Potent and Potentially Non-Cardiotoxic Anthracyclines: Their Synthesis, Biological Evaluation, and Comparison of Hydrozone-Mediated Reductions

After nearly half a century since medical approval, the anthracycline doxorubicin (DOX) remains one of the most potent and clinically useful anticancer agents. In spite of its long history, however, the cytotoxic mechanisms of DOX have been debated and remain controversial. Several well-supported mechanisms will be discussed, such as the potential to intercalate DNA and induce apoptosis through topoisomerase poisoning, free radical formation, and DNA cross-linking. While DOX has substantial medical importance, it is plagued by a life-threatening dose-dependent cardiotoxic side effect associated with several structural groups. A number of modifications to DOX have been accomplished to attempt to remove treatment-induced cardiotoxicity, including the reduction of the C-13 carbonyl to a methylene and conversion of the quinone moiety to a less reactive iminoquinone. This modified form, termed 5-imino-13-deoxydoxorubicin (DIDOX), has displayed no cardiotoxic side effects in any clinical setting. However, these structural changes have reduced the potency of the drug more than four-fold. In this work, six different analogs of DIDOX were synthesized and evaluated for in vitro cytotoxicity against an array of cancer cell lines. The six analogs were designed to incorporate reactive moieties attached to the 3\u27-amine of the daunasamine sugar. Of the six synthesized, four were at least as cytotoxic as DOX, and several were up to 100-fold more potent. Preliminary results also suggest that modifications to the 3\u27-amine attenuate the multidrug resistance observed during anthracycline treatment. In addition to the synthesis and preliminary evaluation of new anthracycline analogs, this work explored methods for improving the synthesis of DIDOX. Specifically, the reduction of DOX’s carbonyl to produce C-13-deoxydoxorubicin (DeoxyDOX) was explored using six different sulfonylhydrazones, and the relative production of the reduced form was compared. Four of the new hydrazones exhibited the potential to improve the overall amount of DeoxyDOX generated, compared to the currently used methods. In summary, the work described presents both the findings for the synthesis of potent and non-cardiotoxic derivatives of doxorubicin that show promise for overcoming multi-drug resistance and potential improvements toward enhancing the overall yield of DIDOX and related analogs

The Power of Facebook for Universities: A Study of Official Facebook Pages of Florida\u27s Universities

The purpose of this mixed methods study was to investigate the potential power of Facebook to be used by higher education institutions as a key communication tool to provide viewers’ emergent impressions, or frames, of the institution. This study was intended to contribute to the knowledge base of social media and higher education by studying the emergent frames formed from the posts on the official Facebook page of each member university of the Florida State University System

Remote ischaemic preconditioning and its effect on coronary physiology and platelet activation

