Aging-accumulated methylmalonic acid serum levels at breast cancer diagnosis are not associated with distant metastases.

PURPOSE: Recent evidence suggests that age-accumulated methylmalonic acid (MMA) promotes breast cancer progression in mice. This study aims to investigate the association between baseline serum MMA concentrations in patients with breast cancer and the development of subsequent distant metastases. METHODS: We included 32 patients with early Luminal B-like breast cancer (LumB, median age 62.4y) and 52 patients with early triple-negative breast cancer (TNBC, median age 50.5y) who developed distant metastases within 5 years. They were matched to an equal number of early breast cancer patients (median age 62.2y for LumB and 50.5y for TNBC) who did not develop distant metastases with at least 5 years of follow-up. RESULTS: Baseline serum MMA levels at breast cancer diagnosis showed a positive correlation with age (P < 0.001) and a negative correlation with renal function and vitamin B12 (all P < 0.02), but no statistical association was found with BMI or tumor stage (P > 0.6). Between matched pairs, no significant difference was observed in MMA levels, after adjusting for kidney function and age (P = 0.19). Additionally, in a mouse model, a significant decline in MMA levels was observed in the tumor-bearing group compared to the group without tumors before and after tumor establishment or at identical times for the control group (P = 0.03). CONCLUSION: Baseline serum MMA levels in patients with breast cancer are not correlated with secondary distant metastasis. Evidence in the mouse model suggests that the presence of a tumor perturbates MMA levels.

Histone H3.1 is a chromatin-embedded redox sensor triggered by tumor cells developing adaptive phenotypic plasticity and multidrug resistance.

Chromatin structure is regulated through posttranslational modifications of histone variants that modulate transcription. Although highly homologous, histone variants display unique amino acid sequences associated with specific functions. Abnormal incorporation of histone variants contributes to cancer initiation, therapy resistance, and metastasis. This study reports that, among its biologic functions, histone H3.1 serves as a chromatin redox sensor that is engaged by mitochondrial H2O2. In breast cancer cells, the oxidation of H3.1Cys96 promotes its eviction and replacement by H3.3 in specific promoters. We also report that this process facilitates the opening of silenced chromatin domains and transcriptional activation of epithelial-to-mesenchymal genes associated with cell plasticity. Scavenging nuclear H2O2 or amino acid substitution of H3.1(C96S) suppresses plasticity, restores sensitivity to chemotherapy, and induces remission of metastatic lesions. Hence, it appears that increased levels of H2O2 produced by mitochondria of breast cancer cells directly promote redox-regulated H3.1-dependent chromatin remodeling involved in chemoresistance and metastasis.

Serum methylmalonic acid concentrations at breast cancer diagnosis significantly correlate with clinical frailty.

Methylmalonic acid (MMA), a by-product of propionate metabolism, is known to increase with age. This study investigates the potential of serum MMA concentrations as a biomarker for age-related clinical frailty in older patients with breast cancer. One hundred nineteen patients ≥ 70 years old with early-stage breast cancer were included (median age 76 years). G8 screening, full geriatric assessment, clinical parameters (i.e., estimated glomerular filtration rate (eGFR) and body mass index (BMI)), and serum sample collection were collected at breast cancer diagnosis before any therapy was administered. MMA concentrations were measured via liquid chromatography with tandem mass spectrometry. MMA concentrations significantly increased with age and eGFR (all P < 0.001) in this older population. The group with an abnormal G8 (≤ 14, 51% of patients) had significantly higher MMA levels than the group with normal G8 (> 14, 49%): 260 nmol/L vs. 188 nmol/L, respectively (P = 0.0004), even after correcting for age and eGFR (P = 0.001). Furthermore, in the detailed assessment, MMA concentrations correlated most with mobility (Eastern Cooperative Oncology Group (ECOG) Performance Status and Activities of Daily Living (ADL) tools, all P ≤ 0.02), comorbidity (Charlson Comorbidity Index (CCI) tool, P = 0.005), and polypharmacy (P < 0.001), whereas no significant associations were noted for instrumental ADL (IADL), Mini-Mental State Examination (MMSE), Geriatric Depression Scale-15 (GDS15), Mini Nutritional Assessment-Short Form (MNA-SF), and pain (all P > 0.1). In addition, our results showed that higher MMA levels correlate with poor overall survival in breast cancer patients (P = 0.003). Elevated serum MMA concentrations at initial diagnosis are significantly associated, not only with age but also independently with clinical frailty, suggesting a possible influence of MMA on clinical frailty in older patients with early-stage breast cancer.

