Preclinical models for drug discovery for metastatic disease.

Despite many advances, metastatic disease remains essentially uncurable. Thus, there is an urgent need to better understand mechanisms that promote metastasis, drive tumor evolution, and underlie innate and acquired drug resistance. Sophisticated preclinical models that recapitulate the complex tumor ecosystem are key to this process. We begin with syngeneic and patient-derived mouse models that are the backbone of most preclinical studies. Second, we present some unique advantages of fish and fly models. Third, we consider the strengths of 3D culture models for resolving remaining knowledge gaps. Finally, we provide vignettes on multiplexed technologies to advance our understanding of metastatic disease.

Enhanced cycling stability of Li-sulfur battery composites by low pressure penetration of PEDOT:PSS coating.

A lithium sulfur composite electrode (SCPV) is prepared by in situ permeation of poly (3,4-dioxyethiophene):poly(styrene sulfonate) (PEDOT:PSS) with a thickness of about 10 nm onto the surface of a SC (sulfur and carbon nanotubes) electrode via a low pressure (3.3 kPa) method. The SCPV electrode exhibits a discharge capacity of 1320.0 mA h g-1, which is higher than that of the SC electrode (1265.8 mA h g-1) at 0.1C; furthermore, it exhibits a discharge capacity of 604.9 mA h g-1, which is almost twice that of the SC electrode (306.8 mA h g-1) at 2C, and it is due to the fact that PEDOT:PSS gel polymers store large amounts of electrolytes and have excellent electronic and ionic conductivities. However, the discharge capacity of a SCPV cathode remains at 91.87% after 200 cycles at 0.5C, which is more than twice that of the SC cathode (44.70%); this superior cycling stability is mainly due to the in situ fixation of PEDOT:PSS inside the SC electrode, which inhibits the shuttle effect and volume change during the cycling process, thus improving the cycling stability.

Centre for Perioperative Care anaemia guideline: implications for anaesthesia.

The Centre for Perioperative Care (CPOC) has published in September 2022 guidance addressing perioperative anaemia. This editorial addresses the definition of anaemia for women and management of borderline anaemia in women. We also address implications of the CPOC guidance for anaesthetists and the future direction of anaemia research and management.

Investigation of the Thermal Stability of Proteinase K for the Melt Processing of Poly(l-lactide).

The enzymatic degradation of aliphatic polyesters offers unique opportunities for various use cases in materials science. Although evidently desirable, the implementation of enzymes in technical applications of polyesters is generally challenging due to the thermal lability of enzymes. To prospectively overcome this intrinsic limitation, we here explored the thermal stability of proteinase K at conditions applicable for polymer melt processing, given that this hydrolytic enzyme is well established for its ability to degrade poly(l-lactide) (PLLA). Using assorted spectroscopic methods and enzymatic assays, we investigated the effects of high temperatures on the structure and specific activity of proteinase K. Whereas in solution, irreversible unfolding occurred at temperatures above 75-80 °C, in the dry, bulk state, proteinase K withstood prolonged incubation at elevated temperatures. Unexpectedly little activity loss occurred during incubation at up to 130 °C, and intermediate levels of catalytic activity were preserved at up to 150 °C. The resistance of bulk proteinase K to thermal treatment was slightly enhanced by absorption into polyacrylamide (PAM) particles. Under these conditions, after 5 min at a temperature of 200 °C, which is required for the melt processing of PLLA, proteinase K was not completely denatured but retained around 2% enzymatic activity. Our findings reveal that the thermal processing of proteinase K in the dry state is principally feasible, but equally, they also identify needs and prospects for improvement. The experimental pipeline we establish for proteinase K analysis stands to benefit efforts directed to this end. More broadly, our work sheds light on enzymatically degradable polymers and the thermal processing of enzymes, which are of increasing economical and societal relevance.

The role of viscoelastic testing in assessing peri-interventional platelet function and coagulation.

