Search

Abstract Background Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) that play an important role in cancer progression. Although the mechanism by which CAFs promote tumorigenesis has been well investigated, the underlying mechanism of CAFs activation by neighboring cancer cells remains elusive. In this study, we aim to investigate the signaling pathways involved in CAFs activation by gastric cancer cells (GC) and to provide insights into the therapeutic targeting of CAFs for overcoming GC. Methods Alteration of receptor tyrosine kinase (RTK) activity in CAFs was analyzed using phospho-RTK array. The expression of CAFs effector genes was determined by RT-qPCR or ELISA. The migration and invasion of GC cells co-cultured with CAFs were examined by transwell migration/invasion assay. Results We found that conditioned media (CM) from GC cells could activate multiple receptor tyrosine kinase signaling pathways, including ERK, AKT, and STAT3. Phospho-RTK array analysis showed that CM from GC cells activated PDGFR tyrosine phosphorylation, but only AKT activation was PDGFR-dependent. Furthermore, we found that connective tissue growth factor (CTGF), a member of the CCN family, was the most pronouncedly induced CAFs effector gene by GC cells. Knockdown of CTGF impaired the ability of CAFs to promote GC cell migration and invasion. Although the PDGFR-AKT pathway was pronouncedly activated in CAFs stimulated by GC cells, its pharmacological inhibition affected neither CTGF induction nor CAFs-induced GC cell migration. Unexpectedly, the knockdown of SRC and SRC-family kinase inhibitors, dasatinib and saracatinib, significantly impaired CTGF induction in activated CAFs and the migration of GC cells co-cultured with CAFs. SRC inhibitors restored the reduced expression of epithelial markers, E-cadherin and Zonula Occludens-1 (ZO-1), in GC cells co-cultured with CAFs, as well as CAFs-induced aggregate formation in a 3D tumor spheroid model. Conclusions This study provides a characterization of the signaling pathways and effector genes involved in CAFs activation, and strategies that could effectively inhibit it in the context of GC. Video Abstract

Backgroud/purpose: The prevalence of carious lesions and traumatic injury in individuals between ages 6 and 12 is high. This study aimed to characterize pediatric patients aged 6–12 treated in the endodontic clinic and investigate the prevalence and patterns of their provided endodontic treatments. Materials and methods: Clinical and radiographic records of patients (ages 6–12) referred to the postgraduate Endodontics clinic from June 2017 to June 2020 were reviewed. Demographics, pre-and post-operative conditions, type of endodontic treatment, and behavioral management were collected. Results: A total of 6350 teeth from 6089 patients were treated in this period, and 425 teeth (6.7%) from 405 patients were included. Ages 9–11 were the most commonly treated age group. Significantly more lower molars (41.9%) and upper anterior teeth (36.7%) were treated (P

Corrosion damage to submarine pressure hulls is a crucial consideration during the structural design phase because it diminishes the structural strength of a submarine, reducing its operational depth and posing a severe risk to the life of the crew. This necessitates using a validated analytical method to estimate the residual strength and assess the safety of corrosion-affected pressure hulls. This paper presents an experimental and numerical investigation of the residual strength of corroded ring-stiffened cylinders, which are typical components of submarine pressure hulls, the main legs of semi-submersibles, and Floating Offshore Wind Turbine (FOWT) foundations. Four steel ring-stiffened cylinder models were fabricated: two remained intact, whereas the other two were artificially corroded by machining. Hydrostatic collapse tests were conducted in a pressure chamber. To evaluate the effect of initial shape imperfections caused by welding fabrication on the strength of the structure, the initial shape imperfections were measured using a three-dimensional coordinate measuring machine. The experimental results illustrate a significant reduction in the residual strengths of the two damaged models compared with those of the intact models. The collapse processes simulated using the Abaqus software package are presented, demonstrating a close agreement between the experimental results and numerical predictions.

