Local government's roles in community health and wellbeing in Australia: Insights from Tasmania.

Issue Addressed: Local governments are well-placed to respond to communities' health and wellbeing needs. However, in the Australian state of Tasmania, the sector's roles in that respect are unclear.

Methods: We interviewed 10 municipal personnel in Tasmania to understand their views on local governments' community health and wellbeing functions.

Tracing memories and meanings of festival landscapes during the COVID-19 pandemic.

COVID-19 has deeply affected mass gatherings and travel and, in the process, has transformed festivals, festival landscapes, and people's sense of place in relation to such events. In this article we argue that it is important to better understand how people's memories of festival landscapes are affected by these larger shifts. We worked from the premise that information-rich cases could provide some initial insights in this respect.

Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma.

FGFR inhibition has been proposed as treatment for dedifferentiated liposarcoma (DDLPS) with amplified , but we previously only demonstrated transient cytostatic effects when treating -amplified DDLPS cells with NVP-BGJ398. Effects of the more potent FGFR inhibitor LY2874455 were investigated in three DDLPS cell lines by measuring effects on cell growth and apoptosis and also testing efficacy . Genome, transcriptome and protein analyses were performed to characterize the signaling components in the FGFR pathway.

Noninvasive Detection of ctDNA Reveals Intratumor Heterogeneity and Is Associated with Tumor Burden in Gastrointestinal Stromal Tumor.

Molecular analysis of circulating tumor DNA (ctDNA) has a large potential for clinical application by capturing tumor-specific aberrations through noninvasive sampling. In gastrointestinal stromal tumor (GIST), analysis of and mutations is important for therapeutic decisions, but the invasiveness of traditional biopsies limits the possibilities for repeated sampling. Using targeted next-generation sequencing, we have analyzed circulating cell-free DNA from 50 GIST patients.

Preclinical Evaluation of Vemurafenib as Therapy for BRAF Mutated Sarcomas.

Unlabelled: The BRAF mutation, which in melanoma is targetable with vemurafenib, is also found in sarcomas and we here evaluate the therapeutic potential in sarcoma cell lines.

Methods: Four sarcoma cell lines harboring the BRAFV600E mutation, representing liposarcomas (SA-4 and SW872), Ewing sarcoma (A673) and atypical synovial sarcoma (SW982), were treated with vemurafenib and the effects on cell growth, apoptosis, cell cycle progression and cell signaling were determined.

Results: Vemurafenib induced a strong cytostatic effect in SA-4 cells, mainly due to cell cycle arrest, whereas only moderate levels of apoptosis were observed.

Pml nuclear body disruption cooperates in APL pathogenesis and impairs DNA damage repair pathways in mice.

A hallmark of acute promyelocytic leukemia (APL) is altered nuclear architecture, with disruption of promyelocytic leukemia (PML) nuclear bodies (NBs) mediated by the PML-retinoic acid receptor α (RARα) oncoprotein. To address whether this phenomenon plays a role in disease pathogenesis, we generated a knock-in mouse model with NB disruption mediated by 2 point mutations (C62A/C65A) in the Pml RING domain. Although no leukemias developed in Pml mice, these transgenic mice also expressing RARα linked to a dimerization domain (p50-RARα model) exhibited a doubling in the rate of leukemia, with a reduced latency period.

Analysis of the miR-34 family functions in breast cancer reveals annotation error of miR-34b.

The microRNAs in the miR-34 family, consisting of miR-34a, miR-34b and miR-34c, are tumour suppressors. The annotated human miR-34b-5p has one additional base at the 5' end of the common miR-34 family seed sequence, compared to miR-34a-5p and miR-34c-5p. This extra base results in a shift of the seed sequence, which would affect the target gene repertoire and have functional consequences.

A PML/Slit Axis Controls Physiological Cell Migration and Cancer Invasion in the CNS.

Cell migration through the brain parenchyma underpins neurogenesis and glioblastoma (GBM) development. Since GBM cells and neuroblasts use the same migratory routes, mechanisms underlying migration during neurogenesis and brain cancer pathogenesis may be similar. Here, we identify a common pathway controlling cell migration in normal and neoplastic cells in the CNS.

Monogenic and polygenic determinants of sarcoma risk: an international genetic study.

