Size-exclusion chromatography-based extracellular vesicle size subtyping and multiplex membrane protein profiling for differentiating gastrointestinal cancer prognosis.

Extracellular vesicles (EVs), as a type of subcellular structure, have been extensively researched for their potential for developing advanced diagnostic technologies for various diseases. However, the biomolecular and biophysical heterogeneity of EVs has restricted their application in clinical settings. In this article, we developed a size-exclusion chromatography-based technique for simultaneous EV size subtyping and protein profiling. By eluting fluorescent aptamer-treated patient plasma through a size-exclusion column, the mixture can be classified into 50 nm aptamer-bound EVs, 100 nm aptamer-bound EVs and free-floating aptamers, which could further enable multiplex EV membrane protein profiling by analyzing the fluorescence intensities of EV-bound aptamers. Using this technique, we successfully identified EV size subtypes for differentiating gastrointestinal cancer prognosis states. Overall, we developed a rapid, user-friendly and low-cost EV size subtyping and protein profiling technique, which holds great potential for identifying crucial EV size subtypes for disease diagnosis in the clinic.

A case of desmoplastic myxoid tumor, SMARCB1 mutant, in the pineal region.

Desmoplastic myxoid tumor (DMT), SMARCB1 mutant is a recently proposed new entity that mainly occurs in the pineal region and has epigenetic features similar to those of atypical teratoid/rhabdoid tumors (AT/RT)-MYC and poorly differentiated chordomas. Herein, we present a new case of a 33-year-old man with headaches, dizziness, nausea, vomiting, and blurred vision, who was initially found to have a suspicious germinoma on imaging. After surgical removal of the lesion, the postoperative pathological diagnosis was DMT, SMARCB1 mutant. To the best of our knowledge, this is the first case reported in China. Our findings also extend the range of the immunohistochemical phenotype of this rare tumor.

Microcystin-LR induces ferroptosis in intestine of common carp (Cyprinus carpio).

Previous studies provide comprehensive evidence of the environmental hazards and intestinal toxicity of microcystin-LR (MC-LR) exposure. However, little is known about the mechanisms underlying the injury of intestine exposed to MC-LR. Juvenile common carp (Cyprinus carpio) were exposed to MC-LR (0 and 10 µg/L) for 15 days. The results suggest that organic anion-transporting polypeptides 3a1, 4a1, 2b1, and 1d1 mediate MC-LR entry into intestinal tissues. Lesion morphological features (vacuolization, deformation and dilation of the endoplasmic reticulum [ER], absence of mitochondrial cristae in mid-intestine), up-regulated mRNA expressions of ER stress (eukaryotic translation initiation factor 2-alpha kinase 3, endoplasmic reticulum to nucleus signaling 1, activating transcription factor [ATF] 6, ATF4, DNA damage-inducible transcript 3), iron accumulation, and down-regulated activity of glutathione peroxidase (GPx) and glutathione (GSH) content were all typical characteristics of ferroptosis in intestinal tissue following MC-LR exposure. GSH levels in intestinal tissue corroborated as the most influential GSH/GPx 4- related metabolic pathway in response to MC-LR exposure. Verrucomicrobiota, Planctomycetes, Bdellovibrionota, Firmicutes and Cyanobacteria were correlated with the ferroptosis-related GSH following MC-LR exposure. These findings provide new perspectives of the ferroptosis mechanism of MC-LR-induced intestinal injury in the common carp.

Vortex soliton molecule in a fiber laser.

We report the generation of vortex soliton molecules (VSMs) in a passively mode-locked fiber laser based on a mode selective coupler (MSC). ±1-order VSMs with variable numbers of molecules are observed. By adjusting the polarization state of the light in the cavity, we further demonstrate the process in which one VSM splits to multiple. During this process, the number of the solitons inside the VSM also varies and their separation gradually increases while the spectral modulation being unobservable, and vice versa. The obtained results have potential applications in fields of optical communications, especially in information coding.

An Aseptic One-Shot Bottom-Up Method To Produce Progesterone Nanocrystals: Controlled Size and Improved Bioavailability.

Progesterone (PG) is an essential sex hormone with a variety of important biological functions, but its insolubility leads to low bioavailability of most water-based formulations. What is more, the commercial oil-based formulations often cause severe side effects after long-term injection due to poor tissue absorption of oil. Herein, we report an aseptic bottom-up method utilizing emulsion freeze-drying technology that produces size-controllable, highly bioavailable, and water-based PG nanocrystal injection. The key factors that can determine the features of nanocrystals were investigated, including solvents, water-to-oil ratio, drug concentrations, type of surfactants, temperature in freeze-drying process, and lyoprotectants. Mechanisms of crystal growth formation process for PG nanocrystals were also analyzed theoretically. The prepared water-based PG nanocrystal suspension injection (PG/NSI) not only showed quick dissolution behaviors but also had significantly improved bioavailability in vivo. Therefore, this method can effectively control the size of nanocrystals, enhance bioavailability of insoluble drugs, and produce aseptic water-based nanocrystals that can be directly used for injection. Moreover, this method can also be used to prepare nanocrystals with the desired size under aseptic conditions for other poorly water-soluble drugs.