ABSTRACT Saccharomyces cerevisiae is a single-celled fungal microorganism. S. cerevisiae-derived vacuoles are closely related to mammalian lysosomes, which play a role in the degradation of macromolecules by various hydrolytic enzymes. This study evaluated the anti-inflammatory efficacy of S. cerevisiae-vacuoles by inhibiting inflammatory mediators induced by lipopolysaccharide (LPS). The results showed that treatment with 5, 10, and 20 µg/mL of S. cerevisiae-derived vacuoles almost completely inhibited the LPS-induced expression of iNOS protein and mRNA. Moreover, vacuoles significantly reduced the mRNA expression of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6) in LPS-stimulated macrophages compared to the control cells. The immunofluorescence analysis confirmed that S. cerevisiae-derived vacuoles inhibited the translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in LPS-stimulated cells. Taken together, the treatment with S. cerevisiae-derived vacuoles alone activated macrophages, but LPS-activated macrophages modulated pro-inflammatory mediators by downregulating the NF-κB pathway. These results suggest that S. cerevisiae-derived vacuoles may have therapeutic potential in the treatment of inflammatory diseases. In conclusion, our study provides new insights into the immunomodulatory effects of S. cerevisiae-derived vacuoles and their potential as a novel anti-inflammatory agent. IMPORTANCE This study investigates the potential of using vacuoles derived from the yeast Saccharomyces cerevisiae as a new anti-inflammatory therapy. Inflammation is a natural response of the immune system to invading pathogens, but when it is dysregulated, it can lead to chronic diseases. The researchers found that treating macrophages with vacuoles significantly reduced the production of pro-inflammatory cytokines and iNOS, markers of inflammation when they were stimulated with lipopolysaccharide. The study also showed that vacuoles inhibited the NF-κB signaling pathway, which is involved in the induction of pro-inflammatory cytokines in macrophages. These findings suggest that S. cerevisiae-derived vacuoles may have potential as a new therapeutic agent for regulating the inflammatory response in various diseases. Further studies are needed to evaluate the efficacy and safety of vacuoles in vivo and to elucidate the underlying mechanisms of their anti-inflammatory effects.

Enzalutamide (ENZ), marketed under the brand name Xtandi® as a soft capsule, is an androgen receptor signaling inhibitor drug actively used in clinical settings for treating prostate cancer. However, ENZ’s low solubility and bioavailability significantly hinder the achievement of optimal therapeutic outcomes. In previous studies, a liquid self-nanoemulsifying drug delivery system (L-SNEDDS) containing ENZ was developed among various solubilization technologies. However, powder formulations that included colloidal silica rapidly formed crystal nuclei in aqueous solutions, leading to a significant decrease in dissolution. Consequently, this study evaluated the efficacy of adding a polymer as a recrystallization inhibitor to a solid SNEDDS (S-SNEDDS) to maintain the drug in a stable, amorphous state in aqueous environments. Polymers were selected based on solubility tests, and the S-SNEDDS formulation was successfully produced via spray drying. The optimized S-SNEDDS formulation demonstrated through X-ray diffraction and differential scanning calorimetry data that it significantly reduced drug crystallinity and enhanced its dissolution rate in simulated gastric and intestinal fluid conditions. In an in vivo study, the bioavailability of orally administered formulations was increased compared to the free drug. Our results highlight the effectiveness of solid-SNEDDS formulations in enhancing the bioavailability of ENZ and outline the potential translational directions for oral drug development.

Abstract The objective of this study was to report that lysosome extracted from egg white could be used as a drug through oral administration for treating diseases by using pH sensitive alginate oligosaccharides. Lysosome-alginate oligosaccharides composite were formulated for oral administration of lysosomes. The dissolution test confirmed the availability of the oral dosage form. When lysosome were used as an independent drug, the activity of protein was lost due to influence of low pH. Its antibacterial activity was also remarkably reduced. However, when lysosome-alginate oligosaccharides composite form was used, antimicrobial activity of lysozyme was maintained. At low pH, a gel-like matrix was formed by alginate oligosaccharides to protect the lysosome. When the pH was increased, alginate oligosaccharides were dissolved and the lysosome was released. SDS–polyacrylamide gel electrophoresis analysis of released lysosomes revealed that alginate oligosaccharide could effectively protect the lysosome from degradation or hydrolysis under acidic conditions for at least 2 h. The results of this study are important for application of lysosomes as therapeutic agents, and also it was confirmed that alginate oligosaccharides have potential as direct delivery system for the oral application of protein derived therapies.

