible. These structures can be accessed through a free Web-based 2D structure search engine or downloaded in SMILES, MOL2, and SDF formats. Subsets include a 10% diversity subset, a drug-like subset, and a lead-like subset that are also freely available for download and virtual screening ( http://mmg.rcsi.ie:8080/tin ).