Background: Sarcomas are rare, phenotypically heterogeneous cancers that disproportionately affect the young. Outside rare syndromes, the nature, extent, and clinical significance of their genetic origins are not known. We aimed to investigate the genetic basis for bone and soft-tissue sarcoma seen in routine clinical practice.

Preclinical evaluation of potential therapeutic targets in dedifferentiated liposarcoma.

Sarcomas are rare cancers with limited treatment options. Patients are generally treated by chemotherapy and/or radiotherapy in combination with surgery, and would benefit from new personalized approaches. In this study we demonstrate the potential of combining personal genomic characterization of patient tumors to identify targetable mutations with in vitro testing of specific drugs in patient-derived cell lines.

HSP90 inhibition blocks ERBB3 and RET phosphorylation in myxoid/round cell liposarcoma and causes massive cell death in vitro and in vivo.

Myxoid sarcoma (MLS) is one of the most common types of malignant soft tissue tumors. MLS is characterized by the FUS-DDIT3 or EWSR1-DDIT3 fusion oncogenes that encode abnormal transcription factors. The receptor tyrosine kinase (RTK) encoding RET was previously identified as a putative downstream target gene to FUS-DDIT3 and here we show that cultured MLS cells expressed phosphorylated RET together with its ligand Persephin.

Metabolic reprogramming of metastatic breast cancer and melanoma by let-7a microRNA.

Let-7 microRNAs (miRNAs) are highly conserved well-established promoters of terminal differentiation that are expressed in healthy adult tissues and frequently repressed in cancer cells. The tumor suppressive role of let-7 in a variety of cancers in vitro and in vivo has been widely documented and prompted these miRNAs to be candidate genes for miRNA replacement therapy. In this study we described a new role of let-7a in reprogramming cancer metabolism, recently identified as a new hallmark of cancer.

Functional genomics analysis reveals a MYC signature associated with a poor clinical prognosis in liposarcomas.

Liposarcomas, which are malignant fatty tumors, are the second most common soft-tissue sarcomas. Several histologically defined liposarcoma subtypes exist, yet little is known about the molecular pathology that drives the diversity in these tumors. We used functional genomics to classify a panel of diverse liposarcoma cell lines based on hierarchical clustering of their gene expression profiles, indicating that liposarcoma gene expression profiles and histologic classification are not directly correlated.

The tankyrase-specific inhibitor JW74 affects cell cycle progression and induces apoptosis and differentiation in osteosarcoma cell lines.

Wnt/β-catenin is a major regulator of stem cell self-renewal and differentiation and this signaling pathway is aberrantly activated in a several cancers, including osteosarcoma (OS). Attenuation of Wnt/β-catenin activity by tankyrase inhibitors is an appealing strategy in treatment of OS. The efficacy of the tankyrase inhibitor JW74 was evaluated in three OS cell lines (KPD, U2OS, and SaOS-2) both at the molecular and functional level.

Epigenetic regulation and functional characterization of microRNA-142 in mesenchymal cells.

The transcripts encoded by the microRNA mir-142 gene are highly active in hematopoietic cells, but expressed at low levels in many other cell types. Treatment with the demethylating agent 5-Aza-2'-deoxycytidine increased both the 1,636 nucleotide primary transcript and mature miR-142-5p/3p in mesenchymal cells, indicating that mir-142 is epigenetically repressed by DNA methylation. The transcription start site was determined to be located 1,205 base pairs upstream of the precursor sequence within a highly conserved CpG island.

Functional characterisation of osteosarcoma cell lines and identification of mRNAs and miRNAs associated with aggressive cancer phenotypes.

Background: Osteosarcoma is the most common primary malignant bone tumour, predominantly affecting children and adolescents. Cancer cell line models are required to understand the underlying mechanisms of tumour progression and for preclinical investigations.

Methods: To identify cell lines that are well suited for studies of critical cancer-related phenotypes, such as tumour initiation, growth and metastasis, we have evaluated 22 osteosarcoma cell lines for in vivo tumorigenicity, in vitro colony-forming ability, invasive/migratory potential and proliferation capacity.

Photochemical internalization of CD133-targeting immunotoxins efficiently depletes sarcoma cells with stem-like properties and reduces tumorigenicity.

