Efficacy of aerobic and resistance exercises on cancer pain: A meta-analysis of randomised controlled trials.

Purpose: To evaluate effects of aerobic and resistance exercises for cancer-related pain in adults with and surviving cancer. Secondary objectives were to a) evaluate the effect of exercise on fatigue, psychological function, physical function, b) assess fidelity to exercise. Design: A systematic search of MEDLINE, EMBASE, AMED, CINAHL and Cochrane Central Register of Controlled Trials was conducted to identify randomised controlled trials (RCTs) comparing aerobic and/or resistance exercise to control groups. The primary endpoint were changes in cancer-related pain intensity from baseline to post intervention. Meta-regression analysis evaluated predictors for heterogeneity between study findings. Tolerability was defined as reporting of exercise-induced adverse events while fidelity evaluated by reported intervention dropout. Results: Twenty-three RCTs including 1954 patients (age 58 ± 8.5 years; 78 % women); 1087 (56 %) and 867 (44 %) allocated to aerobic/resistance exercise therapy and control group, respectively. Exercise therapy was associated with small to moderate decreases in cancer-related pain compared to controls (SMD = 0.38, 95 % CI: 0.17, 0.58). Although there was significant heterogeneity between individual and pooled study effects (Q = 205.25, p < 0.0001), there was no publication bias. Meta-regression including supervision, age, duration and exercise type as moderators showed no significant differences in reported outcomes. Analysis of secondary outcomes revealed a moderate effect for improvements in physical function, fatigue and psychological symptoms. Conclusions: Aerobic and resistance exercises are tolerable and effective adjunct therapies to reduce cancer-related pain while also improving physical function, fatigue and mood. Future RCTs of dose, frequency, compliance and exercise type in specific cancer settings are required.

Modulation of the pre-metastatic bone niche: molecular changes mediated by bone-homing prostate cancer extracellular vesicles.

Prostate cancer (PCa) is a leading male malignancy worldwide, often progressing to bone metastasis, with limited curative options. Extracellular vesicles (EVs) have emerged as key players in cancer communication and metastasis, promoting the formation of supportive microenvironments in distant sites. Our previous studies have highlighted the role of PCa EVs in modulating osteoblasts and facilitating tumor progression. However, the early pre-metastatic changes induced by PCa EVs within the bone microenvironment remain poorly understood. To investigate the early effects of repeated exposure to PCa EVs in vivo, mimicking EVs being shed from the primary tumor, PCa EVs isolated from cell line PC3MLuc2a were fluorescently labelled and repeatedly administered via tail vein injection to adult CD1 NuNu male mice for a period of 4 weeks. In vivo imagining, histological analysis and gene expression profiling were performed to assess the impact of PCa EVs on the bone microenvironment. We demonstrate for the first time that PCa EVs home to both bone and lymph nodes following repeated exposures. Furthermore, the accumulation of EVs within the bone leads to distinct molecular changes indicative of disrupted bone homeostasis (e.g., changes to signaling pathways such as Paxillin p = 0.0163, Estrogen Receptor p = 0.0271, RHOA p = 0.0287, Ribonucleotide reductase p = 0.0307 and ERK/MAPK p = 0.0299). Changes in key regulators of these pathways were confirmed in vitro on human osteoblasts. In addition, our data compares the known gene signature of osteocytes and demonstrates a high proportion of overlap (52.2%), suggesting a potential role for this cell type in response to PCa EV exposure. No changes in bone histology or immunohistochemistry were detected, indicating that PCa EV mediated changes were induced at the molecular level. This study provides novel insights into the alterations induced by PCa EVs on the bone microenvironment. The observed molecular changes indicate changes in key pathways and suggest a role for osteocytes in these EV mediated early changes to bone. Further research to understand these early events may aid in the development of targeted interventions to disrupt the metastatic cascade in PCa.

Application of a 3D hydrogel-based model to replace use of animals for passaging patient-derived xenografts.