We carried out a literature search in MEDLINE (PubMed) and EMBASE literature databases to provide a concise review of the role of viscoelastic testing in assessing peri-interventional platelet function and coagulation. The search identified 130 articles that were relevant for the review, covering the basic science of VHA and VHA in clinical settings including cardiac surgery, cardiology, neurology, trauma, non-cardiac surgery, obstetrics, liver disease, and COVID-19. Evidence from these articles is used to describe the important role of VHAs and platelet function testing in various peri-interventional setups. VHAs can help us to comprehensively assess the contribution of platelets and coagulation dynamics to clotting at the site-of-care much faster than standard laboratory measures. In addition to standard coagulation tests, VHAs are beneficial in reducing allogeneic transfusion requirements and bleeding, in predicting ischemic events, and improving outcomes in several peri-interventional care settings. Further focused studies are needed to confirm their utility in the peri-interventional case.

High Cycling Stability of the LiNi0.8 Co0.1 Mn0.1 O2 Cathode via Surface Modification with Polyimide/Multi-Walled Carbon Nanotubes Composite Coating.

The Ni-rich LiNi0.8 Co0.10 Mn0.1 O2 (NCM811) cathode coated by combining with multi-walled carbon nanotubes (MWCNTs) and polyimide (PI) produces a PI3-NCM811 cathode, which markedly improves cycling stability and suppresses secondary crystal cracking. The initial discharge capacity of the PI3-NCM811 cathode is 199.6 mAh g-1 between 2.8 and 4.3 V at 0.1 C @ 25 °C, which is slightly lower than that of NCM811 (201.1 mAh g-1 ). The PI3-NCM811 and NCM811 cathodes keep 90.6% and 64.8% of their initial discharge capacity at 1 C between 2.8 and 4.3 V after 500 cycles, respectively. Furthermore, the difference (21.1%) in capacity retention rate between PI3-NCM811 and NCM811 under the condition of 2.8-4.5 V became smaller compared with the difference (25.8%) under the condition of 2.8-4.3 V. This better cyclic stability is mainly attributed to the toughness and elasticity of PI, which inhibits the secondary cracking, maintains the structural integrity of the cathode particles, and protects the particles from electrolyte damage during long-term cycling.

Modulation of Transaminase Activity by Encapsulation in Temperature-Sensitive Poly(N-acryloyl glycinamide) Hydrogels.

Smart hydrogels hold much potential for biocatalysis, not only for the immobilization of enzymes, but also for the control of enzyme activity. We investigated upper critical solution temperature-type poly N-acryloyl glycinamide (pNAGA) hydrogels as a smart matrix for the amine transaminase from Bacillus megaterium (BmTA). Physical entrapment of BmTA in pNAGA hydrogels results in high immobilization efficiency (>89 %) and high activity (97 %). The temperature-sensitiveness of pNAGA is preserved upon immobilization of BmTA and shows a gradual deswelling upon temperature reduction. While enzyme activity is mainly controlled by temperature, deactivation tended to be higher for immobilized BmTA (≈62-68 %) than for free BmTA (≈44 %), suggesting a deactivating effect due to deswelling of the pNAGA gel. Although the deactivation in response to hydrogel deswelling is not yet suitable for controlling enzyme activity sufficiently, it is nevertheless a good starting point for further optimization.

Interfacial Polymerization at the Alkane/Ionic Liquid Interface.

Polymerization at the liquid-liquid interface has attracted much attention for synthesizing ultrathin polymer films for molecular sieving. However, it remains a major challenge to conduct this process outside the alkane-water interface since it not only suffers water-caused side reactions but also is limited to water-soluble monomers. Here, we report the interfacial polymerization at the alkane/ionic liquid interface (IP@AILI) where the ionic liquid acts as the universal solvent for diversified amines to synthesize task-specific polyamide nanofilms. We propose that IP@AILI occurs when acyl chloride diffuses from the alkane into the ionic liquid instead of being triggered by the diffusion of amines as in the conventional alkane-water system, which is demonstrated by thermodynamic partitioning and kinetic monitoring. The prepared polyamide nanofilms with precisely adjustable pore sizes display unprecedented permeability and selectivity in various separation processes.

