Anti-proliferative but not anti-angiogenic tyrosine kinase inhibitors enrich for cancer stem cells in soft tissue sarcoma.

BackgroundIncreasing studies implicate cancer stem cells (CSCs) as the source of resistance and relapse following conventional cytotoxic therapies. Few studies have examined the response of CSCs to targeted therapies, such as tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs would have differential effects on CSC populations depending on their mechanism of action (anti-proliferative vs. anti-angiogenic).MethodsWe exposed human sarcoma cell lines to sorafenib, regorafenib, and pazopanib and assessed cell viability and expression of CSC markers (ALDH, CD24, CD44, and CD133). We evaluated survival and CSC phenotype in mice harboring sarcoma metastases after TKI therapy. We exposed dissociated primary sarcoma tumors to sorafenib, regorafenib, and pazopanib, and we used tissue microarray (TMA) and primary sarcoma samples to evaluate the frequency and intensity of CSC markers after neoadjuvant therapy with sorafenib and pazopanib. Parametric and non-parametric statistical analyses were performed as appropriate.ResultsAfter functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P < 0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P < 0.05). In contrast, we observed negligible effects on viability and CSC sub-populations with pazopanib. At low doses, there was progressive CSC enrichment in vitro after longer term exposure to sorafenib although the anti-proliferative effects were attenuated. In vivo, sorafenib improved median survival by 11 days (P < 0.05), but enriched ALDHbright cells 2.5 - 2.8 fold (P < 0.05). Analysis of primary human sarcoma samples revealed direct cytotoxicity following exposure to sorafenib and regorafenib with a corresponding increase in ALDHbright cells (P < 0.05). Again, negligible effects from pazopanib were observed. TMA analysis of archived specimens from sarcoma patients treated with sorafenib demonstrated significant enrichment for ALDHbright cells in the post-treatment resection specimen (P < 0.05), whereas clinical specimens obtained longitudinally from a patient treated with pazopanib showed no enrichment for ALDHbright cells (P > 0.05).ConclusionsAnti-proliferative TKIs appear to enrich for sarcoma CSCs while anti-angiogenic TKIs do not. The rational selection of targeted therapies for sarcoma patients may benefit from an awareness of the differential impact of TKIs on CSC populations

The Synthesis, Reduction, and Chlorination of 5-alkoxy-2,3-diphenylterephthalates

A series of alkoxy, phenylated terephthalates has been synthesized as monomer precursors to the corresponding poly(phenylene vinylene)s (PPV). The hydroxy, phenylated terephthalate was synthesized via: 1) a Diels-Alder cycloaddition between an ethynyl boronic ester and a cyclopentadienone (CPD) with subsequent hydrolysis/oxidation of the boronate ester or 2) a Diels-Alder cycloaddition between vinylene carbonate and CPD followed by thermolysis of the bridged adduct. The hydroxy, phenylated terephthalate was alkylated via a phase-transfer reaction with iodomethane, propargyl bromide, benzyl chloride, allyl bromide, and bromobutane to produce the alkoxy, phenylated terephthalates in yields from 38.6- 91.1%. The alkoxyterephthlates were reduced with lithium aluminum hydride to either the corresponding 5-alkoxy- (methoxy, benzyloxy) or 5-hydroxy-1,4-di(hydroxymethyl)-3,4-diphenylbenzene (allyloxy, propargyloxy) in yields from 40.9-94.0%. The methoxy and benzyloxy-1,4-di(hydroxymethyl)-3,4-diphenylbenzenes were reacted with thionyl chloride to yield the corresponding 1,4-di(chloromethyl)-3,4-diphenylbenzenes. The polymerization of 5-methoxy-1,4-di(chloromethyl)-3,4-diphenylbenzene with t-BuOK yielded the insoluble polymer 5-methoxy-2,3-diphenyl-1,4-poly(phenylene vinylene)

Anti-proliferative but not anti-angiogenic tyrosine kinase inhibitors enrich for cancer stem cells in soft tissue sarcoma

The templated zeolite-analogue GaPO-34 (CHA structure type) crystallises from a gel precursor Ga2O3:2H3PO4:1HF:1.7SDA:70H2O (where SDA = structure directing agent), treated hydrothermally for 24 hours at 170 °C using either pyridine or 1-methylimizadole as SDA and one of either poorly crystalline ε-Ga2O3 or γ-Ga2O3 as gallium precursor. If the same gels are stirred for periods shorter than 2 hours but treated under identical hydrothermal conditions, then a second phase crystallises, free of GaPO-34. If β-Ga2O3 is used as a reagent only the second phase is found to crystallise, irrespective of gel aging time. The competing phase, which we denote GaPO-34A, has been structurally characterised using synchrotron powder X-ray diffraction for the pyridine material, GaPO-34A(pyr), and using single-crystal X-ray diffraction for the 1-methylimiazole material, GaPO-34A(mim). The structure of GaPO-34A(pyr), P1 @#x0305;, a = 10.22682(6) Å, b = 12.09585(7) Å, c = 13.86713(8) Å, α = 104.6531(4) °, β = 100.8111(6) °, γ = 102.5228(6) °, contains 7 unique gallium sites and 6 phosphorus sites, with empirical formula [Ga7P6O24(OH)2F3(H2O)2].2(C5NH6). GaPO-34A(mim) is isostructural but is modelled as a half volume unit cell, P1 @#x0305;, a = 5.0991(2) Å, b = 12.0631(6) Å, c = 13.8405(9) Å, α = 104.626(5) °, β = 100.346(5) °, γ = 101.936(4) °, with a gallium and a bridging fluoride partially occupied and two partially occupied SDA sites. Solid-state 31P and 71Ga NMR spectroscopy confirms the structural complexity of GaPO-34A with signals resulting from overlapping lineshapes from multiple Ga and P sites, while 1H and 13C solid-state NMR spectra confirm the presence of the protonated SDA and provide evidence for disorder in the SDA. The protonated SDA is located in 14-ring one-dimensional channels with hydrogen bonding deduced from the SDA nitrogens to framework oxygen distances. Upon thermal treatment to investigate SDA removal, structure collapse occurs, which may be due the large number of bridging hydroxides and fluorides in the as-made material, and the unequal amounts of gallium and phosphorus present