Purpose: This 3D in vitro cancer model for propagation of patient-derived cells, using a synthetic self-assembling peptide gel, allows the formation of a fully characterised, tailorable tumour microenvironment. Unlike many existing 3D cancer models, the peptide gel is inert, apart from molecules and motifs deliberately added or produced by cells within the model. Methods: Breast cancer patient-derived xenografts (PDXs) were disaggregated and embedded in a peptide hydrogel. Growth was monitored by microscopic examination and at intervals, cells were extracted from the gels and passaged on into fresh gels. Passaged cells were assessed by qPCR and immunostaining techniques for the retention of characteristic markers. Results: Breast cancer PDXs were shown to be capable of expansion over four or more passages in the peptide gel. Contaminating mouse cells were found to be rapidly removed by successive passages. The resulting human cells were shown to be compatible with a range of common assays useful for assessing survival, growth and maintenance of heterogeneity. Conclusions: Based on these findings, the hydrogel has the potential to provide an effective and practical breast cancer model for the passage of PDXs which will have the added benefits of being relatively cheap, fully-defined and free from the use of animals or animal products. Encapsulated cells will require further validation to confirm the maintenance of cell heterogeneity, genotypes and phenotypes across passage, but with further development, including the addition of bespoke cell and matrix components of the tumour microenvironment, there is clear potential to model other cancer types. Supplementary Information: The online version contains supplementary material available at 10.1007/s44164-023-00048-x.

Chain-extension in hyperbranched polymers alters tissue distribution and cytotoxicity profiles in orthotopic models of triple negative breast cancers.

The therapeutic efficacy of nanomedicines is highly dependent on their access to target sites in the body, and this in turn is markedly affected by their size, shape and transport properties in tissue. Although there have been many studies in this area, the ability to design nanomaterials with optimal physicochemical properties for in vivo efficacy remains a significant challenge. In particular, it is often difficult to quantify the detailed effects of cancer drug delivery systems in vivo as tumour volume reduction, a commonly reported marker of efficacy, does not always correlate with cytotoxicity in tumour tissue. Here, we studied the behaviour in vivo of two specific poly(2-hydroxypropyl methacrylamide) (pHPMA) pro-drugs, with hyperbranched and chain-extended branched architectures, redox-responsive backbone components, and pH-sensitive linkers to the anti-cancer drug doxorubicin. Evaluation of the biodistribution of these polymers following systemic injection indicated differences in the circulation time and organ distribution of the two polymers, despite their very similar hydrodynamic radii (∼10 and 15 nm) and architectures. In addition, both polymers showed improved tumour accumulation in orthotopic triple-negative breast cancers in mice, and decreased accumulation in healthy tissue, as compared to free doxorubicin, even though neither polymer-doxorubicin pro-drug decreased overall tumour volume as much as the free drug under the dosing regimens selected. However, the results of histopathological examinations by haematoxylin and eosin, and TUNEL staining indicated a higher population of apoptotic cells in the tumours for both polymer pro-drug treatments, and in turn a lower population of apoptotic cells in the heart, liver and spleen, as compared to free doxorubicin treatment. These data suggest that the penetration of these polymer pro-drugs was enhanced in tumour tissue relative to free doxorubicin, and that the combination of size, architecture, bioresponsive backbone and drug linker degradation yielded greater efficacy for the polymers as measured by biomarkers than that of tumour volume. We suggest therefore that the effects of nanomedicines may be different at various length scales relative to small molecule free drugs, and that penetration into tumour tissue for some nanomedicines may not be as problematic as prior reports have suggested. Furthermore, the data indicate that dual-responsive crosslinked polymer-prodrugs in this study may be effective nanomedicines for breast cancer chemotherapy, and that endpoints beyond tumour volume reduction can be valuable in selecting candidates for pre-clinical trials.

Selective Killing of BRCA2-Deficient Ovarian Cancer Cells via MRE11 Blockade.

