Method for evaluating the fit of custom-fit Continuous Positive Airway Pressure masks using finite element analysis.

Continuous Positive Airway Pressure (CPAP) is a common therapy used to treat breathing disorders such as obstructive sleep apnea. In previous work, we designed a custom-fit CPAP mask to address comfort and leakage issues patients often experience. This paper presents a method to create a finite element (FE) model to evaluate the fit of the custom-fit mask before fabrication. The model includes details such as a skull to represent the variable soft tissue thicknesses on the face, and two strap configurations, original and X. The model was tested on four subjects and results show that the X strap configuration results in a more even stress distribution, measured by standard deviation, on the face compared to the original strap, indicating better fit. The simulations also show gaps in the stress distribution that seem to correspond to areas of leakage based on two initial in vivo tests on two subjects. This simulation method proves to be a valuable tool for custom-fit mask development by allowing us to evaluate designs before fabrication.

Development of a Novel Soft Tissue Measurement Device for Individualized Finite Element Modeling in Custom-Fit CPAP Mask Evaluation.

PURPOSE: Individual facial soft tissue properties are necessary for creating individualized finite element (FE) models to evaluate medical devices such as continuous positive airway pressure (CPAP) masks. There are no standard tools available to measure facial soft tissue elastic moduli, and techniques in literature require advanced equipment or custom parts to replicate. METHODS: We propose a simple and inexpensive soft tissue measurement (STM) indenter device to estimate facial soft tissue elasticity at five sites: chin, cheek near lip, below cheekbone, cheekbone, and cheek. The STM device consists of a probe with a linear actuator and force sensor, an adjustment system for probe orientation, a head support frame, and a controller. The device was validated on six ballistics gel samples and then tested on 28 subjects. Soft tissue thickness was also collected for each subject using ultrasound. RESULTS: Thickness and elastic modulus measurements were successfully collected for all subjects. The mean elastic modulus for each site is Ec = 53.04 ± 20.97 kPa for the chin, El = 16.33 ± 8.37 kPa for the cheek near lip, Ebc = 27.09 ± 11.38 kPa for below cheekbone, Ecb = 64.79 ± 17.12 kPa for the cheekbone, and Ech = 16.20 ± 5.09 kPa for the cheek. The thickness and elastic modulus values are in the range of previously reported values. One subject's measured soft tissue elastic moduli and thickness were used to evaluate custom-fit CPAP mask fit in comparison to a model of that subject with arbitrary elastic moduli and thickness. The model with measured values more closely resembles in vivo leakage results. CONCLUSION: Overall, the STM provides a first estimate of facial soft tissue elasticity and is affordable and easy to build with mostly off-the-shelf parts. These values can be used to create personalized FE models to evaluate custom-fit CPAP masks.

Exploring the clinical connections between epilepsy and diabetes mellitus: Promising therapeutic strategies utilizing agmatine and metformin.

PURPOSE: Diabetes mellitus (DM) and epilepsy and the psychological and socio-economic implications that are associated with their treatments can be quite perplexing. Metformin is an antihyperglycemic medication that is used to treat type 2 DM. In addition, metformin elicits protective actions against multiple diseases, including neurodegeneration and epilepsy. Recent studies indicate that metformin alters the resident gut microbiota in favor of species producing agmatine, an arginine metabolite which, in addition to beneficially altering metabolic pathways, is a potent neuroprotectant and neuromodulant. METHODS: We first examine the literature for epidemiological and clinical evidences linking DM and epilepsy. Next, basing our analyses on published literature, we propose the possible complementarity of agmatine and metformin in the treatment of DM and epilepsy. RESULTS: Our analyses of the clinical data suggest a significant association between pathogeneses of epilepsy and DM. Further, both agmatine and metformin appear to be multimodal therapeutic agents and have robust antiepileptogenic and antidiabetic properties. Data from animal and clinical studies largely support the use of metformin/agmatine as a double-edged pharmacotherapeutic agent against DM and epilepsy, particularly in their concurrent pathological occurrences. CONCLUSION: The present review explores the evidences and available data on possible uses of metformin/agmatine as pertinent antidiabetic and antiepileptic agents. Our hope is that this will stimulate further research on the therapeutic actions of these multimodal agents, particularly for subject-specific clinical outcomes.

Gum Ghatti: A Comprehensive Review on Production, Processing, Remarkable Properties, and Diverse Applications.