Background Remote ischaemic preconditioning (RIPC) is the phenomenon where brief non-harmful ischaemia to a remote organ can confer protection to the heart against a future insult. Most commonly delivered with a sphygmomanometer on the arm, RIPC has been shown to confer protection when delivered prior to primary or elective percutaneous coronary intervention (PCI). The mechanism by which this occurs is not clearly defined. Coronary microcirculatory function is an important determinant of patient prognosis at the time of PCI. Platelets play an important role in the pathophysiology of coronary atherosclerosis related thrombotic events, with platelet inhibition an integral component of the clinical management of patients with coronary artery disease (CAD) including those undergoing PCI. Given the important role of both the microcirculation and platelet inhibition at the time of PCI, this project was designed to investigate the effect of RIPC on these two prognostically important factors. Methods and results This thesis has examined 1) the effect of RIPC on coronary artery physiology and 2) the effect of RIPC on platelet activation in response to platelet agonists and the interaction between these effects and antiplatelet medications. To study the effect of RIPC on coronary artery physiology and microcirculatory function, a randomised blinded placebo controlled trial was performed. Patients with a clinical indication for fractional flow reserve (FFR) measurement were randomised to receive RIPC or sham treatment while on the catheterisation table. A comprehensive coronary physiology study was performed with a temperature-pressure sensor coronary guidewire before and immediately after the allocated treatment. The index of microcirculatory resistance (IMR) and coronary flow reserve (CFR) were measured as markers of microcirculatory function. RIPC was associated with a significant reduction in the calculated IMR (median (interquartile range), 22.6 (17.9-25.6) vs 17.5 (14.5-21.3), P=0.007) and a significant increase in the CFR (mean ± standard deviation, 2.6 ± 0.9 vs 3.8 ± 1.7, P=0.001). These changes were associated with a reduction in hyperaemic transit time (0.33 (0.26-0.40) vs 0.25 (0.20-0.30), P=0.01) indicating an increase in coronary blood flow. There was no effect on FFR. Sham treatment had no effect on any coronary physiology parameter. Analysis of plasma stored from blood collected before and after RIPC/sham treatment found no changes in plasma nitrite, cGMP or adrenomedullin with RIPC. There was a reduction in plasma 6-keto-PGF1α (the metabolite of prostacyclin) with RIPC. The effect of RIPC on platelet activation was studied in a separate randomised controlled trial where patients referred for coronary angiography were randomised prior to their procedure to RIPC or sham treatment. Venous blood was collected from the contralateral arm before and immediately after their allocated treatment, prior to cardiac catheterisation. Platelets were stimulated in whole blood with adenosine diphosphate, protease activated receptor-1 agonist (SFLLRN), thrombin with and without collagen, and analysed by flow cytometry for expression of CD62P (marker of α-granule release), CD63 (marker of dense granule and lysosome release) and conformationally active glycoprotein IIb/IIIa (GPIIb/IIIa) (PAC-1 binding). RIPC was associated with decreased platelet PAC-1 binding in response to SFLLRN (50.4% (31.3-73.2) vs 49.3% (23.0-67.7), P=0.002) and thrombin and collagen (79.5 ± 11.9% vs 68.9 ± 22.5%, P<0.001). Similar effects were seen in patients on both aspirin and a P2Y12 receptor inhibitor. Despite their role in regulating GPIIb/IIIa activation, there was no effect of RIPC on plasma cAMP and cGMP levels or intra-platelet phosphorylated-VASP levels. RIPC was also assessed for its effects on the generation of procoagulant platelets, identified by the uptake of 4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid (GSAO, an intracellular cell death marker) and staining for CD62P (GSAO+/CD62P+). RIPC decreased circulating levels of procoagulant platelets in the circulation (2.0% (1.3-2.4) vs 1.3% (1.1-2.1), P=0.01), whereas sham had no effect. In the subgroup of patients on aspirin monotherapy, RIPC was associated with a reduction in procoagulant platelet formation in response to SFLLRN (11.4±5.2% vs 8.9±2.8%, P=0.04) and thrombin (12.9±5.9% vs 8.7±3.2%, P=0.04). In order to determine the mechanism behind the RIPC-mediated attenuation of procoagulant platelet formation, further patients were studied to assess for the effects of RIPC on platelet mitochondrial membrane potential using a fluorescent potential-sensitive probe (TMRE). RIPC was associated with a significant reduction in platelet mitochondrial membrane depolarisation in response to a range of thrombin (P=0.001) and thrombin and collagen (P=0.01) concentrations. To investigate whether RIPC modifies the plasma microRNA profile, plasma stored from blood collected before and after RIPC/sham in the platelet cohort was analysed. Plasma microRNA was extracted from paired plasma samples collected from 4 patients treated with RIPC. The plasma microRNA profile before and after RIPC was compared with a card based quantitative polymerase chain reaction (qPCR) array system and identified 6 candidate species which appeared to be increased with RIPC. A validation study was performed in the entire randomised platelet cohort (n=60) by extracting microRNA from paired plasma samples collected from patients before and after treatment with either RIPC or sham, and measuring the levels of the 6 candidate species with specific reverse transcription and qPCR reactions. This demonstrated no definite difference with RIPC over sham treatment in any of the 6 microRNA species. Conclusion RIPC leads to rapid improvements in coronary microcirculatory function as demonstrated by validated catheterisation based coronary physiology measurements. Additionally, RIPC attenuated platelet GPIIb/IIIa activation in response to potent platelet agonists which are present at the site of complicated atherosclerotic plaques. Attenuation of GPIIb/IIIa activation was evident in patients on contemporary antiplatelet therapy, suggesting benefit additional to these medications. RIPC also reduced the level of circulating procoagulant platelets. Reductions in procoagulant platelet activity appeared to be due to RIPC-mediated reduction in platelet mitochondrial membrane depolarisation. These novel actions of RIPC are likely to contribute to the beneficial effects of RIPC during elective and primary PCI

Parental stress increases body mass index trajectory in pre-adolescents.

What is already known about this subjectRates of childhood obesity have increased since the mid-1970s. Research into behavioural determinants has focused on physical inactivity and unhealthy diets. Cross-sectional studies indicate an association between psychological stress experienced by parents and obesity in pre-adolescents.What this study addsWe provide evidence of a prospective association between parental psychological stress and increased weight gain in pre-adolescents. Family-level support for those experiencing chronic stress might help promote healthy diet and exercise behaviours in children.ObjectiveWe examined the impact of parental psychological stress on body mass index (BMI) in pre-adolescent children over 4 years of follow-up.MethodsWe included 4078 children aged 5-10 years (90% were between 5.5 and 7.5 years) at study entry (2002-2003) in the Children's Health Study, a prospective cohort study in southern California. A multi-level linear model simultaneously examined the effect of parental stress at study entry on the attained BMI at age 10 and the slope of change across annual measures of BMI during follow-up, controlled for the child's age and sex. BMI was calculated based on objective measurements of height and weight by trained technicians following a standardized procedure.ResultsA two standard deviation increase in parental stress at study entry was associated with an increase in predicted BMI attained by age 10 of 0.287 kg m(-2) (95% confidence interval 0.016-0.558; a 2% increase at this age for a participant of average attained BMI). The same increase in parental stress was also associated with an increased trajectory of weight gain over follow-up, with the slope of change in BMI increased by 0.054 kg m(-2) (95% confidence interval 0.007-0.100; a 7% increase in the slope of change for a participant of average BMI trajectory).ConclusionsWe prospectively demonstrated a small effect of parental stress on BMI at age 10 and weight gain earlier in life than reported previously. Interventions to address the burden of childhood obesity should address the role of parental stress in children