The MRE11 nuclease is essential during DNA damage recognition, homologous recombination, and replication. BRCA2 plays important roles during homologous recombination and replication. Here, we show that effecting an MRE11 blockade using a prototypical inhibitor (Mirin) induces synthetic lethality (SL) in BRCA2-deficient ovarian cancer cells, HeLa cells, and 3D spheroids compared to BRCA2-proficient controls. Increased cytotoxicity was associated with double-strand break accumulation, S-phase cell cycle arrest, and increased apoptosis. An in silico analysis revealed Mirin docking onto the active site of MRE11. While Mirin sensitises DT40 MRE11+/- cells to the Top1 poison SN-38, it does not sensitise nuclease-dead MRE11 cells to this compound confirming that Mirin specifically inhibits Mre11 nuclease activity. MRE11 knockdown reduced cell viability in BRCA2-deficient PEO1 cells but not in BRCA2-proficient PEO4 cells. In a Mirin-resistant model, we show the downregulation of 53BP1 and DNA repair upregulation, leading to resistance, including in in vivo xenograft models. In a clinical cohort of human ovarian tumours, low levels of BRCA2 expression with high levels of MRE11 co-expression were linked with worse progression-free survival (PFS) (p = 0.005) and overall survival (OS) (p = 0.001). We conclude that MRE11 is an attractive SL target, and the pharmaceutical development of MRE11 inhibitors for precision oncology therapeutics may be of clinical benefit.

Improving Seed Morphology and Germination Potential in Australian Native Grasses Using Seed Enhancement Technologies.

Difficult to handle seed material and poor germination commonly limit the uptake of native grasses in restoration and commercial-scale seeding efforts. Seed enhancement technologies (SETs) offer valuable solutions for improving the handling of seed material and optimising germination. This study considered eight widespread Australian native grasses; two representative of Mediterranean to temperate climates ('cool-climate' species) and six representative of arid to subtropical climates ('warm-climate' species). Through a series of experiments, this study logically selected and applied SET treatments to improve seed handling and germination for each study species. Seed handling was prioritised and addressed using flash flaming and/or acid digestion, while hydropriming was used following seed-handling treatments to enhance germination. Flash flaming and acid digestion were both applied to successfully reduce or remove bulky floret structures while maintaining or improving germination. Flaming at 110 ± 10 °C with continuous exposure for 10 min and acid digestion concentrations of 75-80% with exposure times of 1-2.5 min were generally successful. Sub-optimal concentrations of sulphuric acid often compromised germination. Hydropriming did not improve germination outcomes when applied following flaming or acid digestion. Optimising SETs for germination, emergence and establishment in different environments, and the viability and costs of application on larger seed batches are key considerations for the implementation and upscaling of SETs in the future.

Ecological restoration in the age of apocalypse.

Billions of dollars are spent annually on ecological restoration efforts around the world and yet successful attainment of restoration targets still falls short in many regions. Globally, ecosystem restoration is becoming increasingly challenged with changes in climate. Years with extreme climatic events that limit plant establishment, such as severe drought, heatwaves, and floods are projected to increase in frequency. A critical evaluation of current ecological restoration practices and changes to those practices are needed to attain global restoration targets. For plant restoration, many efforts globally focus on planting in a single year following disturbance. The odds of restoration efforts being conducted in a year that is inconducive to plant establishment may be calculated using climatic risk data. We propose a risk-mitigation approach to restoration wherein plantings are conducted across multiple years for projects in a bet-hedging strategy and evaluated through an adaptive management approach.

Clinically Translatable Transcrocetin Delivery Platform for Correction of Tumor Hypoxia and Enhancement of Radiation Therapy Effects.

Improving the tumor reoxygenation to sensitize the tumor to radiation therapy is a cornerstone in radiation oncology. Here, the pre-clinical development of a clinically transferable liposomal formulation encapsulating trans sodium crocetinate (NP TSC) is reported to improve oxygen diffusion through the tumor environment. Early pharmacokinetic analysis of the clinical trial of this molecule performed on 37 patients orient to define the optimal fixed dosage to use in a triple-negative breast cancer model to validate the therapeutic combination of radiation therapy and NP TSC. Notably, it is reported that this formulation is non-toxic in both humans and mice at the defined fixed concentration, provides a normalization of the tumor vasculature within 72 h window after systemic injection, leads to a transient increase (50% improvement) in the tumor oxygenation, and significantly improves the efficacy of both mono-fractionated and fractionated radiation therapy treatment. Together, these findings support the introduction of a first-in-class therapeutic construct capable of tumor-specific reoxygenation without associated toxicities.

Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts.

The chemotherapy resistance of esophageal adenocarcinomas (EACs) is underpinned by cancer cell extrinsic mechanisms of the tumor microenvironment (TME). We demonstrate that, by targeting the tumor-promoting functions of the predominant TME cell type, cancer-associated fibroblasts (CAFs) with phosphodiesterase type 5 inhibitors (PDE5i), we can enhance the efficacy of standard-of-care chemotherapy. In ex vivo conditions, PDE5i prevent the transdifferentiation of normal fibroblasts to CAF and abolish the tumor-promoting function of established EAC CAFs. Using shotgun proteomics and single-cell RNA-seq, we reveal PDE5i-specific regulation of pathways related to fibroblast activation and tumor promotion. Finally, we confirm the efficacy of PDE5i in combination with chemotherapy in close-to-patient and in vivo PDX-based model systems. These findings demonstrate that CAFs drive chemotherapy resistance in EACs and can be targeted by repurposing PDE5i, a safe and well-tolerated class of drug administered to millions of patients world-wide to treat erectile dysfunction.

Synthesis, characterisation and evaluation of hyperbranched N-(2-hydroxypropyl) methacrylamides for transport and delivery in pancreatic cell lines in vitro and in vivo.

Hyperbranched polymers have many promising features for drug delivery, owing to their ease of synthesis, multiple functional group content, and potential for high drug loading with retention of solubility. Here we prepared hyperbranched N-(2-hydroxypropyl)methacrylamide (HPMA) polymers with a range of molar masses and particle sizes, and with attached dyes, radiolabel or the anticancer drug gemcitabine. Reversible addition-fragmentation chain transfer (RAFT) polymerisation enabled the synthesis of pHPMA polymers and a gemcitabine-comonomer functionalised pHPMA polymer pro-drug, with diameters of the polymer particles ranging from 7-40 nm. The non-drug loaded polymers were well-tolerated in cancer cell lines and macrophages, and were rapidly internalised in 2D cell culture and transported efficiently to the centre of dense pancreatic cancer 3D spheroids. The gemcitabine-loaded polymer pro-drug was found to be toxic both to 2D cultures of MIA PaCa-2 cells and also in reducing the volume of MIA PaCa-2 spheroids. The non-drug loaded polymers caused no short-term adverse effects in healthy mice following systemic injection, and derivatives of these polymers labelled with 89Zr-were tracked for their distribution in the organs of healthy and MIA PaCa-2 xenograft bearing Balb/c nude mice. Tumour accumulation, although variable across the samples, was highest in individual animals for the pHPMA polymer of ∼20 nm size, and accordingly a gemcitabine pHPMA polymer pro-drug of ∼18 nm diameter was evaluated for efficacy in the tumour-bearing animals. The efficacy of the pHPMA polymer pro-drug was very similar to that of free gemcitabine in terms of tumour growth retardation, and although there was a survival benefit after 70 days for the polymer pro-drug, there was no difference at day 80. These data suggest that while polymer pro-drugs of this type can be effective, better tumour targeting and enhanced in situ release remain as key obstacles to clinical translation even for relatively simple polymers such as pHPMA.

Targeting hypoxia regulated sodium driven bicarbonate transporters reduces triple negative breast cancer metastasis.

Regions of low oxygen (hypoxia) are found in >50% of breast tumours, most frequently in the more aggressive triple negative breast cancer subtype (TNBC). Metastasis is the cause of 90% of breast cancer patient deaths. Regions of tumour hypoxia tend to be more acidic and both hypoxia and acidosis increase tumour metastasis. In line with this the metastatic process is dependent on pH regulatory mechanisms. We and others have previously identified increased hypoxic expression of Na+ driven bicarbonate transporters (NDBTs) as a major mechanism of tumour pH regulation. Hypoxia induced the expression of NDBTs in TNBC, most frequently SLC4A4 and SLC4A5. NDBT inhibition (S0859) and shRNA knockdown suppressed migration (40% reduction) and invasion (70% reduction) in vitro. Tumour xenograft metastasis in vivo was significantly reduced by NDBT knockdown. To investigate the mechanism by which NDBTs support metastasis, we investigated their role in regulation of phospho-signalling, epithelial-to-mesenchymal transition (EMT) and metabolism. NDBT knockdown resulted in an attenuation in hypoxic phospho-signalling activation; most notably LYN (Y397) reduced by 75%, and LCK (Y394) by 72%. The metastatic process is associated with EMT. We showed that NDBT knockdown inhibited EMT, modulating the expression of key EMT transcription factors and ablating the expression of vimentin whilst increasing the expression of E-cadherin. NDBT knockdown also altered metabolic activity reducing overall ATP and extracellular lactate levels. These results demonstrate that targeting hypoxia-induced NDBT can be used as an approach to modulate phospho-signalling, EMT, and metabolic activity and reduce tumour migration, invasion, and metastasis in vivo.