Examining multi-sector women-only leadership development programs: a scoping review of recruitment processes, design and instruction methods, content and outcomes

Organisations are recognising that more needs to be done to support female talent. One response to this is women-only leadership development programmes (WLDPs). To date, no scoping review has previously been conducted to examine the design and outcomes of these programmes. The purpose of the present review was therefore to bring together current knowledge of these interventions. In June 2022, a scoping review of the academic literature was performed using Business Source Premier (EBSCO), PsycINFO and SCOPUS, resulting in 13 articles meeting the inclusion criteria. Findings indicate encouraging signs that these programmes support women's development through incorporating intersectionality and positive psychology theories, as well as curricula on networking, conflict management and career planning. Whilst the specifics about the design and delivered content of these theories are unclear, their inclusion appears to lead participants in the reviewed WLDPs to report increased self-awareness, clarity of purpose and enhanced feelings of authenticity. This review also raises questions regarding the rigour of the selection methods by which participants are given access to the programmes, and the transparent reporting of the design and delivery methodologies. Further, research directions and implications for both theory and practice are provided

First nation voices matter! Multi-level community consultations determine the design elements of a modified sport programme to promote healthy ageing in First Nation men

Public health faces the global impact of rising physical inactivity on health and quality of life. The link between physical activity and health is well recognized, however the effectiveness of health promoting physical activity and sport programmes in First Nation populations is unclear. Study objective: to identify appropriate programmes, design elements and potential participation barriers and enablers: aim to design a sport programme for Sunshine Coast dwelling First Nation Australian men. Qualitative data were collected from two participant groups of First Nation Australian men ≥ 18 years (n = 23) and analysed using descriptive summary and content analysis. Multi-level community consultation identified perceived enablers and barriers to participation and sport programme elements. The significant finding was the emergence of the sport programme design through First Nation voices, over multiple levels of community consultation, that facilitated the progression of the research project from stage two to stage three (sport programme implementation)

Techniques for valuing adaptive capacity in flood risk management

Flood and coastal erosion risk management has always faced the challenge of decision making in the face of multiple uncertainties relating to the climate, the economy and society. Traditionally, this has been addressed by adopting a precautionary approach that seeks to protect against a reasonable worst case. However, a managed adaptive approach can offer advantages. The benefits include improved resilience to negative changes, enabling opportunities from positive changes and greater cost effectiveness. The absence of clear methods and tools to value adaptive approaches has been recognised as an obstacle to wider adoption. This paper proposes a staged approach to building in adaptive capacity, which systematically analyses uncertainties, identifies opportunities to incorporate adaptability and appraises benefits through the analysis of decision trees. A case study is presented. The methodology is set in the context of appraisal processes used in England by the Environment Agency, based on cost–benefit analysis guidance issued by HM Treasury. The approach is transferable to other situations worldwide, where decision making is based on quantified assessment of costs and benefits. The work should help decision makers fully appraise the benefits of building in adaptive capacity and make the economic and technical case for adaptive flood risk management in an uncertain environment

Experiences of health professionals caring for people presenting to the emergency department after taking crystal methamphetamine ("ICE")

Globally addiction to 'ICE' (crystal methamphetamine) is increasing presenting emergency health care services personnel with a number of challenges. This paper reports the first of two major themes arising from a qualitative study investigating health professionals' experiences managing people presenting to the Emergency Department (ED) after taking 'ICE'. The theme 'Caring for people who use "ICE" when presenting to EDs' comprises five subthemes. These are: (i) expecting the unexpected: 'they are just off their heads'; (ii) complexity of care: 'underlying trauma and emotional dysregulation'; (iii) connecting and relationships: 'engaging in a calm and helpful way'; (iv) coordinating care and teamwork: 'keeping them quiet and away from everybody'; and (v) learning and reflection: 'we need to rethink our treatment options'. These findings highlight the complexity and resource-intensity associated with providing emergency care to persons affected by ICE, and the need for thoughtful strategies that can further develop the capacity and capability of health professionals to provide optimal care to people using ICE

Anti-schistosomal activities of quinoxaline-containing compounds:From hit identification to lead optimisation

Schistosomiasis is a neglected disease of poverty that is caused by infection with blood fluke species contained within the genus Schistosoma. For the last 40 years, control of schistosomiasis in endemic regions has predominantly been facilitated by administration of a single drug, praziquantel. Due to limitations in this mono-chemotherapeutic approach for sustaining schistosomiasis control into the future, alternative anti-schistosomal compounds are increasingly being sought by the drug discovery community. Herein, we describe a multi-pronged, integrated strategy that led to the identification and further exploration of the quinoxaline core as a promising anti-schistosomal scaffold

What has been learned about converting climate hazard data to climate risk information?

• Understanding climate risks requires consideration of the hazard, vulnerability and exposure. • The understanding and quantification of climate vulnerabilities is central to developing valuable assessments of future risks, with close communication between stakeholders and researchers crucial to achieving this. • Access to existing exposure and vulnerability data is highly frag-mented; a centralised authoritative repository, where such data could be combined with climate data, would widen access and facilitate research. • There is an ongoing need for multiple risk frameworks and tools to address the breadth of climate resilience issues. • The analysis of compound, cascading and systemic risks would benefit from more focus in the context of national scale risk assess-ments