Translational studies on the vascular targeting agent combretastatin A4 phosphate

This thesis describes in vitro experiments with the novel vascular targeting agent Combretastatin A4 Phosphate (CA4P) and non-invasive magnetic resonance imaging (MRI) measurements in patients treated with CA4P to derive parameters which reflect tumour and normal tissue blood flow and permeability. Shape changes induced following tubulin depolymerisation by CA4P are quantified in human umbilical vein endothelial cells (HUVECs) and are measurable after only 10 minutes exposure. The effect is more marked in proliferating than confluent HUVECs, and begins at doses that have no anti-proliferative activity. In contrast, human smooth muscle cells show no shape change after treatment. The similar time course of HUVEC shape changes in vitro and tumour vascular shutdown in vitro suggest that this might be an early event involved in vascular shutdown. The effects and recovery rates of several other tubulin-binding agents are compared with CA4P. Colchicine and vinblastine also induce changes in HUVEC shape but unlike CA4P, HUVECs do not recover after drug removal. For these drugs, shape change and antiproliferative effects occur at similar doses. ZD6126, which like CA4P also has vascular targeting activity at well tolerated doses, induces recoverable changes in HUVEC shape at doses with no anti-proliferative activity. The difference in recovery rates with different tubulin-binding agents might therefore be related to their therapeutic window. The reproducibility of dynamic contrast enhanced MRI is measured in 21 patients who had 2 pre treatment scans within a week. Comparing the technique in rats with an established method for measuring absolute blood flow provides verification that the kinetic parameters derived from this technique reflect blood flow changes. Significant reductions in these parameters in patients' tumours are seen 4 and 24 hours after treatment at well tolerated doses of CA4P at 52mg/m2 to 68 mg/m2. No significant mean changes are seen in kidney, liver, spleen or skeletal muscle, although a small proportion of patients have significant reductions which are generally not maintained, and not associated with clinical consequences

Spontaneous coronary artery dissection: a systematic review of physical and psychosocial recovery following discharge from hospital

IntroductionSpontaneous coronary artery dissection (SCAD) is increasingly recognised as an important cause of myocardial infarction, particularly among women. SCAD survivors may not know what physical activity is safe and effective and there may be a psychosocial burden of living with a SCAD diagnosis. This review aimed to determine the evidence regarding physical activity, cardiovascular risk factors, or associated factors, and the psychosocial impact of SCAD for SCAD survivors after hospital discharge.MethodsA systematic review completed in accordance with PRISMA guidelines (Prospero CRD42021254798).ResultsThe review included 28 studies. These used a range of methods. None were randomised controlled trials. There were 4167 SCAD participants although some were sourced from the same SCAD registries, so may not be unique. They were mainly female (n=3897 93.5%, range=57.7%-100%), with mean age 48.0±9.8 years at index event. Participants mostly came from the USA, Canada, or the Netherlands. We found very limited evidence for cardiorespiratory fitness improvements following cardiac rehabilitation (CR). Existing CR was not tailored to SCAD specific needs and SCAD survivors lacked guidance about appropriate physical activity. Some participants had high levels of psychosocial distress. SCAD survivors highlighted the need for tailored support that included family members. Many SCAD survivors have traditional risk factors including hypertension, hyperlipidaemia and overweight/obesity. Chest pain following SCAD is common.ConclusionsThere is an urgent need to develop physical and psychological recovery programmes for SCAD survivors, and test effectiveness via randomised controlled trials. Psychosocial support is particularly required, given the high burden of psychosocial issues

Phocine Distemper Virus in Seals, East Coast, United States, 2006

: Phocine Distemper Virus in Seal

2023 ESC Guidelines for the management of acute coronary syndromes.

S

Effects of a refugee elective on medical student perceptions

<p>Abstract</p> <p>Background</p> <p>There are growing numbers of refugees throughout the world. Refugee health is a relatively unstudied and rarely taught component of medical education. In response to this need, a Refugee Health Elective was begun. Medical student perceptions toward cultural aspects of medicine and refugee health before and after participation in the elective were measured.</p> <p>Methods</p> <p>Preliminary questionnaires were given to all preclinical students at the academic year commencement with follow-up questionnaires at the refugee elective's conclusion. Both questionnaires examined students' comfort in interacting with patients and familiarity with refugee medical issues, alternative medical practices, and social hindrances to medical care. The preliminary answers served as a control and follow-up questionnaire data were separated into participant/non-participant categories. All preclinical medical students at two Midwestern medical schools were provided the opportunity to participate in the Refugee Health Elective and surveys. The 3 data groups were compared using unadjusted and adjusted analysis techniques with the Kruskall-Wallis, Bonferroni and ANCOVA adjustment. P-values < 0.05 were considered significant.</p> <p>Results</p> <p>408 and 403 students filled out the preliminary and follow-up questionnaires, respectfully, 42 of whom participated in the elective. Students considering themselves minorities or multilingual were more likely to participate. Elective participants were more likely to be able to recognize the medical/mental health issues common to refugees, to feel comfortable interacting with foreign-born patients, and to identify cultural differences in understanding medical/mental health conditions, after adjusting for minority or multilingual status.</p> <p>Conclusion</p> <p>As medical schools integrate a more multicultural curriculum, a Refugee Health Elective for preclinical students can enhance awareness and promote change in attitude toward medical/mental health issues common to refugees. This elective format offers tangible and effective avenues for these topics to be addressed.</p

The interpretation of systematic reviews with meta-analyses: an objective or subjective process?

<p>Abstract</p> <p>Background</p> <p>Discrepancies between the conclusions of different meta-analyses (quantitative syntheses of systematic reviews) are often ascribed to methodological differences. The objective of this study was to determine the discordance in interpretations when meta-analysts are presented with identical data.</p> <p>Methods</p> <p>We searched the literature for all randomized clinical trials (RCT) and review articles on the efficacy of intravenous magnesium in the early post-myocardial infarction period. We organized the articles chronologically and grouped them in packages. The first package included the first RCT, and a summary of the review articles published prior to first RCT. The second package contained the second and third RCT, a meta-analysis based on the data, and a summary of all review articles published prior to the third RCT. Similar packages were created for the 5^thRCT, 10^thRCT, 20^thRCT and 23^rdRCT (all articles). We presented the packages one at a time to eight different reviewers and asked them to answer three clinical questions after each package based solely on the information provided. The clinical questions included whether 1) they believed magnesium is now proven beneficial, 2) they believed magnesium will eventually be proven to be beneficial, and 3) they would recommend its use at this time.</p> <p>Results</p> <p>There was considerable disagreement among the reviewers for each package, and for each question. The discrepancies increased when the heterogeneity of the data increased. In addition, some reviewers became more sceptical of the effectiveness of magnesium over time, and some reviewers became less sceptical.</p> <p>Conclusion</p> <p>The interpretation of the results of systematic reviews with meta-analyses includes a subjective component that can lead to discordant conclusions that are independent of the methodology used to obtain or analyse the data.</p

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN