Inhibiting BRAF/EGFR/MEK suppresses cancer stemness and drug resistance of primary colorectal cancer cells.

Drug resistance is a major barrier against successful treatments of cancer patients. Gain of stemness under drug pressure is a major mechanism that renders treatments ineffective. Identifying approaches to target cancer stem cells (CSCs) is expected to improve treatment outcomes for patients. To elucidate the role of cancer stemness in resistance of colorectal cancer cells to targeted therapies, we developed spheroid cultures of patient-derived BRAFmut and KRASmut tumor cells and studied resistance mechanisms to inhibition of MAPK pathway through phenotypic and gene and protein expression analysis. We found that treatments enriched the expression of CSC markers CD166, ALDH1A3, CD133, and LGR5 and activated PI3K/Akt pathway in cancer cells. We examined various combination treatments to block these activities and found that a triple combination against BRAF, EGFR, and MEK significantly reduced stemness and activities of oncogenic signaling pathways. This study demonstrates the feasibility of blocking stemness-mediated drug resistance and tumorigenic activities in colorectal cancer.

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.

A Breast Cancer Image Classification Algorithm with 2c Multiclass Support Vector Machine.

Breast cancer is the most frequent type of cancer in women; however, early identification has reduced the mortality rate associated with the condition. Studies have demonstrated that the earlier this sickness is detected by mammography, the lower the death rate. Breast mammography is a critical technique in the early identification of breast cancer since it can detect abnormalities in the breast months or years before a patient is aware of the presence of such abnormalities. Mammography is a type of breast scanning used in medical imaging that involves using x-rays to image the breasts. It is a method that produces high-resolution digital pictures of the breasts known as mammography. Immediately following the capture of digital images and transmission of those images to a piece of high-tech digital mammography equipment, our radiologists evaluate the photos to establish the specific position and degree of the sickness in the breast. When compared to the many classifiers typically used in the literature, the suggested Multiclass Support Vector Machine (MSVM) approach produces promising results, according to the authors. This method may pave the way for developing more advanced statistical characteristics based on most cancer prognostic models shortly. It is demonstrated in this paper that the suggested 2C algorithm with MSVM outperforms a decision tree model in terms of accuracy, which follows prior findings. According to our findings, new screening mammography technologies can increase the accuracy and accessibility of screening mammography around the world.

Biodegradable polymers boost reproduction in the earthworm Eisenia fetida.

Microplastic contamination in soil has become a global environmental threat as it adversely affects terrestrial organisms like earthworms as well as soil properties. Especially biodegradable polymers have recently been used as an alternative to conventional polymer types, although their impact remains poorly understood. Thus, we studied the effect of conventional (polystyrene: PS, polyethylene terephthalate: PET, polypropylene: PP) versus aliphatic polyesters classified as biodegradable polymers (poly-(l-lactide): PLLA, polycaprolactone: PCL) on the earthworm Eisenia fetida and soil properties (pH and cation exchange capacity). We addressed direct effects on the weight gain and reproductive success of E. fetida, and indirect effects, like changes in the gut microbial composition as well as the production of short-chain fatty acids by the gut microbiota. Earthworms were exposed for eight weeks in an artificial soil amended with two environmentally relevant concentrations (1 % and 2.5 % (w/w)) of the different microplastic types. PLLA and PCL boosted the number of cocoons produced by 135 % and 54 %, respectively. Additionally, exposure to these two polymers increased number of hatched juveniles, changed gut microbial beta-diversity, and increased the production of the short chain fatty acid lactate compared to the control treatments. Interestingly, we also found a positive effect of PP on the earthworm's bodyweight and reproductive success. The interaction of microplastic and earthworms decreased soil pH by about 1.5 units in the presence of PLLA and PCL. No polymer effect on the cation exchange capacity of soil was found. In general, neither the presence of conventional nor biodegradable polymers had any adverse effects on any of the studied endpoints. Our results suggest that the effects of microplastic highly depend on the polymer type, and that the degradation of biodegradable polymers might be enhanced in the gut of earthworms, which implies that they may use biodegradable polymers as a potential carbon source.

Thoroughly Hydrophilized Electrospun Poly(L-Lactide)/ Poly(ε-Caprolactone) Sponges for Tissue Engineering Application.

Biodegradable electrospun sponges are of interest for various applications including tissue engineering, drug release, dental therapy, plant protection, and plant fertilization. Biodegradable electrospun poly(l-lactide)/poly(ε-caprolactone) (PLLA/PCL) blend fiber-based sponge with hierarchical pore structure is inherently hydrophobic, which is disadvantageous for application in tissue engineering, fertilization, and drug delivery. Contact angles and model studies for staining with a hydrophilic dye for untreated, plasma-treated, and surfactant-treated PLLA/PCL sponges are reported. Thorough hydrophilization of PLLA/PCL sponges is found only with surfactant-treated sponges. The MTT assay on the leachates from the sponges does not indicate any cell incompatibility. Furthermore, the cell proliferation and penetration of the hydrophilized sponges are verified by in vitro cell culture studies using MG63 and human fibroblast cells.

Biological Tissue-Inspired Ultrasoft, Ultrathin, and Mechanically Enhanced Microfiber Composite Hydrogel for Flexible Bioelectronics.

Hydrogels offer tissue-like softness, stretchability, fracture toughness, ionic conductivity, and compatibility with biological tissues, which make them promising candidates for fabricating flexible bioelectronics. A soft hydrogel film offers an ideal interface to directly bridge thin-film electronics with the soft tissues. However, it remains difficult to fabricate a soft hydrogel film with an ultrathin configuration and excellent mechanical strength. Here we report a biological tissue-inspired ultrasoft microfiber composite ultrathin (< 5 µm) hydrogel film, which is currently the thinnest hydrogel film as far as we know. The embedded microfibers endow the composite hydrogel with prominent mechanical strength (tensile stress ~ 6 MPa) and anti-tearing property. Moreover, our microfiber composite hydrogel offers the capability of tunable mechanical properties in a broad range, allowing for matching the modulus of most biological tissues and organs. The incorporation of glycerol and salt ions imparts the microfiber composite hydrogel with high ionic conductivity and prominent anti-dehydration behavior. Such microfiber composite hydrogels are promising for constructing attaching-type flexible bioelectronics to monitor biosignals.

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.

Chronic poly(l-lactide) (PLA)- microplastic ingestion affects social behavior of juvenile European perch (Perca fluviatilis).

Juvenile perch were exposed to 2 % (w/w) poly(l-lactide) (PLA) microplastic particles (90-150 µm) in food pellets, or 2 % (w/w) kaolin particles, and a non-particle control food over 6 months. Chronic ingestion of PLA microplastics significantly affected the social behavior of juvenile perch, evident as a significantly increased reaction to the vision of conspecifics. PLA ingestion did not alter life cycle parameters, or gene expression levels. In addition to reactions to conspecifics, fish that ingested microplastic particles showed tendencies to decrease locomotion, internal schooling distance, and active predator responses. The ingestion of natural particles (kaolin) significantly downregulated the expression of genes related to oxidative stress and androgenesis in the liver of juvenile perch, and we found tendencies to downregulated expression of genes related to xenobiotic response, inflammatory response, and thyroid disruption. The present study demonstrated the importance of natural particle inclusion and the potential behavioral toxicity of one of the commercially available biobased and biodegradable polymers.

Propagated Circulating Tumor Cells Uncover the Potential Role of NFκB, EMT, and TGFß Signaling Pathways and COP1 in Metastasis.

Circulating tumor cells (CTCs), a population of cancer cells that represent the seeds of metastatic nodules, are a promising model system for studying metastasis. However, the expansion of patient-derived CTCs ex vivo is challenging and dependent on the collection of high numbers of CTCs, which are ultra-rare. Here we report the development of a combined CTC and cultured CTC-derived xenograft (CDX) platform for expanding and studying patient-derived CTCs from metastatic colon, lung, and pancreatic cancers. The propagated CTCs yielded a highly aggressive population of cells that could be used to routinely and robustly establish primary tumors and metastatic lesions in CDXs. Differential gene analysis of the resultant CTC models emphasized a role for NF-κB, EMT, and TGFß signaling as pan-cancer signaling pathways involved in metastasis. Furthermore, metastatic CTCs were identified through a prospective five-gene signature (BCAR1, COL1A1, IGSF3, RRAD, and TFPI2). Whole-exome sequencing of CDX models and metastases further identified mutations in constitutive photomorphogenesis protein 1 (COP1) as a potential driver of metastasis. These findings illustrate the utility of the combined patient-derived CTC model and provide a glimpse of the promise of CTCs in identifying drivers of cancer metastasis.

Extremely low thermal conductivity and high electrical conductivity of sustainable carbon-ceramic electrospun nonwoven materials.

Materials with an extremely low thermal and high electrical conductivity that are easy to process, foldable, and nonflammable are required for sustainable applications, notably in energy converters, miniaturized electronics, and high-temperature fuel cells. Given the inherent correlation between high thermal and high electrical conductivity, innovative design concepts that decouple phonon and electron transport are necessary. We achieved this unique combination of thermal conductivity 19.8 ± 7.8 mW/m/K (cross-plane) and 31.8 ± 11.8 mW/m/K (in-plane); electrical conductivity 4.2 S/cm in-plane in electrospun nonwovens comprising carbon as the matrix and silicon-based ceramics as nano-sized inclusions with a sea-island nanostructure. The carbon phase modulates electronic transport for high electrical conductivity, and the ceramic phase induces phonon scattering for low thermal conductivity by excessive boundary scattering. Our strategy can be used to fabricate the unique nonwoven materials for real-world applications and will inspire the design of materials made from carbon and ceramic.

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.

High Strength and High Toughness Electrospun Multifibrillar Yarns with Highly Aligned Hierarchy Intended as Anisotropic Extracellular Matrix.

Electrospun nanofibers can be effectively used as a surrogate for extracellular matrices (ECMs). However, in the context of cellular mechanobiology, their mechanical performances can be enhanced by using nanofibrous materials with a high level of structural organization. Herein, this work develops multifibrillar yarns with superior mechanical performance based on biocompatible polyacrylonitrile (PAN) as surrogate ECM. Nearly perfect aligned nanofibers along with the axis of the multifibrillar yarn are prepared. These highly aligned yarns exhibit high strength, high toughness, good stress relaxation behavior, and are robust enough for technical or medical applications. Further, this work analyzes the influence of the highly aligned-hierarchical topological structure of the material on cell proliferation and cell orientation using cells derived from epithelial and connective tissues. Compared to nonoriented electrospun multifibrillar yarns and flat films, the well-ordered topology in the electrospun PAN multifibrillar yarns triggers an improved proliferation of fibroblasts and epithelial cells. Fibroblasts acquire an elongated morphology analogous to their behavior in the natural ECM. Hence, this heterogeneous multifibrillar material can be used to restore or reproduce the ECM for tissue engineering applications, notably in the skeletal muscle and tendon.

Beyond microplastics: Water soluble synthetic polymers exert sublethal adverse effects in the freshwater cladoceran Daphnia magna.

Plastic pollution is considered one of the causes of global change. However, water soluble synthetic polymers (WSSPs) have been neglected so far, although they are used in several industrial, dietary, domestic and biomedical products. Moreover, they are applied in wastewater treatment plants (WWTPs) as flocculants and coagulant agents. Hence, their presence in the aquatic environment as well as their uptake by aquatic organisms is probable, whereas no data are available regarding their potential adverse effects. Here we show in the freshwater key species D. magna exposed to five different WSSPs life history changes along with an altered level of reactive oxygen species, although acute mortality was not observed. Since daphnids act as keystone species in lake ecosystems by controlling phytoplankton biomass, even sublethal effects such as WSSPs induced changes in life history may result in cascading effects, from lower to higher trophic levels, which in turn could affect the whole food web.

Identifying drivers of breast cancer metastasis in progressively invasive subpopulations of zebrafish-xenografted MDA-MB-231.

Cancer metastasis is the primary cause of the high mortality rate among human cancers. Efforts to identify therapeutic agents targeting cancer metastasis frequently fail to demonstrate efficacy in clinical trials despite strong preclinical evidence. Until recently, most preclinical studies used mouse models to evaluate anti-metastatic agents. Mouse models are time-consuming and expensive. In addition, an important drawback is that mouse models inadequately model the early stages of metastasis which plausibly leads to the poor correlation with clinical outcomes.Here, we report an in vivo model based on xenografted zebrafish embryos where we select for progressively invasive subpopulations of MDA-MB-231 breast cancer cells. A subpopulation analogous to circulating tumor cells found in human cancers was selected by injection of MDA-MB-231 cells into the yolk sacs of 2 days post-fertilized zebrafish embryos and selecting cells that migrated to the tail. The selected subpopulation derived from MDA-MB-231 cells were increasingly invasive in zebrafish. Isolation of these subpopulations and propagation in vitro revealed morphological changes consistent with activation of an epithelial-mesenchymal transition program. Differential gene analysis and knockdown of genes identified gene-candidates (DDIT4, MT1X, CTSD, and SERPINE1) as potential targets for anti-metastasis therapeutics. Furthermore, RNA-splicing analysis reinforced the importance of BIRC5 splice variants in breast cancer metastasis. This is the first report using zebrafish to isolate and expand progressively invasive populations of human cancer cells. The model has potential applications in understanding the metastatic process, identification and/or development of therapeutics that specifically target metastatic cells and formulating personalized treatment strategies for individual cancer patients.

Municipal biowaste treatment plants contribute to the contamination of the environment with residues of biodegradable plastics with putative higher persistence potential.