Methylmalonic acid in aging and disease.

Metabolic byproducts have conventionally been disregarded as waste products without functions. In this opinion article, we bring to light the multifaceted role of methylmalonic acid (MMA), a byproduct of the propionate metabolism pathway mostly commonly known as a clinical biomarker of vitamin B12 deficiency. MMA is normally present at low levels in the body, but increased levels can come from different sources, such as vitamin B12 deficiency, genetic mutations in enzymes related to the propionate pathway, the gut microbiota, and aggressive cancers. Here, we describe the diverse metabolic and signaling functions of MMA and discuss the consequences of increased MMA levels, such as during the aging process, for several age-related human pathologies.

Investigating the Architecture and Characteristics of Asian Hornet Nests: A Biomimetics Examination of Structure and Materials.

This study investigates the internal architecture of Asian hornet nests (AHNs) using advanced imaging techniques, such as CT scanning and X-ray radiography, to understand their construction and function. The primary objective and significance of this study centre on drawing inspiration from the creative way Asian hornets construct their nests, with a particular focus on the architecture, design, functionality, and building materials of these nests. The architectural principles governing the construction of these nests, such as the arrangement of hexagonal cells, pedicels for load bearing, and adhesive materials, serve as a source of inspiration for innovative and sustainable design practices. The pedicels in Asian hornet nests play a crucial role in transferring load and ensuring stability. Additionally, AHNs' adhesion to tree branches is essential for preventing collapse, and the pedicels provide necessary structural support. The knowledge gained from studying AHNs' internal architecture could be applied directly to the architecture and civil engineering fields to improve structure stability and durability. The microstructure analysis of the paper-like material that hornets produce to build their nests indicates a complex and heterogeneous structure, composed of various plant fragments and fibres. This unique composition creates intricate grooves and pores, which are essential for regulating temperature and humidity levels within the outer envelope of the nest. The study of Asian hornet nests' internal structure demonstrated that nature's engineering principles inspire the design of durable and resilient structures in the construction industry. Civil engineers can incorporate similar principles into their designs to enhance the structural integrity and performance of buildings, bridges, and other infrastructure.

The Sustainable Bioactive Dyeing of Textiles: A Novel Strategy Using Bacterial Pigments, Natural Antibacterial Ingredients, and Deep Eutectic Solvents.

The textile industry stands as a prominent contributor to global environmental pollution, primarily attributable to its extensive reliance on synthetic dyes, hazardous components, and solvents throughout the textile dyeing and treatment processes. Consequently, the pursuit of sustainable textile solutions becomes imperative, aimed at replacing these environmentally unfriendly constituents with biobased and bioactive pigments, antibacterial agents, and, notably, natural solvents. Achieving this goal is a formidable yet indispensable challenge. In this study, the dyeing ability of the crude gel prodigiosin, produced by non-pathogenic bacteria Serratia plymuthica, was investigated on various multifiber fabrics at different conditions (temperature and pH) and by using salts and alternative mordants (the conventional Ferrous Sulphate (FeSO4) and a new bio-mordant, L-Cysteine (L-Cys)). Additionally, a novel gel-based Choline chloride (ChCl)/Lactic acid (LA) (1:2) deep eutectic solvent (DES) dyeing medium was studied to replace the organic solvents. Nylon fabrics dyed with 3.0% over the weight of the fiber (owf) L-Cys at pH = 8.3 had improved color fastness to washing, while the gel-based ChCl/LA (1:2) DES dyebath provided a better color fastness to light. Moreover, nylon fabrics under these conditions exhibited remarkable antimicrobial activity against Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa). In conclusion, the utilization of the crude gel-based prodigiosin pigment demonstrates a distinct advantage in dyeing textile materials, aligning with the growing consumer demand for more eco-friendly and sustainable products. Additionally, the application of the natural reducing agent L-Cys, previously untested as a bio-mordant, in conjunction with the use of gel-based DES as a dyeing medium, has showcased improved colorimetric and antibacterial properties when applied to nylon that is dyed with the crude gel prodigiosin pigment.

Interactions between ploidy and resource availability shape clonal interference at initiation and recurrence of glioblastoma.

Glioblastoma (GBM) is the most aggressive form of primary brain tumor. Complete surgical resection of GBM is almost impossible due to the infiltrative nature of the cancer. While no evidence for recent selection events have been found after diagnosis, the selective forces that govern gliomagenesis are strong, shaping the tumor's cell composition during the initial progression to malignancy with late consequences for invasiveness and therapy response. We present a mathematical model that simulates the growth and invasion of a glioma, given its ploidy level and the nature of its brain tissue micro-environment (TME), and use it to make inferences about GBM initiation and response to standard-of-care treatment. We approximate the spatial distribution of resource access in the TME through integration of in-silico modelling, multi-omics data and image analysis of primary and recurrent GBM. In the pre-malignant setting, our in-silico results suggest that low ploidy cancer cells are more resistant to starvation-induced cell death. In the malignant setting, between first and second surgery, simulated tumors with different ploidy compositions progressed at different rates. Whether higher ploidy predicted fast recurrence, however, depended on the TME. Historical data supports this dependence on TME resources, as shown by a significant correlation between the median glucose uptake rates in human tissues and the median ploidy of cancer types that arise in the respective tissues (Spearman r = -0.70; P = 0.026). Taken together our findings suggest that availability of metabolic substrates in the TME drives different cell fate decisions for cancer cells with different ploidy and shapes GBM disease initiation and relapse characteristics.

Upcycling Wool Waste into Keratin Gel-Based Nanofibers Using Deep Eutectic Solvents.

Millions of tons of wool waste are produced yearly by textile industries, which may become a serious environmental hazard in the near future. Given this concern, it is crucial to explore strategies to reduce the amount of wool waste generated worldwide and adopt more sustainable practices for dissolving and regenerating wool keratin (WK) from textile waste. Most traditional methods involve the use of expensive, toxic, harmful, and poorly biodegradable compounds. To overcome these limitations and facilitate the reuse of wool waste through a cascade valorization strategy, researchers have started testing the use of deep eutectic solvents (DES) as a more sustainable and eco-friendly alternative for WK dissolution and regeneration. In this study, the potential of two different DES mixtures, Choline chloride (ChCl): Urea and L-Cysteine (L-Cys): Lactic acid (LA), was explored for dissolving wool waste. Subsequently, the gels obtained based on DES-WK were blended with polyvinyl alcohol (PVA) in different ratios to produce nanofibers using the electrospinning technique. The PVA/L-Cys: LA DES-WK proved to be the most effective DES mixture for fabricating WK gel-based nanofibers. Furthermore, their antioxidant and antimicrobial abilities were evaluated, thus confirming their bioactivity. The results obtained revealed that this approach to valorizing textile waste offers a unique avenue for the development of sustainable functional materials with potential applications in various biomedical and industrial fields.

Nanoemulsions and Solid Microparticles Containing Pentyl Cinnamate to Control Aedes aegypti.

The Aedes aegypti mosquito is a vector of severe diseases with high morbidity and mortality rates. The most commonly used industrial larvicides have considerable toxicity for non-target organisms. This study aimed to develop and evaluate liquid and solid carrier systems to use pentyl cinnamate (PC), derived from natural sources, to control Ae. aegypti larvae. The liquid systems consisting of nanoemulsions with different lecithins systems were obtained and evaluated for stability over 30 days. Microparticles (MPs) were obtained by the spray drying of the nanoemulsions using maltodextrin as an adjuvant. Thermal, NMR and FTIR analysis indicated the presence of PC in microparticles. Indeed, the best nanoemulsion system was also the most stable and generated the highest MP yield. The PC larvicidal activity was increased in the PC nanoemulsion system. Therefore, it was possible to develop, characterize and obtain PC carrier systems active against Ae. aegypti larvae.

Emulsion Electrospinning of PLLA/PVA/Chitosan with Hypericum perforatum L. as an Antibacterial Nanofibrous Wound Dressing.

Chronic wounds are one of the most severe health problems that affect millions of people worldwide. These types of injuries impair healing and lead to life-threatening complications. Therefore, suitable wound dressing materials are essential to prevent the risk of infection and to provide an excellent healing environment. The present research reports the development of an electrospun Poly (L-lactic acid) (PLLA)/Poly (vinyl alcohol) (PVA)/Chitosan (CS) wound dressing material, produced via emulsion electrospinning in a single step using homogeneous gel-like suspensions of two different and incompatible polymer solutions. The electrospun PLLA/PVA/CS fiber mats were loaded with two different amounts of Hypericum perforatum L. (HP) (2.5% and 5.0% owf). The results revealed that the produced electrospun PLLA/PVA/CS fiber mats displayed ideal properties as a wound dressing due to a total porosity, wettability, water vapor transmission rate (WVTR), and swelling properties similar to those reported for the extracellular matrix (ECM) of the skin, mainly when 2.5% owf HP was incorporated. Moreover, the electrospun PLLA/PVA/CS fiber mats containing HP were able to prevent the growth of gram-positive bacterium Staphylococcus aureus (S. aureus) without causing cytotoxicity to normal human dermal fibroblasts (NHDF). These findings suggest that these electrospun dressing mats are helpful for preventing wound infections as well as an appropriate support and microenvironment for wound healing.

NADK-mediated de novo NADP(H) synthesis is a metabolic adaptation essential for breast cancer metastasis.

Metabolic reprogramming and metabolic plasticity allow cancer cells to fine-tune their metabolism and adapt to the ever-changing environments of the metastatic cascade, for which lipid metabolism and oxidative stress are of particular importance. NADPH is a central co-factor for both lipid and redox homeostasis, suggesting that cancer cells may require larger pools of NADPH to efficiently metastasize. NADPH is recycled through reduction of NADP+ by several enzymatic systems in cells; however, de novo NADP+ is synthesized only through one known enzymatic reaction, catalyzed by NAD+ kinase (NADK). Here, we show that NADK is upregulated in metastatic breast cancer cells enabling de novo production of NADP(H) and the expansion of the NADP(H) pools thereby increasing the ability of these cells to adapt to the challenges of the metastatic cascade and efficiently metastasize. Mechanistically, we found that metastatic signals lead to a histone H3.3 variant-mediated epigenetic regulation of the NADK promoter, resulting in increased NADK levels in cells with metastatic ability. Together, our work presents a previously uncharacterized role for NADK and de novo NADP(H) production as a contributor to breast cancer progression and suggests that NADK constitutes an important and much needed therapeutic target for metastatic breast cancers.

Comparison of conventional and contemporary root canal disinfection protocols against bacteria, lipoteichoic acid (LTA), and lipopolysaccharide (LPS).

This study devised a dual-species biofilm model to investigate bacteria, lipoteichoic acid (LTA), and lipopolysaccharide (LPS) simultaneously, and compared the efficacy of conventional and contemporary disinfection protocols. Seventy single-rooted mandibular premolars were included. Fourteen teeth were negative control, and 56 teeth were infected with 3-week-old E. faecalis and E. coli GFP biofilm. Fourteen/56 teeth were positive control, with seven teeth processed for CLSM analysis and seven teeth sampled with paper points (PPs) and cryogenically ground for bacterial, LTA, and LPS analyses. Forty-two teeth were randomly divided into three groups: GWS (GentleWave system) + MIT (minimally invasive technique), PUI (passive ultrasonic irrigation) + CIT (conventional instrumentation technique), and XP-EF (XP-endo Finisher) + CIT (All, n = 14). Samples were collected before (s1) and after disinfection (s2) with PPs and after cryogenically ground (s3). CFUs were counted, and LTA and LPS were quantified with LTA-ELISA and LAL assay, respectively. XP-EF was as effective as PUI (p > 0.05). GWS + MIT was the most effective disinfection protocol against bacteria, LTA, and LPS (p < 0.05). In conclusion, PUI, XP-EF, and GWS were highly effective against bacteria, LTA, and LPS, with GWS being the most effective.