Background/purpose: Sodium hypochlorite (NaOCl) is a highly alkaline solution which exhibits antimicrobial properties. However, it causes corrosion to endodontic rotary files. This study investigated the effect of NaOCl on the metal surface of five different unused endodontic rotary files in vitro. Materials and methods: Two non-heat-treated nickel-titanium (NiTi) files, ProTaper, BioRace, and three heat-treated NiTi files, VortexBlue, TRUShape, and EdgeFile X7 files, were immersed in 4% NaOCl for 5, 10, and 20 min, and 1, 6 and 24 h. The corrosion susceptibility was evaluated by visual inspection and scanning electron microscopy (SEM). Results: In the TRUShape group, the black particulate matter was mostly formed at the file's curvature and shaft. A large amount of precipitate accumulated in the EdgeFile group. The extent and prevalence of surface defects were found to be consistently higher in EdgeFile X7 instruments than in any other instruments. EdgeFile X7 and TRUShape files exhibited a greater corrosive tendency to NaOCl than BioRace, ProTaper, and VortexBlue not only under visual inspection, but also under SEM analysis after prolonged immersion (1, 6, 24 h) in 4% NaOCl. However, shorter immersion periods (5, 10, 20 min) showed little surface corrosion across all experimental groups. Conclusion: Within the limitations of this study, EdgeFile X7 and TRUShape files exhibit greater corrosive tendencies to NaOCl in vitro than BioRace, ProTaper, and VortexBlue files after prolonged immersion in 4% NaOCl. However, shorter immersion periods, which more closely approximate clinical conditions during single root canal therapy, may not show surface corrosion across all experimental groups.

Removal of agricultural pipes used in crop support and greenhouse agriculture is manpower-intensive. However, most agricultural workers are elderly. Therefore, auxiliary devices should be used to allow pipe removal with as little force as possible. In this study, the design parameters of an extraction device were optimized within constraints to minimize the force required to remove agricultural pipes. The optimization parameters are the length of each link and the initial link angle of the device. The driving force, according to the design parameters, was calculated by applying the theory of kinematics. An optimal design plan was derived using an optimization algorithm to minimize the force driving the device within the desired constraint. As a result of the optimization, it was confirmed that the force required to remove the pipe was reduced by 87.1% compared with the initial design value and was designed to suit the user’s convenience.

In this study, we propose the direct diagnosis of thyroid cancer using a small probe. The probe can easily check the abnormalities of existing thyroid tissue without relying on experts, which reduces the cost of examining thyroid tissue and enables the initial self-examination of thyroid cancer with high accuracy. A multi-layer silicon-structured probe module is used to photograph light scattered by elastic changes in thyroid tissue under pressure to obtain a tactile image of the thyroid gland. In the thyroid tissue under pressure, light scatters to the outside depending on the presence of malignant and positive properties. A simple and easy-to-use tactile-sensation imaging system is developed by documenting the characteristics of the organization of tissues by using non-invasive technology for analyzing tactile images and judging the properties of abnormal tissues.

The subiculum is positioned at a critical juncture at the interface of the hippocampus with the rest of the brain. However, the exact roles of the subiculum in most hippocampal-dependent memory tasks remain largely unknown. One obstacle to make comparisons of neural firing patterns between the subiculum and hippocampus is the broad firing fields of the subicular cells. Here, we used spiking phases in relation to theta rhythm to parse the broad firing field of a subicular neuron into multiple subfields to find the unique functional contribution of the subiculum while male rats performed a hippocampal-dependent visual scene memory task. Some of the broad firing fields of the subicular neurons were successfully divided into multiple subfields similar to those in the CA1 by using the theta phase precession cycle. The new paradigm significantly improved the detection of task-relevant information in subicular cells without affecting the information content represented by CA1 cells. Notably, we found that multiple fields of a single subicular neuron, unlike those in the CA1, carried heterogeneous task-related information such as visual context and choice response. Our findings suggest that the subicular cells integrate multiple task-related factors by using theta rhythm to associate environmental context with action.

We present a case of nonspecific granulomatous prostatitis (GP), a clinical mimic of prostate adenocarcinoma. A 54-year-old man presented with lower urinary tract symptoms and raised prostate-specific antigen. Magnetic resonance imaging showed features consistent with prostate cancer, including low T2-signal intensity in the peripheral and transition zones with signs of extracapsular extension. Diffusion-weighted imaging showed high-signal intensity, with low apparent diffusion coefficient values, whereas dynamic contrast enhancement demonstrated a type 3 washout curve, similar to that found in prostate cancer. Transperineal sector-guided prostate biopsy confirmed nonspecific GP, and the patient was treated conservatively. We discuss and compare nonspecific, chronic GP as a radiologic mimic of prostate adenocarcinoma patient.

Bone-marrow-derived human mesenchymal stem cells (hMSCs) which are important cell source for hard tissue regeneration stay near periapical lesions of tooth, playing an essential role in periodontal regeneration. Since the biomineralization process of MSCs is largely governed by the initial local environment, it is crucial to know the biological effects of dental bioceramic (mineral trioxide aggregate (MTA)) right after implantation. The purpose of this study was to evaluate the initial cytotoxicity of 4 different commercially available MTA materials (Endocem MTA, Ortho MTA, ProRoot MTA, and MTA Angelus) against hMSCs during or after setting using extracts of materials. The materials were mixed separately and placed into disk-shaped Teflon split molds (10 mm diameter and 2 mm thickness), and the sample discs were separated and eluted in the culture medium for 24 h. The extracts were exposed to hMSCs, and cytotoxicity was evaluated by the WST assay. In the present study, all 4 MTA products tested showed severe cytotoxicity at 100% and 50% extract, while 25% and 12.5% revealed 30∼100% depending on the MTA products. Endocem MTA showed severe cytotoxicity at 12.5% extract, while others showed relatively higher cell viability compared to Endocem MTA. Images of live and dead cells represented less live cells at 25% and 12.5%, confirming cell viability assay. Therefore, careful consideration of the concentration of MTA extracts is necessary, especially when applying MTA to the elderly patients to maintain the viability of hMSCs.

The proper choice of dental composite resins is necessary based on the minimal cytotoxicity and antiodontogenesis on human dental pulp stem cells for dental pulp-dentin tissue repair and regeneration. The aim of this study was to evaluate the cytotoxicity and antidifferentiation effects of dental bulk-fill resins, able to be polymerized as a bulk status for filling deep cavity of a tooth by single light curing, against human dental pulp stem cells (hDPSCs) from three compartments corresponding to depth (0-2, 2-4, and 4-6 mm) from the light-curing site. Three bulk-fill composite resins (SDR, Venus bulk-fill (VBF), and Beautifil Bulk Flowable (BBF)) and a conventional flowable composite resin (Filtek Z350 XT flowable restorative (ZFF)) were individually filled into a cylindrical hole (h=2 mm, Ф=10 mm), and three compartments (total ~6 mm of height) were combined as a single assembly for light curing. The resin samples from the three layers were separated and eluted in the culture medium. The extracts were exposed to hDPSCs, and cytotoxicity and differentiation capability were evaluated. Depth of cure and surface hardness according to depth were determined. All bulk-fill resins except BBF revealed cytotoxicity from 4 to 6 or 2 to 4 mm, while ZFF was cytotoxic at over 2 mm. Depth of cure was detected from 3.55 to 4.02 mm in the bulk-fill resins (vs. ~2.25 mm in conventional resin), and 80% hardness compared with that of a fully polymerized top surface was determined from 4.2 to 6 mm in the bulk-fill resin (vs. 2.4 mm in conventional resin). Antidifferentiation was revealed at a depth of 4-6 mm in the bulk-fill resin. There was a difference in depth of cytotoxicity and antidifferentiation between the bulk-fill composite resins, which was mainly due to different cure depths and ingredients. Therefore, careful consideration of choice of bulk-fill resins is necessary especially for restoration of deep cavities for maintaining the viability and differentiation ability of dental pulp stem cells.

Underactive bladder (UAB) is an important and complex urological condition resulting from the urodynamic finding of detrusor underactivity. It can manifest in a wide range of lower urinary tract symptoms, from voiding to storage complaints, and can overlap with other conditions, including overactive bladder and bladder outlet obstruction. However, UAB continues to be poorly understood and inadequately researched. In this article, we review the contemporary literature pertaining to recent advances in defining, understanding, and managing UAB.

BackgroundTuberculous sputum provides a sample of bacilli that must be eliminated by chemotherapy and that may go on to transmit infection. A preliminary observation that Mycobacterium tuberculosis cells contain triacylglycerol lipid bodies in sputum, but not when growing in vitro, led us to investigate the extent of this phenomenon and its physiological basis.Methods and findingsMicroscopy-positive sputum samples from the UK and The Gambia were investigated for their content of lipid body-positive mycobacteria by combined Nile red and auramine staining. All samples contained a lipid body-positive population varying from 3% to 86% of the acid-fast bacilli present. The recent finding that triacylglycerol synthase is expressed by mycobacteria when they enter in vitro nonreplicating persistence led us to investigate whether this state was also associated with lipid body formation. We found that, when placed in laboratory conditions inducing nonreplicating persistence, two M. tuberculosis strains had lipid body levels comparable to those found in sputum. We investigated these physiological findings further by comparing the M. tuberculosis transcriptome of growing and nonreplicating persistence cultures with that obtained directly from sputum samples. Although sputum has traditionally been thought to contain actively growing tubercle bacilli, our transcript analyses refute the hypothesis that these cells predominate. Rather, they reinforce the results of the lipid body analyses by revealing transcriptional signatures that can be clearly attributed to slowly replicating or nonreplicating mycobacteria. Finally, the lipid body count was highly correlated (R(2) = 0.64, p < 0.03) with time to positivity in diagnostic liquid cultures, thereby establishing a direct link between this cytological feature and the size of a potential nonreplicating population.ConclusionAs nonreplicating tubercle bacilli are tolerant to the cidal action of antibiotics and resistant to multiple stresses, identification of this persister-like population of tubercle bacilli in sputum presents exciting and tractable new opportunities to investigate both responses to chemotherapy and the transmission of tuberculosis.