Restored and remnant Banksia woodlands elicit different foraging behavior in avian pollinators.

Pollinators and the pollination services they provide are critical for seed set and self-sustainability of most flowering plants. Despite this, pollinators are rarely assessed in restored plant communities, where their services are largely assumed to re-establish. Bird-pollinator richness, foraging, and interaction behavior were compared between natural and restored Banksia woodland sites in Western Australia to assess their re-establishment in restored sites. These parameters were measured for natural communities of varying size and degree of fragmentation, and restored plant communities of high and low complexity for three years, in the summer and winter flowering of Banksia attenuata and B. menziesii, respectively. Bird visitor communities varied in composition, richness, foraging movement distances, and aggression among sites. Bird richness and abundance were lowest in fragmented remnants. Differences in the composition were associated with the size and degree of fragmentation in natural sites, but this did not differ between seasons. Restored sites and their adjacent natural sites had similar species composition, suggesting proximity supports pollinator re-establishment. Pollinator foraging movements were influenced by the territorial behavior of different species. Using a network analysis approach, we found foraging behavior varied, with more frequent aggressive chases observed in restored sites, resulting in more movements out of the survey areas, than observed in natural sites. Aggressors were larger-bodied Western Wattlebirds (Anthochaera chrysoptera) and New Holland Honeyeaters (Phylidonyris novaehollandiae) that dominated nectar resources, particularly in winter. Restored sites had re-established pollination services, albeit with clear differences, as the degree of variability in the composition and behavior of bird pollinators for Banksias in the natural sites created a broad completion target against which restored sites were assessed. The abundance, diversity, and behavior of pollinator services to remnant and restored Banksia woodland sites were impacted by the size and degree of fragmentation, which in turn influenced bird-pollinator composition, and were further influenced by seasonal changes between summer and winter. Consideration of the spatial and temporal landscape context of restored sites, along with plant community diversity, is needed to ensure the maintenance of the effective movement of pollinators between natural remnant woodlands and restored sites.

A global review of seed enhancement technology use to inform improved applications in restoration.

Seed-based restoration often experiences poor success due to a range of edaphic and biotic issues. Seed enhancement technologies (SETs) are a novel approach that can alleviate these pressures and improve restoration success. Broadly, SETs have been reviewed for agricultural and horticultural purposes, for specific types of SETs such as coating or priming, or for focal ecosystems. However, information is lacking for SETs within a restoration focused context, and how they are being used to alleviate certain barriers. This review aimed to synthesise the current literature on SETs to understand what SETs are being tested, in which sectors and locations they are being tested, what issues are faced within restoration using SETs, and how SETs are being used to approach these issues. Priming was highlighted as the main SET investigated. Inoculation, pesticide application and magnetic fields were also commonly tested (SETs we termed 'prospective techniques'). SET research mainly occurred in the agricultural sector. More recently, other sectors, such as restoration and rangeland management, have increased efforts into SET research. The restoration sector has focused on extruded pelleting and coating (with activated carbon), in combination with herbicide application, to overcome invasive species, and coating with certain additives to alleviate edaphic issues. Other sectors outside restoration were largely focused on evaluating priming for overcoming these barriers. The majority of priming research has been completed on crop species and differences between these species and ecosystems must be considered in future restoration efforts that focus on native seed use. Generally, SETs require further refinement, including identifying ideal additives and their optimum concentrations to target certain issues, refining formulations for coating and extruded pelleting and developing flash flaming. A bet-hedging approach using multiple SETs and/or combinations of SETs may be advantageous in overcoming a wide range of barriers in seed-based restoration.