Phytochemicals inhibit migration of triple negative breast cancer cells by targeting kinase signaling.

BACKGROUND: Cell migration and invasion are essential processes for metastatic dissemination of cancer cells. Significant progress has been made in developing new therapies against oncogenic signaling to eliminate cancer cells and shrink tumors. However, inherent heterogeneity and treatment-induced adaptation to drugs commonly enable subsets of cancer cells to survive therapy. In addition to local recurrence, these cells escape a primary tumor and migrate through the stroma to access the circulation and metastasize to different organs, leading to an incurable disease. As such, therapeutics that block migration and invasion of cancer cells may inhibit or reduce metastasis and significantly improve cancer therapy. This is particularly more important for cancers, such as triple negative breast cancer, that currently lack targeted drugs. METHODS: We used cell migration, 3D invasion, zebrafish metastasis model, and phosphorylation analysis of 43 protein kinases in nine triple negative breast cancer (TNBC) cell lines to study effects of fisetin and quercetin on inhibition of TNBC cell migration, invasion, and metastasis. RESULTS: Fisetin and quercetin were highly effective against migration of all nine TNBC cell lines with up to 76 and 74% inhibitory effects, respectively. In addition, treatments significantly reduced 3D invasion of highly motile TNBC cells from spheroids into a collagen matrix and their metastasis in vivo. Fisetin and quercetin commonly targeted different components and substrates of the oncogenic PI3K/AKT pathway and significantly reduced their activities. Additionally, both compounds disrupted activities of several protein kinases in MAPK and STAT pathways. We used molecular inhibitors specific to these signaling proteins to establish the migration-inhibitory role of the two phytochemicals against TNBC cells. CONCLUSIONS: We established that fisetin and quercetin potently inhibit migration of metastatic TNBC cells by interfering with activities of oncogenic protein kinases in multiple pathways.

Viscoelastic testing in cardiac surgery.

Bleeding complications are common in cardiac surgery and lead to an increase in morbidity and mortality. This is multifactorial in aetiology including the effects of cardiopulmonary bypass, the drugs given to manipulate the coagulation system and the vascular nature of the surgery itself. Viscoelastic tests provide a point of care, rapid assessment of coagulation which offer the advantage of faster turnaround times and a nuanced view of the elements of the coagulation system allowing targeted therapy to be delivered quickly. Both thomboelastography (TEG)and thromboelastometry (ROTEM) have been recommended for use in cardiac surgery, both have shown a reduction in transfusion and bleeding when used as part of a testing algorithm. They are particularly useful in assessing residual heparinisation and fibrinogen levels. Additionally, TEG allows the evaluation of the effects of anti-platelet agents on platelet function. This review discusses the mechanisms by which bleeding occurs in cardiac surgery and explores three uses of viscoelastic testing in cardiac surgery: to predict bleeding, to assess platelet function and peri-operative testing to reduce transfusion.

Perfusion Cultivation of Artificial Liver Extracellular Matrix in Fibrous Polymer Sponges Biomimicking Scaffolds for Tissue Engineering.