Biodegradable plastics (BDP) are expected to mineralize easily, in particular under conditions of technical composting. However, the complexity of the sample matrix has largely prevented degradation studies under realistic conditions. Here composts and fertilizers from state-of-the-art municipal combined anaerobic/aerobic biowaste treatment plants were investigated for residues of BDP. We found BDP fragments > 1 mm in significant numbers in the final composts intended as fertilizer for agriculture and gardening. Compared to pristine compostable bags, the recovered BDP fragments showed differences in their material properties, which potentially renders them less prone to further biodegradation. BDP fragments < 1 mm were extracted in bulk and came up to 0.43 wt% of compost dry weight. Finally, the liquid fertilizer produced during the anaerobic treatment contained several thousand BDP fragments < 500 µm per liter. Hence, our study questions, if currently available BDP are compatible with applications in areas of environmental relevance, such as fertilizer production.

Ultralight Heat-Insulating, Electrically Conductive Carbon Fibrous Sponges for Wearable Mechanosensing Devices with Advanced Warming Function.

Ultralight highly porous sponges are attractive for electronic devices due to superelasticity, outstanding resilience, and thermal insulation. However, fabricating an ultralight conductive sponge with low thermal conductivity, mechanical flexibility, and piezoresistivity, as well as adjustable heating behavior, is still a challenge. Here, an ultralight carbon nanofibrous sponge fabricated by pyrolyzing a graphene oxide coated polyimide sponge is reported. The resulting carbon sponge demonstrates a high electrical conductivity of 0.03-4.72 S m-1 and a low thermal conductivity of 0.027-0.038 W m-1 K-1 (20 °C, in ambient air), as well as a low density to ∼6 mg cm-3. Additionally, the sponge exhibits mechanical flexibility, stability, excellent piezoresistivity, and an adjustable heating behavior. Hence, it could be utilized as a sensing device, including thermal management, making them promising for use in smart sportswear, human-machine interfaces, and wearable healthcare devices.

Microplastic sample purification methods - Assessing detrimental effects of purification procedures on specific plastic types.

In search of effective, fast, and cheap methods to purify environmental samples for microplastic analysis, scientific literature provides various purification protocols. However, while most of these protocols effectively purify the samples, some may also degrade the targeted polymers. This study was conducted to systematically compare the effects of purification protocols based on acidic, alkaline, oxidative, and enzymatic digestion and extraction via density separation on eight of the most relevant plastic types. It offers insights into how specific purification protocols may compromise microplastic detection by documenting visible and gravimetric effects, analyzing potential surface degradation using Fourier transform infrared spectroscopy (FTIR) and bulk erosion on a molecular level using gel permeation chromatography (GPC). For example, protocols using strong acids and high temperatures are likely to completely dissolve or cause strong degradation to a wide range of polymers (PA, PC, PET, PS, PUR & PVC), while strong alkaline solutions may damage PC and PET. Contrarily, Fenton's reagent, multiple enzymatic digestion steps, as well as treatment with a zinc chloride solution frequently used for density-separation, do not degrade the eight polymers tested here. Therefore, their implementation in microplastic sample processing may be considered an essential stepping-stone towards a standardized protocol for future microplastics analyses.

A review of European guidelines for patient blood management with a particular emphasis on antifibrinolytic drug administration for cardiac surgery.

The concept of patient blood management (PBM) was introduced by the World Health Organization in 2011 and is defined as a "patient-focused, evidence-based and systematic approach for optimizing the management of patients and transfusion of blood products to ensure high quality and effective patient care". Patient blood management is a multimodal approach based on three pillars: optimization of blood mass, minimization of blood loss and optimization of patient tolerance to anaemia. Antifibrinolytics play a major role in cardiac surgery, where the risk of perioperative bleeding is high and affects a majority of patients, by effectively reducing bleeding, transfusions, re-operations, as well as their associated morbidity and mortality. They represent an essential part of the pharmacological arsenal of patient blood management. However, despite the trend towards high-level PBM practices, currently very few European countries have national PBM guidelines and these guidelines, taken as a whole, are heterogeneous in form and content. In particular, the use of antifibrinolytics in cardiac surgery is often not discussed in detail beyond general prophylactic use and any recommendations lack detail including choice of drug, dosing, and mode of administration. Thus, the implementation of PBM programs in Europe is still challenging. In 2021, the WHO published a new document highlighting the urgent need to close the gap in PBM awareness and implementation and announced their upcoming initiative to develop specific PBM implementation guidelines. This review aims first, to summarize the role played by fibrinolysis in haemostatic disorders; second, to give an overview of the current available guidelines in Europe detailing PBM implementation in cardiac surgery; and third, to analyse the place and use of antifibrinolytics in these guidelines.

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.