From Hemp Waste to Bioactive Nanofiber Composites: Deep Eutectic Solvents and Electrospinning in Upcycling Endeavors.

Natural fibers have attracted increasing interest as an alternative to produce environmentally friendly and sustainable materials. Particularly, hemp fibers have been widely used in various industrial applications due to their extremely unique properties. However, hemp can generate a large amount of agro-waste, and it results in an attractive source of biopolymers for the development of low-cost materials as an alternative to the raw materials and conventional petroleum-based plastics. In addition, deep eutectic solvents (DESs), a new type of truly green solvents, have been shown to remove gums, lignin, and other non-cellulosic components from hemp fibers. Reusing these components dissolved into the DESs to fabricate new materials directly by electrospinning is a very attractive but still unexplored endeavor. Thus, this innovative research to venture new upcycling pathways is focused on the fabrication of composite nanofibers by electrospinning of a gel-based blend of Poly(vinyl alcohol) (PVA) and hemp agro-waste (HW) dissolved into choline chloride (ChCl):Glycerol (1:2) and ChCl:Urea (1:2) DES mixtures. The results obtained revealed that the produced nanofibers displayed uniform appearance with diameters ranging from 257.7 ± 65.6 nm to 380.8 ± 134.0 nm. In addition, the mechanical properties of the electrospun composite nanofibers produced from the gel-based blends of HW dissolved in DESs and PVA (HW-DESs_PVA) were found to be superior, resulting in an enhanced tensile strength and Young's modulus. Furthermore, the incorporation of HW into the nanofibers was able to provide bioactive antioxidant and antibacterial properties. Overall, this study demonstrated a promising, more sustainable, and eco-friendly way to produce electrospun composite nanofibers using HW in a circular economy perspective.

Leaf surfaces and neolithization - the case of Arundo donax L.

Arundo donax L. (Arundinoideae subfamily, Poaceae family) is a sub-tropical and temperate climate reed that grows in arid and semi-arid environmental conditions, from eastern China to the Mediterranean basin, suggesting potential adaptations at the epicuticular level. A thorough physical-chemical examination of the adaxial and abaxial surfaces of A. donax leaf was performed herein in an attempt to track such chemophenetic adaptations. This sort of approach is of the utmost importance for the current debate about the hypothetical invasiveness of this species in the Mediterranean basin versus its natural colonization along the Plio-Pleistocene period. We concluded that the leaf surfaces contain, apart from stomata, prickles, and long, thin trichomes, and silicon-rich tetralobate phytolits. Chemically, the dominating elements in the leaf ashes are oxygen and potassium; minor amounts of calcium, silicon, magnesium, phosphorous, sulphur, and chlorine were also detected. In both surfaces the epicuticular waxes (whose density is higher in the adaxial surface than in the abaxial surface) form randomly orientated platelets, with irregular shape and variable size, and aggregated rodlets with variable diameter around the stomata. In the case of green mature leaves, the dominating organic compounds of the epicuticular waxes of both surfaces are triterpenoids. Both surfaces feature identical hydrophobic behaviour, and exhibit the same total transmittance, total reflectance, and absorption of incident light. The above findings suggest easy growth of the plant, remarkable epidermic robustness of the leaf, and control of water loss. These chemophenetic characteristics and human influence support a neolithization process of this species along the Mediterranean basin.

Design and Preparation of a Biobased Colorimetric pH Indicator from Cellulose and Pigments of Bacterial Origin, for Potential Application as Smart Food Packaging.

Nowadays, worldwide challenges such as global warming, pollution, unsustainable consumption patterns, and scarcity of natural resources are key drivers toward future-oriented bioeconomy strategies, which rely on renewable biobased resources, such as bacterial pigments and bacterial cellulose (BC), for materials production. Therefore, the purpose of this study was to functionalize bacterial cellulose with violacein, flexirubin-type pigment, and prodigiosin and test their suitability as pH indicators, due to the pigments' sensitivity to pH alterations. The screening of the most suitable conditions to obtain the BC-pigment indicators was achieved using a full factorial design, for a more sustainable functionalization process. Then, the pH response of functionalized BC to buffer solutions was assessed, with color changes at acidic pH (BC-violacein indicator) and at alkaline pH (BC-violacein, BC-prodigiosin, and BC-flexirubin-type pigment indicators). Moreover, the indicators also revealed sensitivity to acid and base vapors. Furthermore, leaching evaluation of the produced indicators showed higher suitability for aqueous foods. Additionally, color stability of the functionalized BC indicators was carried out, after light exposure and storage at 4 °C, to evaluate the indicators' capacity to maintain color/sensitivity. Thus, BC membranes functionalized with bacterial pigments have the potential to be further developed and used as pH indicators.