A major challenge in tissue engineering and artificial scaffolding is to combine easily tunable scaffolds biomimicking the extracellular matrix of native organs with delivery-controlled cell culturing to create fully cellularized, large artificial 3D scaffolds. Aiming at bioartificial liver construction, we present our research using galactose-functionalized, ultraporous polylactide 3D nanofiber sponges fabricated out of electrospun fibers. Sponge biomodification by blend galactosylation and in-solution coating is performed, respectively, using a polylactide-galactose carrier-copolymer that promotes cell delivery and features a pronounced autofluorescence. It allows us to verify the galactosylation success, evaluate its quality, and record dye-free, high-resolution images of the sponge network using confocal laser scanning microscopy. The galactose carrier and its impact on scaffold cellularization is validated in benchmark to several reference systems. Verification of the human hepatic cell asialoglycoprotein receptor presence and galactose interaction in culture is performed by Cu2+ receptor-blocking experiments. The culture results are extensively investigated in and ex situ to trace and quantify the cell culture progress, cell activity, and viability at different culture stages. Bioreactor cultivation of sponges reveals that the galactose carrier does not only facilitate cell adhesion but also enhances cellular distribution throughout the scaffold. The promising 3D culture results allow us to move forward to create mature in vitro liver model research systems. The elaboration into ex vivo testing platforms could help judging native cell material interactions with drugs or therapeutics, without the need of direct human or animal testing.

UCST-Type Copolymer through the Combination of Water-Soluble Polyacrylamide and Polycaprolactone-Like Polyester.

Copolymers of acrylamide (AAm) and hydrophobic monomers are known as non-ionic polymers to show an upper critical solution temperature (UCST) in aqueous solution. By utilizing cyclic ketene acetals and carrying out the radical ring opening polymerization along with copolymerization with AAm, a UCST polymer, poly(acrylamide-co-2-methylene-1,3-dioxepane) (P(AAm-co-MDO)), is obtained. The AAm/MDO content results in the shift of UCST phase transition temperature. The present work shows how the combination of water-soluble PAAm and polycaprolactone-like structured PMDO develops a new type of thermoresponsive polymer which can be expected for bio-related applications.

Preoperative intravenous iron before cardiac surgery: a prospective multicentre feasibility study.

BACKGROUND: Preoperative anaemia affects one third of patients undergoing cardiac surgery and is associated with increased mortality and morbidity. Although it is recommended that perioperative teams should identify and treat patients with preoperative anaemia before surgery, introducing new treatment protocols can be challenging in surgical pathways. The aim of this study was to assess the feasibility and effectiveness of introducing a preoperative intravenous iron service as a national initiative in cardiac surgery. METHODS: We performed a multicentre, stepped, observational study using the UK Association of Cardiothoracic Anaesthesia and Critical Care Research Network. The primary feasibility outcome was the ability to set up an anaemia and intravenous iron clinic at each site. The primary efficacy outcome was change in haemoglobin (Hb) concentration between intervention and operation. Secondary outcomes included blood transfusion and hospital stay. Patients with anaemia were compared with non-anaemic patients and with those who received intravenous iron as part of their routine treatment protocol. RESULTS: Seven out of 11 NHS hospitals successfully set up iron clinics over 2 yr, and 228 patients were recruited into this study. Patients with anaemia who received intravenous iron were at higher surgical risk, were more likely to have a known previous history of iron deficiency or anaemia, had a higher rate of chronic kidney disease, and were slightly more anaemic than the non-treated group. Intravenous iron was administered a median (inter-quartile range, IQR [range]) of 33 (15-53 [4-303]) days before surgery. Preoperative intravenous iron increased [Hb] from baseline to pre-surgery; mean (95% confidence interval) change was +8.4 (5.0-11.8) g L-1 (P<0.001). Overall, anaemic compared with non-anaemic patients were more likely to be transfused (49% [59/136] vs 27% (22/92), P=0.001) and stayed longer in hospital (median days [IQR], 9 [7-15] vs 8 [6-11]; P=0.014). The number of days alive and at home was lower in the anaemic group (median days [IQR], 20 [14-22] vs 21 [17-23]; P=0.033). CONCLUSION: The development of an intravenous iron pathway is feasible but appears limited to selected high-risk cardiac patients in routine NHS practise. Although intravenous iron increased [Hb], there is a need for an appropriately powered clinical trial to assess the clinical effect of intravenous iron on patient-centred outcomes.