Elevated uric acid levels are linked with obesity and diabetes. Existing research mainly examines the relationship between sugar-sweetened carbonated beverage (SSB) consumption and uric acid levels. This study explored the association between the quantity and frequency of SSB consumption and elevated uric acid levels in Korean adults. Data from 2881 participants aged 19–64 years (1066 men and 1815 women) in the 2016 Korea National Health and Nutrition Examination Survey were analyzed. Serum uric acid levels were categorized into quartiles, with the highest defined as high uric acid (men, ≥6.7 mg/dL; women, ≥4.8 mg/dL). SSB consumption was classified into quartiles (almost never, <1 cup (<200 mL), 1–3 cups (200–600 mL), ≥3 cups (≥600 mL)) and frequency into tertiles (almost never, ≤1/week, ≥2/week). Multivariate logistic regression assessed the association, with separate analyses for men and women. Increased daily SSB consumption and frequency were significantly associated with high uric acid levels in men but not in women. After adjusting for sociodemographic and health characteristics, consuming ≥3 cups (≥600 mL) of SSBs per day and SSBs ≥ 2/week were significantly associated with high serum uric acid levels in men, but this association was not observed in women. The study concludes that increased SSB intake is linked to elevated uric acid levels in Korean men, but not in women. [ABSTRACT FROM AUTHOR]

Intentional replantation (IR) is the intentional extraction of a tooth followed by its replacement back into its socket fur the purpose of performing a root-end surgery or other necessary repairs. The procedure may be considered a favorable alternative to conventional microsurgery, especially when surgical access is restricted due to specific anatomical challenges. With advancements in magnification, bioceramics, and instrumentation, IR has become a well-established, scientifically supported treatment modality and is cost-effective when compared to single-implant placement. This article discusses the rationale and indications fur IR, describes treatment protocols, and reports on its outcomes. [ABSTRACT FROM AUTHOR]

Background: Intrathecal baclofen (ITB) therapy, a viable alternative for unsuitable candidates of conventional spasticity medications, is a preferred method of administration over the oral route. Owing to its enhanced bioavailability, ITB ensures a more effective delivery at the target site. Objective: There is a lack of conclusive evidence regarding the use of ITB treatment in managing ambulatory patients with spastic dystonia. Before ITB pump implantation, patients commonly undergo an ITB bolus injection trial to rule out potential adverse reactions and verify the therapeutic effects on hypertonic issues. In this report, we highlight a case of spastic dystonia, particularly focusing on an ambulatory patient who demonstrated significant improvement in both the modified Ashworth scale (MAS) score and gait pattern following the ITB injection trial. Case report: This case report outlines the medical history of a 67-year-old male diagnosed with left-side hemiplegia and spastic dystonia, resulting from his second episode of intracranial hemorrhage in the right thalamus. An ITB injection trial was initiated because the patient was not suitable for continued botulinum toxin injections and oral medications. This was due to the persistent occurrence of spastic dystonia in both the upper and lower extremities. The patient underwent a four-day ITB injection trial with progressively increasing doses, resulting in improved MAS scores and gait parameters, including cadence, step length, step time, stride length, and stride time were increased. Particularly, kinematic gait analysis demonstrates a substantial improvement of increased knee flexion in the swing phase in stiff knee gait pattern. These findings indicated a gradual reduction in spasticity-related symptoms, signifying the positive effect of the ITB injection trial. The patient eventually received an ITB pump implantation. Conclusion: In this post-stroke patient with spastic dystonia, ITB therapy has demonstrated effective and substantial management of spasticity, along with improvement in gait patterns. [ABSTRACT FROM AUTHOR]