Gum ghatti, popularly known as Indian gum and obtained from Anogeissus latifolia, is a complex high-molecular-weight, water-soluble, and swellable nonstarch polysaccharide comprised of magnesium and calcium salts of ghattic acids and multiple monosugars. Unlike other nontimber forest produce, gums ghatti is a low-volume but high-value product. It has several applications and is widely used as food, in pharmaceuticals, and for wastewater treatment and hydrogel formation, and it has attracted a great deal of attention in the fields of energy, environmental science, and nanotechnology. Industrial applications of gum ghatti are primarily due to its excellent emulsification, stabilization, thickening, heat tolerance, pH stability, carrier, and biodegradable properties. However, utilization of gum ghatti is poorly explored and implemented due to a lack of knowledge of its production, processing, and properties. Nevertheless, there has been interest among investigators in recent times for exploring its production, processing, molecular skeleton, and functional properties. This present review focuses on production scenarios, processing aspects, structural and functional properties, and potential applications in the food, pharmaceuticals, nonfood, and other indigenous and industrial usages.

Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects.

Chronic lymphocytic leukemia (CLL) cell survival and growth is fueled by the induction of B-cell receptor (BCR) signaling within the tumor microenvironment (TME) driving activation of NFκB signaling and the unfolded protein response (UPR). Malignant cells have higher basal levels of UPR posing a unique therapeutic window to combat CLL cell growth using pharmacologic agents that induce accumulation of misfolded proteins. Frontline CLL therapeutics that directly target BCR signaling such as Bruton tyrosine kinase (BTK) inhibitors (e.g., ibrutinib) have enhanced patient survival. However, resistance mechanisms wherein tumor cells bypass BTK inhibition through acquired BTK mutations, and/or activation of alternative survival mechanisms have rendered ibrutinib ineffective, imposing the need for novel therapeutics. We evaluated SpiD3, a novel spirocyclic dimer, in CLL cell lines, patient-derived CLL samples, ibrutinib-resistant CLL cells, and in the Eµ-TCL1 mouse model. Our integrated multi-omics and functional analyses revealed BCR signaling, NFκB signaling, and endoplasmic reticulum stress among the top pathways modulated by SpiD3. This was accompanied by marked upregulation of the UPR and inhibition of global protein synthesis in CLL cell lines and patient-derived CLL cells. In ibrutinib-resistant CLL cells, SpiD3 retained its antileukemic effects, mirrored in reduced activation of key proliferative pathways (e.g., PRAS, ERK, MYC). Translationally, we observed reduced tumor burden in SpiD3-treated Eµ-TCL1 mice. Our findings reveal that SpiD3 exploits critical vulnerabilities in CLL cells including NFκB signaling and the UPR, culminating in profound antitumor properties independent of TME stimuli. SIGNIFICANCE: SpiD3 demonstrates cytotoxicity in CLL partially through inhibition of NFκB signaling independent of tumor-supportive stimuli. By inducing the accumulation of unfolded proteins, SpiD3 activates the UPR and hinders protein synthesis in CLL cells. Overall, SpiD3 exploits critical CLL vulnerabilities (i.e., the NFκB pathway and UPR) highlighting its use in drug-resistant CLL.

Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis.

The ability of tumour cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. Here we show that pancreatic cancer-associated fibroblasts (CAFs) regulate tumour cell metabolism through the secretion of acetate, which can be blocked by silencing ATP citrate lyase (ACLY) in CAFs. We further show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) channels the exogenous acetate to regulate the dynamic cancer epigenome and transcriptome, thereby facilitating cancer cell survival in an acidic microenvironment. Comparative H3K27ac ChIP-seq and RNA-seq analyses revealed alterations in polyamine homeostasis through regulation of SAT1 gene expression and enrichment of the SP1-responsive signature. We identified acetate/ACSS2-mediated acetylation of SP1 at the lysine 19 residue that increased SP1 protein stability and transcriptional activity. Genetic or pharmacologic inhibition of the ACSS2-SP1-SAT1 axis diminished the tumour burden in mouse models. These results reveal that the metabolic flexibility imparted by the stroma-derived acetate enabled cancer cell survival under acidosis via the ACSS2-SP1-SAT1 axis.

Recent Advances in the Extraction of Pectin from Various Sources and Industrial Applications.

Pectin is a structural polysaccharide present in plants that primarily consists of galacturonic acid units. This Review discusses the chemistry of pectin, including its composition and molecular weight. Pectin is conventionally extracted from agricultural waste (fruit and vegetable peels) using an acidic or basic aqueous medium at high temperatures. These processes are time- and energy-consuming and also result in severe environmental problems due to the production of acidic effluents and equipment corrosion. As pectin usage is increasing in food industries for developing different products and it is also used as an excipient in pharmaceutical products, better extraction procedures are required to maximize the yield and purity. The Review encompasses various alternate green approaches for the extraction of pectin, including traditional acid extraction and various emerging technologies such as deep eutectic solvent-based extraction, enzyme-assisted extraction, subcritical fluid extraction, ultrasound-assisted extraction, and microwave-based extraction, and evaluates the yield and physicochemical characteristics of the extracted pectin. This work aims to provide a platform for attracting more thorough research focused on the engineering of novel and more efficient green methods for the extraction of pectin and its utilization for various biotechnological purposes.