Perioperative Anemia Management as Part of PBM in Cardiac Surgery - A Narrative Updated Review.

Anemia is common in patients with cardiac disease. Iron deficiency is the cause of anemia in about 80% of all cases. Preoperative anemia is associated with an increased morbidity and mortality in patients undergoing cardiac surgery. The risk of receiving red blood cell transfusions, which are potentially associated with severe side effects, is very high in these patients. Patient Blood Management (PBM) is a multidisciplinary approach to manage anemia, minimize unnecessary blood loss, and optimize transfusion therapy. PBM comprises 3 pillars: (1) detection and treatment of preoperative anemia, (2) reduction of perioperative blood loss, and (3) optimization of allogeneic blood therapy. The World Health Organization has urged all Member States to implement PBM. This narrative review focuses on pre-, intra-, and postoperative strategies to detect, prevent, and treat anemia as part of PBM in cardiac surgery.

Precise 2D-Patterned Incompatible Catalysts for Reactions in One-Pot.

Precise and direct two-dimensional (2D) printing of the incompatible polymer acid-base catalysts and their utility in one-pot two-step reactions were shown. Multistep catalytic reactions using incompatible catalysts in a one-pot reaction cascade requires special methods and materials to isolate the catalysts from each other. In general, this is a tedious process requiring special polymer architectures as the carrier for the catalysts to preserve the activity of otherwise incompatible catalysts. We propose the immobilization of incompatible polymer catalysts, such as polymer acid and base catalysts, on a substrate in variable sizes and amounts by precise 2D printing. The terpolymers with basic (4-vinylpyridine) and acidic (styrene sulfonic acid) functionalities and methacryloyl benzophenone as a UV cross-linking unit were used for 2D printing on poly(ethylene terephthalate) (PET). The printed meshes were immersed together in a reaction solution containing (dimethoxymethyl)benzene and ethyl cyanoformate, resulting in a two-step acid-base catalyzed cascade reaction; that is, deacetalization followed by carbon-building reaction. The time-dependent consumption of (dimethoxymethyl)benzene to the intermediate benzaldehyde and the product was monitored, and a kinetic model was developed to investigate the underlying reaction dynamics. The complexity of multistep Wolf-Lamb-type reactions was generally significantly decreased by using our approach because of the easy polymerization and immobilization procedure.

Wolf-Lamb-type Catalysis in One Pot Using Electrospun Polymeric Catalyst Membranes.

Multistep catalytic transformations using incompatible catalysts (Wolf-Lamb-type) in a one-pot reaction cascade require site isolation of different catalysts by compartmentalization. In this work, the use of different electrospun catalytic membranes in a modular way as individual compartments is shown for one-pot Wolf-Lamb-type reaction cascades. The data are presented for one-pot cascade reaction sequences catalyzed by acidic and basic membranes made by electrospinning polymeric acid (poly(styrene-co-styrene sulfonic acid-co-4-methacryloyl-oxybenzophen)) and basic (poly(styrene-co-4-vinylpyridine-co-4-methacryloyl-oxybenzophen)) catalysts, respectively. The two-step, one-pot system used is the acidic catalyzed deacetylation of dimethoxybenzylacetale to benzaldehyde, which reacts with ethyl cyanoformate to result in a high yield of product (over 90%) under base-catalyzed conditions. The reaction kinetics are further monitored and evaluated by using differential equations, showing the necessity of a parameter Δt to represent a retarded start for the second reaction step. The concept provides an easy and upscalable approach for use in Wolf-Lamb-type systems.

Spin-Crossover Iron(II) Coordination Polymer with Fluorescent Properties: Correlation between Emission Properties and Spin State.