Metabolic reprogramming: a bridge between aging and tumorigenesis.

Aging is the most robust risk factor for cancer development, with more than 60% of cancers occurring in those aged 60 and above. However, how aging and tumorigenesis are intertwined is poorly understood and a matter of significant debate. Metabolic changes are hallmarks of both aging and tumorigenesis. The deleterious consequences of aging include dysfunctional cellular processes, the build-up of metabolic byproducts and waste molecules in circulation and within tissues, and stiffer connective tissues that impede blood flow and oxygenation. Collectively, these age-driven changes lead to metabolic reprogramming in different cell types of a given tissue that significantly affects their cellular functions. Here, we put forward the idea that metabolic changes that happen during aging help create a favorable environment for tumorigenesis. We review parallels in metabolic changes that happen during aging and how these changes function both as adaptive mechanisms that enable the development of malignant phenotypes in a cell-autonomous manner and as mechanisms that suppress immune surveillance, collectively creating the perfect environment for cancers to thrive. Hence, antiaging therapeutic strategies that target the metabolic reprogramming that occurs as we age might provide new opportunities to prevent cancer initiation and/or improve responses to standard-of-care anticancer therapies.

Altered propionate metabolism contributes to tumour progression and aggressiveness.

The alteration of metabolic pathways is a critical strategy for cancer cells to attain the traits necessary for metastasis in disease progression. Here, we find that dysregulation of propionate metabolism produces a pro-aggressive signature in breast and lung cancer cells, increasing their metastatic potential. This occurs through the downregulation of methylmalonyl coenzyme A epimerase (MCEE), mediated by an extracellular signal-regulated kinase 2-driven transcription factor Sp1/early growth response protein 1 transcriptional switch driven by metastatic signalling at its promoter level. The loss of MCEE results in reduced propionate-driven anaplerotic flux and intracellular and intratumoral accumulation of methylmalonic acid, a by-product of propionate metabolism that promotes cancer cell invasiveness. Altogether, we present a previously uncharacterized dysregulation of propionate metabolism as an important contributor to cancer and a valuable potential target in the therapeutic treatment of metastatic carcinomas.

Comparison of GentleWave system and passive ultrasonic irrigation with minimally invasive and conventional instrumentation against LPS in infected root canals.

This study compared the effectiveness of GentleWave system (GWS) and passive ultrasonic irrigation (PUI) in removing lipopolysaccharides (LPS) from infected root canals after minimally invasive (MIT) and conventional instrumentation (CIT) techniques. Sixty first premolars with two roots were inoculated with fluorescent LPS conjugate (Alexa Fluor 594). Of those, twelve were dentin pretreated, inoculated with fluorescent LPS conjugate, and submitted to confocal laser scanning microscopy (CLSM) to validate the LPS-infection model. Forty-eight teeth were randomly divided into treatment groups: GWS + MIT, GWS + CIT, PUI + MIT, and PUI + CIT (all, n = 12). Teeth were instrumented with Vortex Blue rotary file size 15/0.04 for MIT and 35/0.04 for CIT. Samples were collected before (s1) and after a root canal procedure (s2) and after cryogenically ground the teeth (s3) for intraradicular LPS analysis. LPS were quantified with LAL assay (KQCL test). GWS + MIT and GWS + CIT were the most effective protocols against LPS, with no difference between them (p > 0.05). PUI + CIT was more effective than PUI + MIT (p < 0.05) but less effective than GWS + MIT and GWS + CIT. GWS was the most effective protocol against LPS in infected root canals using MIT and CIT techniques.