Long-term exposure to ambient ozone and mortality : A quantitative systematic review and meta-analysis of evidence from cohort studies

Objectives: While there is good evidence for associations between short-term exposure to ozone and a range of adverse health outcomes, the evidence from narrative reviews for long-term exposure is suggestive of associations with respiratory mortality only. We conducted a systematic, quantitative evaluation of the evidence from cohort studies, reporting associations between long-term exposure to ozone and mortality. Methods: Cohort studies published in peer-reviewed journals indexed in EMBASE and MEDLINE to September 2015 and PubMed to October 2015 and cited in reviews/key publications were identified via search strings using terms relating to study design, pollutant and health outcome. Study details and estimate information were extracted and used to calculate standardised effect estimates expressed as HRs per 10 ppb increment in long-term ozone concentrations. Results: 14 publications from 8 cohorts presented results for ozone and all-cause and cause-specific mortality. We found no evidence of associations between long-term annual O3 concentrations and the risk of death from all causes, cardiovascular or respiratory diseases, or lung cancer. 4 cohorts assessed ozone concentrations measured during the warm season. Summary HRs for cardiovascular and respiratory causes of death derived from 3 cohorts were 1.01 (95% CI 1.00 to 1.02) and 1.03 (95% CI 1.01 to 1.05) per 10 ppb, respectively. Conclusions: Our quantitative review revealed a paucity of independent studies regarding the associations between long-term exposure to ozone and mortality. The potential impact of climate change and increasing anthropogenic emissions of ozone precursors on ozone levels worldwide suggests further studies of the long-term effects of exposure to high ozone levels are warranted

Governance Indicators Can Make Sense: Under-five Mortality Rates are an Example

Governance indicators have come under fire in recent years, especially the World Governance Indicators (WGIs). Critics present these indicators as a-theoretical and biased. Critics of the critics counter that no better alternatives exist. We suggest otherwise, arguing that more appropriate ‘governance’ indicators will (i) have theoretical grounding, (ii) focus on specific fields of engagement, (iii) emphasize outcomes, and (iv) control for key contextual differences in comparing countries. Such measures can help indicate where countries seem to have governance problems, allowing second stage analyses of what these problems are. We present under national five mortality rates adjusted for country income groups as an example of such measure, presenting data for contextually controlled outcomes in this specific field to show where governance seems better and worse. The United States is shown up as relatively weak, whereas a country like Pakistan seems to have better governance in this sector than other low income countries. The indicator allows questions about why governance of this sector might be problematic in certain contexts and easier in others

Optimizing Multiple Simultaneous Objectives for Voting and Facility Location

We study the classic facility location setting, where we are given $n$ clients and $m$ possible facility locations in some arbitrary metric space, and want to choose a location to build a facility. The exact same setting also arises in spatial social choice, where voters are the clients and the goal is to choose a candidate or outcome, with the distance from a voter to an outcome representing the cost of this outcome for the voter (e.g., based on their ideological differences). Unlike most previous work, we do not focus on a single objective to optimize (e.g., the total distance from clients to the facility, or the maximum distance, etc.), but instead attempt to optimize several different objectives simultaneously. More specifically, we consider the $l$-centrum family of objectives, which includes the total distance, max distance, and many others. We present tight bounds on how well any pair of such objectives (e.g., max and sum) can be simultaneously approximated compared to their optimum outcomes. In particular, we show that for any such pair of objectives, it is always possible to choose an outcome which simultaneously approximates both objectives within a factor of $1+\sqrt{2}$, and give a precise characterization of how this factor improves as the two objectives being optimized become more similar. For $q>2$ different centrum objectives, we show that it is always possible to approximate all $q$ of these objectives within a small constant, and that this constant approaches 3 as $q\rightarrow \infty$. Our results show that when optimizing only a few simultaneous objectives, it is always possible to form an outcome which is a significantly better than 3 approximation for all of these objectives.Comment: To be published in the Proceedings of 37th Conference on Artificial Intelligence (AAAI 2023