ABCB1 inhibition provides a novel therapeutic target to block TWIST1-induced migration in medulloblastoma.

BACKGROUND: Therapeutic intervention in metastatic medulloblastoma is dependent on elucidating the underlying metastatic mechanism. We investigated whether an epithelial-mesenchymal transition (EMT)-like pathway could drive medulloblastoma metastasis. METHODS: A 3D Basement Membrane Extract (3D-BME) model was used to investigate medulloblastoma cell migration. Cell line growth was quantified with AlamarBlue metabolic assays and the morphology assessed by time-lapse imaging. Gene expression was analyzed by qRT-PCR and protein expression by immunohistochemistry of patient tissue microarrays and mouse orthotopic xenografts. Chromatin immunoprecipitation was used to determine whether the EMT transcription factor TWIST1 bound to the promoter of the multidrug pump ABCB1. TWIST1 was overexpressed in MED6 cells by lentiviral transduction (MED6-TWIST1). Inhibition of ABCB1 was mediated by vardenafil, and TWIST1 expression was reduced by either Harmine or shRNA. RESULTS: Metastatic cells migrated to form large metabolically active aggregates, whereas non-tumorigenic/non-metastatic cells formed small aggregates with decreasing metabolic activity. TWIST1 expression was upregulated in the 3D-BME model. TWIST1 and ABCB1 were significantly associated with metastasis in patients (P = .041 and P = .04, respectively). High nuclear TWIST1 expression was observed in the invasive edge of the MED1 orthotopic model, and TWIST1 knockdown in cell lines was associated with reduced cell migration (P < .05). TWIST1 bound to the ABCB1 promoter (P = .03) and induced cell aggregation in metastatic and TWIST1-overexpressing, non-metastatic (MED6-TWIST1) cells, which was significantly attenuated by vardenafil (P < .05). CONCLUSIONS: In this study, we identified a TWIST1-ABCB1 signaling axis during medulloblastoma migration, which can be therapeutically targeted with the clinically approved ABCB1 inhibitor, vardenafil.

"A good death but there was all this tension around"- perspectives of residential managers on the experience of delivering end of life care for people living with dementia.

BACKGROUND: End of life care for residents with advanced dementia in the aged care setting is complex. There is prolonged and progressive cognitive decline, uncertain disease trajectory, significant symptom burden and infrequent access to specialist palliative care. Residential aged care managers offer a unique perspective in understanding the experience of providing end of life care for residents with advanced dementia. They bring insight from the coalface to the broader policy context. The aim of this study was to describe the experience and perspectives of residential aged care managers on providing end of life care for residents living with dementia. METHODS: Focus groups and semi-structured interviews were conducted with residential or care managers from various care homes from one dementia specific aged care organisation in Australia. A comprehensive sampling strategy was used in participating care homes. Transcripts were analysed using thematic analysis. RESULTS: 20 residential or care managers from 11 aged care homes in two states of Australia participated in two focus groups (total 16 participants) or individual interviews (4 participants). Six themes were identified: laying the ground work to establish what families understand about dementia, playing the peacemaker in the face of unrealistic family demands and expectations, chipping away at denial and cultivating a path towards acceptance of death, recruiting general practitioners as allies, supporting and strengthening the front line, and dedication to optimal care is relentless but rewarding. CONCLUSION: Aged care manager participants described provision of end of life dementia care as a rewarding but sometimes fraught experience requiring persistent personalisation of care and communication to enable family acceptance of the resident's terminal condition. The findings suggest that continuous front line aged care staff skill development, iterative family discussions, and partnership building between aged care staff and general practitioners, are all required to promote optimal end of life dementia care in residential aged care settings.

METTL3 Regulates Angiogenesis by Modulating let-7e-5p and miRNA-18a-5p Expression in Endothelial Cells.

[Figure: see text].