A spin-crossover coordination polymer [Fe(L1)(bipy)]n (where L = a N2O22- coordinating Schiff base-like ligand bearing a phenazine fluorophore and bipy = 4,4'-bipyridine) was synthesized and exhibits a 48 K wide thermal hysteresis above room temperature (T1/2↑ = 371 K and T1/2↓ = 323 K) that is stable for several cycles. The spin transition was characterized using magnetic measurements, Mössbauer spectroscopy, and DSC measurements. T-dependent X-ray powder diffraction reveals a structural phase transition coupled with the spin transition phenomenon. The dimeric excerpt {(µ-bipy)[FeL1(MeOH)]2}·2MeOH of the coordination polymer chain crystallizes in the triclinic space group P1̅ and reveals that the packing of the molecules in the crystal is dominated by hydrogen bonds. Investigation of the emission properties of the complexes with regard to temperature shows that the spin crossover can be tracked by monitoring the emission spectra, since the emission color changes from greenish to a yellow color upon the low spin-to-high spin transition.

Let There be Light: Polymeric Micelles with Upper Critical Solution Temperature as Light-Triggered Heat Nanogenerators for Combating Drug-Resistant Cancer.

Complete drug release and efficient drug retention are two critical factors in reversing drug resistance in cancer therapy. In this regard, polymeric micelles with an upper critical solution temperature (UCST) are designed as a new exploration to reverse drug resistance. The amphiphilic UCST-type block copolymers are used to encapsulate photothermal agent IR780 and doxorubicin (DOX) simultaneously. The integrated UCST-type drug nanocarriers show light-triggered multiple synergistic effects to reverse drug resistance and are expected to kill three birds with one stone: First, owing to the photothermal effect of IR780, the nanocarriers will be dissociated upon exposure to laser irradiation, leading to complete drug release. Second, the photothermal effect-induced hyperthermia is expected to avoid the efflux of DOX and realize efficient drug retention. Last but not least, photothermal ablation of cancer cells can be achieved after laser irradiation. Therefore, the UCST-type drug nanocarriers provide a new strategy in reversing drug resistance in cancer therapy.

Ultraporous, Compressible, Wettable Polylactide/Polycaprolactone Sponges for Tissue Engineering.

Ultraporous, degradable sponges made of either polylactide or of blends of polylactide/poly(ε-caprolactone) are prepared by freeze-drying of dispersions of short electrospun fibers and subsequent thermal annealing. The sponges feature ultrahigh porosity (99.6%), a hierarchical cellular structure, and high reversible compressibility with fast recovery from deformation in the dry as well as in the wet state. The sponge properties depend on the fiber dispersion concentration and the annealing temperature. Sponge characteristics like fiber density (2.5-20 mg/cm3), size, shape, crystallinity, mechanical strength, wetability, and structural integrity are user adjustable. Cell culture experiments were successfully performed with Jurkat cells with Confocal Laser Scanning Microscopy and MTT staining showing rapid cell proliferation. Live/Dead staining demonstrated high viability of the seeded cells. The sponge characteristics and modifications investigated and presented here reveal that these sponges are highly promising for tissue engineering applications.

pH-Responsive Biohybrid Carrier Material for Phenol Decontamination in Wastewater.

Smart polymers are a valuable platform to protect and control the activity of biological agents over a wide range of conditions, such as low pH, by proper encapsulation. Such conditions are present in olive oil mill wastewater with phenol as one of the most problematic constituents. We show that elastic and pH-responsive diblock copolymer fibers are a suitable carrier for Corynebacterium glutamicum, i.e., bacteria which are known for their ability to degrade phenol. Free C. glutamicum does not survive low pH conditions and fails to degrade phenol at low pH conditions. Our tea-bag like biohybrid system, where the pH-responsive diblock copolymer acts as a protecting outer shell for the embedded bacteria, allows phenol degradation even at low pH. Utilizing a two-step encapsulation process, planktonic cells were first encapsulated in poly(vinyl alcohol) to protect the bacteria against the organic solvents used in the second step employing coaxial electrospinning.