Background: The normal stem cell marker CD133 is also a putative marker of cancer stem cells (CSCs) in different types of cancers. Hence, a major challenge when targeting CD133-expressing CSCs is to prevent depletion of the normal stem cell pool. We hypothesized that the site-specific and light-controlled drug delivery method photochemical internalization (PCI) may have the potential to enhance selectivity and endosomal escape of CD133-targeting immunotoxins in stem-like sarcoma cells.

Characterization of liposarcoma cell lines for preclinical and biological studies.

Liposarcoma cell lines represent in vitro models for studying disease mechanisms at the cellular level and for preclinical evaluation of novel drugs. To date there are a limited number of well-characterized models available. In this study, nine immortal liposarcoma cell lines were evaluated for tumor-forming ability, stem cell- and differentiation potential, and metastatic potential, with the aim to generate a well-characterized liposarcoma cell line panel.

Liposarcoma Cells with Aldefluor and CD133 Activity have a Cancer Stem Cell Potential.

Aldehyde dehydrogenase (ALDH) has recently been shown to be a marker of cancer stem-like cells (CSCs) across tumour types. The primary goals of this study were to investigate whether ALDH is expressed in liposarcomas, and whether CSCs can be identified in the ALDHhigh subpopulation. We have demonstrated that ALDH is indeed expressed in 10 out of 10 liposarcoma patient samples.

Involvement of 5-HT receptors in the regulation of food intake in Siberian hamsters.

The Siberian hamster provides a physiological model for understanding the hypothalamic control of energy metabolism as it undergoes annual photoperiod-regulated cycles of body weight (i.e. fattening in summer, and catabolism of fat stores in winter).

Capital assets and intercultural borderlands: socio-cultural challenges for natural resource management.

In their design or implementation, many natural resource management (NRM) programs ignore critical socio-cultural dimensions of the challenge to advance sustainability. Building on particular ideas about culture and human ecosystems, we combine the strengths of the capital assets model of sustainability and the idea of intercultural borderlands to respond to this gap. To advance our thesis about the utility of these tools, we critically reviewed and analysed a cross-disciplinary literature relating to the socio-cultural dimensions of NRM.

Health and nature in the 19th century Australian women's popular press.

This paper asks how health and nature are represented in the Australian women's press during the late nineteenth century. A time of significant social change during which women, and sympathetic male colleagues, challenged traditional roles as pathological creatures of the domestic sphere, this period is explored through the writing of women working for popular magazines. As women captured, transformed and redeployed stereotypical views of them as essentially and naturally ill, they consolidated their push into the public realm, while also convincing themselves and others of their vital place in the private sphere, but as capable, well and fit creators of people and of a nation.

Synthesis of aminomethyl-substituted cyclic imide derivatives for evaluation as anticonvulsants.

A series of aminomethyl-substituted cyclic imides (II) based on the 2,5-pyrrolidinedione (X = CH2, succinimide) and 2,4-imidazolidinedione (X = NH, hydantoin) ring systems have been prepared. The compounds were designed on the basis of a potential interaction in the gamma-aminobutyric acid (GABA) neurotransmitter system and evaluated for anticonvulsant activity. The 3-(aminomethyl)-2,5-pyrrolidinediones were prepared by a dehydration procedure beginning with N-benzyl-2-(aminomethyl)succinic acid, whereas the 3-(aminomethyl)-3-methyl-2,3-pyrrolidinediones were best obtained by fusion of the amine salts of 2-(aminomethyl)-2-methylsuccinic acid.

Synthesis and biological activity of cocaine analogues. 2. 6H-[2]Benzopyrano[4,3-c]pyridin-6-ones.

1,2,3,4-Tetrahydro-2-methyl-6H-[2]benzopyrano[4,3-c]pyridin-6-one (20) and cis- and trans-1,2,3,4,4a,10b-hexahydro-2-methyl-6H-[2]benzopyrano[4,3-c]pyridin-6-one (3a and 3b) were synthesized. The design of 3b was based on the proposal that the active conformation of cocaine is one in which the phenyl and amino groups are arranged in a manner that will superimpose upon a beta-phenethylamine in a trans-staggered conformation. The compounds were compared with cocaine and tropacocaine for their ability to inhibit uptake of [3H]norepinephrine by rat brain synaptosomal preparations.