Corrigendum to: ABCB1 inhibition provides a novel therapeutic target to block TWIST1-induced migration in medulloblastoma.

[This corrects the article DOI: 10.1093/noajnl/vdab030.].

Synthesis of Passerini-3CR Polymers and Assembly into Cytocompatible Polymersomes.

The versatility of the Passerini three component reaction (Passerini-3CR) is herein exploited for the synthesis of an amphiphilic diblock copolymer, which self-assembles into polymersomes. Carboxy-functionalized poly(ethylene glycol) methyl ether is reacted with AB-type bifunctional monomers and tert-butyl isocyanide in a single process via Passerini-3CR. The resultant diblock copolymer (P1) is obtained in good yield and molar mass dispersity and is well tolerated in model cell lines. The Passerini-3CR versatility and reproducibility are shown by the synthesis of P2, P3, and P4 copolymers. The ability of the Passerini P1 polymersomes to incorporate hydrophilic molecules is verified by loading doxorubicin hydrochloride in P1DOX polymersomes. The flexibility of the synthesis is further demonstrated by simple post-functionalization with a dye, Cyanine-5 (Cy5). The obtained P1-Cy5 polymersomes rapidly internalize in 2D cell monolayers and penetrate deep into 3D spheroids of MDA-MB-231 triple-negative breast cancer cells. P1-Cy5 polymersomes injected systemically in healthy mice are well tolerated and no visible adverse effects are seen under the conditions tested. These data demonstrate that new, biodegradable, biocompatible polymersomes having properties suitable for future use in drug delivery can be easily synthesized by the Passerini-3CR.

Flash Flaming Improves Flow Properties of Mediterranean Grasses Used for Direct Seeding.

The demand for native grasses is increasing in restoration and agriculture, though their use is often limited due to seed handling challenges. The external structures surrounding the grass seed (i.e., the floret) possess hairs, awns, and appendages which create blockages in conventional seeding equipment. Flash flaming is a patented technology which allows precision exposure of floret material to flames to singe off hairs and appendages. We used two grasses native to Mediterranean ecosystems of Western Australia (Amphipogon turbinatus R.Br. and Neurachne alopecuoidea R.Br.) to evaluate the effects of different flaming techniques on flow properties and germination. Flaming significantly improved flowability in both species and had both neutral (A. turbinatus) and negative (N. alopecuroidea) effects on germination. Flaming torch size influenced germination, though flaming temperature (low or high) and whether this was kept constant or alternating had no effect. The best evaluation of germination following flaming was achieved by cleaning flamed florets to seed and/or germinating in the presence of karrikinolide (KAR1) or gibberellic acid (GA3). We suggest that flaming settings (particularly torch size) require species-specific evaluation and optimisation. Removing seeds from flamed florets and germination testing this material in the presence of stimulants may be a useful protocol for future flaming evaluations.

Effects of Polymer 3D Architecture, Size, and Chemistry on Biological Transport and Drug Delivery In Vitro and in Orthotopic Triple Negative Breast Cancer Models.

The size, shape, and underlying chemistries of drug delivery particles are key parameters which govern their ultimate performance in vivo. Responsive particles are desirable for triggered drug delivery, achievable through architecture change and biodegradation to control in vivo fate. Here, polymeric materials are synthesized with linear, hyperbranched, star, and micellar-like architectures based on 2-hydroxypropyl methacrylamide (HPMA), and the effects of 3D architecture and redox-responsive biodegradation on biological transport are investigated. Variations in "stealth" behavior between the materials are quantified in vitro and in vivo, whereby reduction-responsive hyperbranched polymers most successfully avoid accumulation within the liver, and none of the materials target the spleen or lungs. Functionalization of selected architectures with doxorubicin (DOX) demonstrates enhanced efficacy over the free drug in 2D and 3D in vitro models, and enhanced efficacy in vivo in a highly aggressive orthotopic breast cancer model when dosed over schedules accounting for the biodistribution of the carriers. These data show it is possible to direct materials of the same chemistries into different cellular and physiological regions via modulation of their 3D architectures, and thus the work overall provides valuable new insight into how nanoparticle architecture and programmed degradation can be tailored to elicit specific biological responses for drug delivery.