Combating Acute Myeloid Leukemia via Sphingosine Kinase 1 Inhibitor-Nanomedicine Combination Therapy with Cytarabine or Venetoclax.

MP-A08 is a novel sphingosine kinase 1 (SPHK1) inhibitor with activity against acute myeloid leukemia (AML). A rationally designed liposome-based encapsulation and delivery system has been shown to overcome the physicochemical challenges of MP-A08 and enable its effective delivery for improved efficacy and survival of mice engrafted with human AML in preclinical models. To establish therapies that overcome AML's heterogeneous nature, here we explored the combination of MP-A08-loaded liposomes with both the standard chemotherapy, cytarabine, and the targeted therapy, venetoclax, against human AML cell lines. Cytarabine (over the dose range of 0.1-0.5 µM) in combination with MP-A08 liposomes showed significant synergistic effects (as confirmed by the Chou-Talalay Combination Index) against the chemosensitised human AML cell lines MV4-11 and OCI-AML3. Venetoclax (over the dose range of 0.5-250 nM) in combination with MP-A08 liposomes showed significant synergistic effects against the chemosensitised human AML cell lines, particularly in venetoclax-resistant human AML cells. This strong synergistic effect is due to multiple mechanisms of action, i.e., inhibiting MCL-1 through SPHK1 inhibition, leading to ceramide accumulation, activation of protein kinase R, ATF4 upregulation, and NOXA activation, ultimately resulting in MCL-1 degradation. These combination therapies warrant further consideration and investigation in the search for a more comprehensive treatment strategy for AML.

Foaming properties of milk samples collected at various processing stages in a dairy processing factory across two seasons.

BACKGROUND: A foam layer makes an essential contribution to the quality of cappuccino-style drinks. Poor foaming of milk occurs quite often, however, especially in summer. The reasons for this are still unknown. Although a substantial number of studies on the foaming process of milk have been reported, these studies have been laboratory based and have used laboratory or pilot-scale equipment to simulate the processing conditions of a dairy processing factory. This study collected about 40 different samples across different processing stages in a dairy factory over two seasons (two batches per season) and investigated their composition and physical and foaming properties by mechanical mixing and steam injection. RESULTS: The results showed that milk samples collected in summer had a significantly higher content of fat, free fatty acids, and Ca2+ ions, and larger particle sizes but a markedly lower concentration of protein and solid non-fat, and surface tension than the samples collected in spring. These differences provided spring milk with a higher steam injection foamability than summer milk. However, steam injection foam stability, and mechanical mixing foamability and foam stability were not affected by seasonal factors. Milk samples collected in different batches within a season were almost identical with regard to the properties that were investigated. CONCLUSION: The variations in composition and physical properties of milk collected between two seasons could be the reasons for their difference in foamability but not for foam stability. Processes such as standardization, homogenization, and pasteurization improved markedly the foaming properties of milk. © 2023 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Gel characteristics of low-acetyl spruce galactoglucomannans.

Galactoglucomannans (GGM) recovered from abundant forest industry side-streams has been widely recognized as a renewable hydrocolloid. The low molar mass and presence of O-acetyl side-groups results in low viscous dispersions and weak intermolecular interactions that make GGM unsuitable for hydrogel formation, unless forcefully chemically derivatized and/or crosslinked with other polymers. Here we present the characterization of hydrogels prepared from GGM after tailoring the degree of acetylation by alkaline treatment during its recovery. Specifically, we investigated gel characteristics of low-acetyl GGM dispersions prepared at varied solid concentrations (5, 10 and 15 %) and pH (4, 7 and 10), and then subjected to ultrasonication. The results indicated that low-acetyl GGM dispersions formed gels (G' > G″) at all other studied solid concentration and pH level combinations except 5 % and pH 4. High pH levels, leading to further removal of acetyl groups, and high solid concentration facilitated the gel formation. GGM hydrogels were weak gels with strong shear-thinning behavior and thixotropic properties, and high hardness and water holding capacity; which were enhanced with increased pH and solid concentration, and prolonged storage time. Our study showed the possibility to utilize low-acetyl GGM as mildly processed gelling or thickening agents, and renewable materials for bio-based hydrogels.

Targeting Acute Myeloid Leukemia Using Sphingosine Kinase 1 Inhibitor-Loaded Liposomes.

Acute myeloid leukemia (AML) kills 75% of patients and represents a major clinical challenge with a need to improve on current treatment approaches. Targeting sphingosine kinase 1 with a novel ATP-competitive-inhibitor, MP-A08, induces cell death in AML. However, limitations in MP-A08's "drug-like properties" (solubility, biodistribution, and potency) hinder its pathway to the clinic. This study demonstrates a liposome-based delivery system of MP-A08 that exhibits enhanced MP-A08 potency against AML cells. MP-A08-liposomes increased MP-A08 efficacy against patient AML cells (>140-fold) and significantly prolonged overall survival of mice with human AML disease (P = 0.03). The significant antileukemic property of MP-A08-liposomes could be attributed to its enhanced specificity, bioaccessibility, and delivery to the bone marrow, as demonstrated in the pharmacokinetic and biodistribution studies. Our findings indicate that MP-A08-liposomes have potential as a novel treatment for AML.

Effect of shearing-induced lipolysis on foaming properties of milk.

BACKGROUND: The attraction of cappuccino-style beverages is attributed to the foam layer, as it greatly improves the texture, appearance, and taste of these products. Typical milk has a low concentration of free fatty acids (FFAs), but their concentration can increase due to lipolysis during processing and storage, which is detrimental to the foamability and foam stability of milk. There are contradictory results in reported studies concerning the effects of FFAs on the foaming properties of milk due to differences in milk sources, methods inducing lipolysis, and methods of creating foam. In this study, the foaming properties and foam structure of milk samples whose lipolysis was induced by ultra-turraxing, homogenisation, and microfluidisation (1.5-3.5 µ-equiv. mL-1 FFAs) were investigated. RESULTS: Compared with others, microfluidised milk samples had the smallest particle size, lowest absolute zeta potential, and highest surface tension; thus exhibited high foamability and foam stability, and very small and homogeneous air bubbles in foam structure. For all shearing methods, increasing FFA content from 1.5 to 3.5 µ-equiv. mL-1 markedly decreased the surface tension, foamability, and foam stability of milk samples. The FFA level that led to undesirable foam structure was 1.5 µ-equiv. mL-1 for ultra-turraxed milk samples and 2.5 µ-equiv. mL-1 for homogenised and microfluidised ones. CONCLUSION: Shearing-induced lipolysis greatly affected the physical properties of milk samples and subsequently their foaming properties and foam structure. At the same FFA level, lipolysis induced by microfluidisation was much less detrimental to the foaming properties of milk than lipolysis induced by ultra-turraxing and homogenisation. © 2023 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Wood hemicelluloses as effective wall materials for spray-dried microcapsulation of polyunsaturated fatty acid-rich oils.

The most commonly-used and effective wall materials (WMs) for spray-dried microencapsulation of bioactive compounds are either costly, or derived from unsustainable sources, which lead to an increasing demand for alternatives derived from sustainable and natural sources, with low calories and low cost. Wood hemicelluloses obtained from by-products of forest industries appear to be attractive alternatives as they have been reported to have good emulsifying properties, low viscosity at high concentrations, high heat stability and low heat transfer. Here, we investigated the applicability of spruce galactoglucomannans (GGM) and birch glucuronoxylans (GX), to encapsulate flaxseed oil (FO, polyunsaturated fatty acid-rich plant based oil) by spray drying; and the results were compared to those of the highly effective WM, gum Arabic (GA). It was found that depending on solid ratios of WM:FO (1:1, 3:1 and 5:1), encapsulation efficiency of GGM was 88-96%, and GX was 63-98%. At the same encapsulation ratio, both GGM and GX had higher encapsulation efficiency than GA (49-92%) due to their ability to produce feed emulsions with a smaller oil droplet size and higher physical stability. In addition, the presence of phenolic residues in GGM and GX powders enabled them to have a greater ability to protect oil from oxidation during spray drying than GA. Physiochemical properties of encapsulated powders including thermal properties, morphology, molecular structure, particle size and water adsorption intake are also investigated. The study has explored a new value-added proposition for wood hemicelluloses which can be used as effective WMs in the production of microcapsules of polyunsaturated fatty acid-rich oils for healthy and functional products in food, pharmaceutical and cosmetic industries.

Polysaccharides as wall materials in spray-dried microencapsulation of bioactive compounds: Physicochemical properties and characterization.

Natural bioactive compounds (BCs) are types of chemicals found in plants and certain foods that promote good health, however they are sensitive to processing and environmental conditions. Microencapsulation by spray drying is a widely used and cost-effective approach to create a coating layer to surround and protect BCs and control their release, enabling the production of high functional products/ingredients with extended shelf life. In this process, wall materials determine protection efficiency, and physical properties, bioavailability, and storage stability of microencapsulated products. Therefore, an understanding of physicochemical properties of wall materials is essential for the successful and effective spray-dried microencapsulation process. Typically, polysaccharide-based wall materials are generated from more sustainable sources and have a wider range of physicochemical properties and applications compared to their protein-based counterparts. In this review, we highlight the essential physicochemical properties of polysaccharide-based wall materials for spray-dried microencapsulation of BCs including solubility, thermal stability, and emulsifying properties, rheological and film forming properties. We provide further insight into possibilities for the chemical structure modification of native wall materials and their controlled release behaviors. Finally, we summarize the most recent studies involving polysaccharide biopolymers as wall materials and/or emulsifiers in spray-dried microencapsulation of BCs.

Bellevue Hospital, the Oldest Public Health Center in the United States of America.

Bellevue Hospital is known as the oldest public hospital in the United States of America. Although its historical beginnings date back to the 1600s, it was officially founded on the second floor of the New York City Almshouse in 1736, 40 years before the American Revolution. It has since been at the forefront of administering comprehensive patient care and medical education. Moreover, Bellevue has built a reputation for serving homeless, immigrant, or minority populations while also delivering care to United States presidents. This tradition of treating patients regardless of socioeconomic or racial status has made Bellevue one of the most historically renowned hospitals in the country. Today, Bellevue hospital represents a significant branch of the New York City health system and a public health leader. Moreover, it has housed pioneers in neurosurgery, including the father of functional ultrasonic neurosurgery, Dr. Russel Meyers, as well as Dr. Dorothy Klenke Nash, the only active female neurosurgeon in the United States from 1928 to 1960. Herein, we will explore Bellevue's historical and medical significance, from its humble beginnings to its current status as a public health leader.

Ceramide-induced integrated stress response overcomes Bcl-2 inhibitor resistance in acute myeloid leukemia.

Inducing cell death by the sphingolipid ceramide is a potential anticancer strategy, but the underlying mechanisms remain poorly defined. In this study, triggering an accumulation of ceramide in acute myeloid leukemia (AML) cells by inhibition of sphingosine kinase induced an apoptotic integrated stress response (ISR) through protein kinase R-mediated activation of the master transcription factor ATF4. This effect led to transcription of the BH3-only protein Noxa and degradation of the prosurvival Mcl-1 protein on which AML cells are highly dependent for survival. Targeting this novel ISR pathway, in combination with the Bcl-2 inhibitor venetoclax, synergistically killed primary AML blasts, including those with venetoclax-resistant mutations, as well as immunophenotypic leukemic stem cells, and reduced leukemic engraftment in patient-derived AML xenografts. Collectively, these findings provide mechanistic insight into the anticancer effects of ceramide and preclinical evidence for new approaches to augment Bcl-2 inhibition in the therapy of AML and other cancers with high Mcl-1 dependency.

Camel milk: A review of its nutritional value, heat stability, and potential food products.

Camel milk is superior to bovine milk and quite close to human milk in terms of its nutritional value. It contains high concentrations of many bioactive compounds that are essential for human health. Despite its profound nutritional and health benefits, food products produced from camel milk are still very limited compared to bovine milk. Differences in the composition of bovine and camel milk make the production processes for bovine milk products unsuitable for camel milk products. Therefore, a comprehensive understanding regarding the composition, bioactive compounds, and the heat stability of camel milk is essential to preserve the inherent nutritional value of camel milk while achieving desirable attributes in the final products. In this review, the properties and functionalities of macro-nutrients in camel milk, especially heat stability of camel milk and its proteins are described. In addition, technical aspects of the production of various camel milk products, including difficulties in their production and directions for further research to enhance their quality, are comprehensively discussed.

Valorization of cereal by-product hemicelluloses: Fractionation and purity considerations.

The biomass from cereal side streams is rich in valuable components, such as hemicelluloses. Among the hemicelluloses, arabinoxylans and ß-glucans are the most acknowledged for potential health benefits. Numerous publications discuss the potential to use purified forms of these hemicelluloses for various applications. However, as the purification of hemicelluloses may not be economically feasible to upscale, sustainable and cost-effective methods are needed to make their valorization more realistic for industrial applications. Co-components present in hemicellulose-rich fractions may also provide added functionality, such as flavonoid content and antioxidant capacity. This review provides an overview on the feasibility of sustainably upscaling hemicellulose extraction processes, focusing on by-products from different cereal streams. We describe the hemicelluloses' physicochemical properties and provide various possible applications of pure and impure fractions from small scale to pilot and industrial scale. Furthermore, real case examples on the industrial utilization of cereal side streams are enclosed. This review provides pathways for future research for developing the hemicellulose extraction methods to obtain fractions with optimized purity, and offers suggestions to valorize them.

Functionality of bovine milk proteins and other factors in foaming properties of milk: a review.

For many dairy products such as cappuccino-style beverages, the top foam layer determines the overall product quality (e.g. their appearance, texture, mouthfeel and coffee aroma release rate) and the consumer acceptance. Proteins in milk are excellent foaming agents, but the foaming properties of milk are greatly affected by several factors such as the protein content, ratio of caseins to whey proteins, casein micelle size, pH, minerals, proteolysis, presence of low molecular weight compounds (lipids and their hydrolyzed products) and high molecular weight compounds (polysaccharides); milk processing conditions (e.g. homogenization, heat treatment and aging); and foaming method and temperature. These factors either induce changes in the molecular structure, charge and surface activity of the milk proteins; or interfere and/or compete with milk proteins in the formation of highly viscoelastic film to stabilize the foam. Some factors affect the foamability while others determine the foam stability. In this review, functionality of milk proteins in the production and stabilization of liquid foam, under effects of these factors is comprehensively discussed. This will help to control the foaming process of milk on demand for a particular application, which still is difficult and challenging for researchers and the dairy industry.

Environmental risk factors of type 2 diabetes-an exposome approach.

Type 2 diabetes is one of the major chronic diseases accounting for a substantial proportion of disease burden in Western countries. The majority of the burden of type 2 diabetes is attributed to environmental risks and modifiable risk factors such as lifestyle. The environment we live in, and changes to it, can thus contribute substantially to the prevention of type 2 diabetes at a population level. The 'exposome' represents the (measurable) totality of environmental, i.e. nongenetic, drivers of health and disease. The external exposome comprises aspects of the built environment, the social environment, the physico-chemical environment and the lifestyle/food environment. The internal exposome comprises measurements at the epigenetic, transcript, proteome, microbiome or metabolome level to study either the exposures directly, the imprints these exposures leave in the biological system, the potential of the body to combat environmental insults and/or the biology itself. In this review, we describe the evidence for environmental risk factors of type 2 diabetes, focusing on both the general external exposome and imprints of this on the internal exposome. Studies provided established associations of air pollution, residential noise and area-level socioeconomic deprivation with an increased risk of type 2 diabetes, while neighbourhood walkability and green space are consistently associated with a reduced risk of type 2 diabetes. There is little or inconsistent evidence on the contribution of the food environment, other aspects of the social environment and outdoor temperature. These environmental factors are thought to affect type 2 diabetes risk mainly through mechanisms incorporating lifestyle factors such as physical activity or diet, the microbiome, inflammation or chronic stress. To further assess causality of these associations, future studies should focus on investigating the longitudinal effects of our environment (and changes to it) in relation to type 2 diabetes risk and whether these associations are explained by these proposed mechanisms.

Enzyme-like catalysis by single chain nanoparticles that use transition metal cofactors.

We report a modular approach in which a noncovalently cross-linked single chain nanoparticle (SCNP) selectively binds catalyst "cofactors" and substrates to increase both the catalytic activity of a Cu-catalyzed alkyne-azide cycloaddition reaction and the Ru-catalyzed cleavage of allylcarbamate groups compared to the free catalysts.

Changes in surface chemical composition relating to rehydration properties of spray-dried camel milk powder during accelerated storage.

Alterations in surface chemical composition relating to rehydration properties of spray-dried camel milk powders during accelerated storage (11-33% RH, 37 °C) over 18 weeks were investigated. The results showed that the surface of the fresh spray-dried camel milk powder (t = 0) was dominated by lipids (78%), followed by proteins (16%) and lactose (6%). During storage, the surface protein and lactose content decreased while the surface lipid content increased, resulting in an increase in surface hydrophobicity and slight agglomeration of the powder, especially for powder kept at 33% RH. Although fresh camel milk powder had very poor wettability, it displayed very high dispersibility and solubility (99%). During storage, dispersibility and solubility declined with increasing storage time and increasing RH levels, which correlated with an increase in surface lipid content. However, at the end of the storage period, camel milk powder still retained very high solubility (>93%).

Measuring association among censored antibody titer data.

Censoring due to a limit of detection or limit of quantification happens quite often in many medical studies. Conventional approaches to deal with censoring when analyzing these data include, for example, the substitution method and the complete case (CC) analysis. More recently, maximum likelihood estimation (MLE) has been increasingly used. While the CC analysis and the substitution method usually lead to biased estimates, the MLE approach appears to perform well in many situations. This article proposes an MLE approach to estimate the association between two measurements in the presence of censoring in one or both quantities. The central idea is to use a copula function to join the marginal distributions of the two measurements. In various simulation studies, we show that our approach outperforms existing conventional methods (CC and substitution analyses). In addition, rank-based measures of global association such as Kendall's tau or Spearman's rho can be studied, hence, attention is not only confined to Pearson's product-moment correlation coefficient capturing solely linear association. We have shown in our simulations that our approach is robust to misspecification of the copula function or marginal distributions given a small association. Furthermore, we propose a straightforward MLE method to fit a (multiple) linear regression model in the presence of censoring in a covariate or both the covariate and the response. Given the marginal distribution of the censored covariate, our method outperforms conventional approaches. We also compare and discuss the performance of our method with multiple imputation and missing indicator model approaches.

A general frailty model to accommodate individual heterogeneity in the acquisition of multiple infections: An application to bivariate current status data.

The analysis of multivariate time-to-event (TTE) data can become complicated due to the presence of clustering, leading to dependence between multiple event times. For a long time, (conditional) frailty models and (marginal) copula models have been used to analyze clustered TTE data. In this article, we propose a general frailty model employing a copula function between the frailty terms to construct flexible (bivariate) frailty distributions with the application to current status data. The model has the advantage to impose a less restrictive correlation structure among latent frailty variables as compared to traditional frailty models. Specifically, our model uses a copula function to join the marginal distributions of the frailty vector. In this article, we considered different copula functions, and we relied on marginal gamma distributions due to their mathematical convenience. Based on a simulation study, our novel model outperformed the commonly used additive correlated gamma frailty model, especially in the case of a negative association between the frailties. At the end of the article, the new methodology is illustrated on real-life data applications entailing bivariate serological survey data.

A novel application of membrane distillation to facilitate nickel recovery from electroplating wastewater.

In many years, the nickel electroplating technique has been applied to coat nickel on other materials for their increased properties. Nickel electroplating has played a vital role in our modern society but also caused considerable environmental concerns due to the mass discharge of its wastewater (i.e. containing nickel and other heavy metals) to the environment. Thus, there is a growing need for treating nickel electroplating wastewater to protect the environment and, in tandem, recover nickel for beneficial use. This study explores a novel application of membrane distillation (MD) for the treatment of nickel electroplating wastewater for a dual purpose: facilitating the nickel recovery and obtaining fresh water. The experimental results demonstrate the technical capability of MD to pre-concentrate nickel in the wastewater (i.e. hence pave the way for subsequent nickel recovery via chemical precipitation or electrodeposition) and extract fresh water. At a low operating feed temperature of 60 °C, the MD process increased the nickel content in the wastewater by more than 100-fold from 0.31 to 33 g/L with only a 20% reduction in the process water flux and obtained pure fresh water. At such high concentration factors, the membrane surface was slightly fouled by inorganic precipitates; however, membrane pore wetting was not evident, confirmed by the purity of the obtained fresh water. The fouled membrane was effectively cleaned using a 3% HCl solution to restore its surface morphology. Finally, the preliminary thermal energy analysis of the combined MD-chemical precipitation/electrodeposition process reveals a considerable reduction in energy consumption of the nickel recovery process.

Changes in physicochemical properties of spray-dried camel milk powder over accelerated storage.

Changes in physiochemical properties of spray-dried camel milk powders during storage at 11-32% RH and 37 °C over 18 weeks were investigated. The results showed that fresh camel milk powders had amorphous structure, clumsy spherical shape particles and almost 100% solubility in water. During storage at controlled low RH levels (<32% RH), reduction in moisture content and aw of the powders caused glass transition signals of lactose to evolve, although the powders exhibited a slight development of crystallinity. True density, colour (L*, a* and whiteness), and morphology were almost unchanged during storage while b* values associated with non-enzymatic browning, and fat oxidation into volatile compounds increased steadily. Over storage period, solubility of the powder declined just slightly and secondary structure of proteins unfolded from α-helices to ß-sheets, loops and ß-turns. These changes were more profound for the powders stored at 32% RH than those kept at 11 and 22% RH.

Vasculogenic properties of adventitial Sca-1+CD45+ progenitor cells in mice: a potential source of vasa vasorum in atherosclerosis.

The cellular origins of vasa vasorum are ill-defined and may involve circulating or local progenitor cells. We previously discovered that murine aortic adventitia contains Sca-1+CD45+ progenitors that produce macrophages. Here we investigated whether they are also vasculogenic. In aortas of C57BL/6 mice, Sca-1+CD45+ cells were localised to adventitia and lacked surface expression of endothelial markers (<1% for CD31, CD144, TIE-2). In contrast, they did show expression of CD31, CD144, TIE-2 and VEGFR2 in atherosclerotic ApoE-/- aortas. Although Sca-1+CD45+ cells from C57BL/6 aorta did not express CD31, they formed CD31+ colonies in endothelial differentiation media and produced interconnecting vascular-like cords in Matrigel that contained both endothelial cells and a small population of macrophages, which were located at branch points. Transfer of aortic Sca-1+CD45+ cells generated endothelial cells and neovessels de novo in a hindlimb model of ischaemia and resulted in a 50% increase in perfusion compared to cell-free control. Similarly, their injection into the carotid adventitia of ApoE-/- mice produced donor-derived adventitial and peri-adventitial microvessels after atherogenic diet, suggestive of newly formed vasa vasorum. These findings show that beyond its content of macrophage progenitors, adventitial Sca-1+CD45+ cells are also vasculogenic and may be a source of vasa vasorum during atherogenesis.