Fibrolipoma of the lower lip: A case report and review of the literature.

BACKGROUND: Fibrolipoma of the lower lip is an uncommon condition with limited documentation in the literature. This paper provides updated insights into oral and maxillofacial lipomas through a detailed case report and comprehensive literature review, discussing clinical features, pathogenesis, diagnostic approaches, histopathology, and therapeutic strategies. CASE PRESENTATION: A 54-year-old female presented with a painless, enlarging mass on the inner aspect of her right lower lip, first noticed 2 years prior. The mass, now the size of a peanut, interfered with her eating and speech. Physical examination revealed a 2.0 × 2.5 × 1.0 cm mass beneath the mucous membrane of the right lower lip. It was firm, well-demarcated, and mobile. Surgical excision was performed, and histopathological analysis confirmed the diagnosis of a lower lip fibrolipoma. The lesion was successfully removed without recurrence. CONCLUSION: Lipomas in the oral and maxillofacial regions are rare, slow-growing benign tumors, particularly within the lips. Although their diagnosis is straightforward based on clinical presentation, histopathological confirmation is essential. Surgical resection remains the treatment of choice, with excellent prognostic outcomes.

Chitosan-based food-grade Pickering emulsion loading with Rosa roxburghii extract against precancerous lesions of gastric carcinoma.

Precancerous lesions of gastric carcinoma (PLGC) are the most important stage in the development of gastric cancer, accompanied by significant oxidative stress and inflammatory response. Rosa roxburghii extract (RRE) has unique advantages in anti-PLGC due to its multi-component, high antioxidant and anti-inflammatory activities. However, the astringency and instability of RRE in the digestive tract seriously hinder its clinical application. Herein, we report a chitosan-based food-grade Pickering emulsion (PE) for loading RRE to block unpleasant taste, improve stability, and promote the entry of RRE into gastric epithelial cells through the gastric adhesion of chitosan, thereby enhancing preventive and therapeutic effects against PLGC. This Pickering emulsion is constructed as a water-in-oil (W/O) emulsion stabilized by the food-grade nanoparticles composed of soybean protein isolate (SPI) and chitosan (CS) through electrostatic interaction (defined as RRE@PE). The experimental results showed that RRE@PE performed better efficacy against PLGC than RRE by scavenging or inhibiting reactive oxygen species generation and reducing inflammatory cytokines. This Pickering emulsion enhances the application potential of RRE and is expected to be used for the treatment of clinical patients with PLGC.

Tulipalin A suppressed the pro-inflammatory polarization of M1 macrophage and mitigated the acute lung injury in mice via interference DNA binding activity of NF-κB.

Acute lung injury (ALI) is an inflammatory disorder accompanied by higher morbidity and mortality. The pathological mechanism of ALI has been reported to be associated with the release of inflammatory cytokines by macrophages. Sesquiterpene lactones (SLs) represent the principal anti-inflammatory components of many natural products. Tulipalin A is a natural small molecule and a conserved moiety in anti-inflammatory SLs. However, the anti-inflammatory potential of Tulipalin A has yet to be fully disclosed. The present study aims to investigate TulipalinA's anti-inflammatory activity and underlying mechanisms in vitro and in vivo. Tulipalin A suppressed inflammatory responses in lipopolysaccharide (LPS)-stimulated bone marrow-derived primary macrophages and ameliorated LPS-induced ALI in mice. Mechanistically, Tulipalin A directly targets the NF-κB p65 and disrupts its DNA binding activity, thereby impeding the activation of NF-κB. Inhibition of NF-κB attenuated M1 polarization of macrophages, consequently suppressing the production of pro-inflammatory mediators and ameliorating the onset and progression of ALI. These findings suggest Tulipalin A's potential to mitigate inflammatory disorders like ALI via targeting NF-κB p65 and disrupting its DNA binding activity.

Polysialic acid driving cardiovascular targeting co-delivery 1,8-cineole and miR-126 to synergistically alleviate lipopolysaccharide-induced acute cardiovascular injury.

Infection-induced cardiovascular damage is the primary pathological mechanism underlying septic cardiac dysfunction. This condition affects the majority of patients in intensive care unit and has an unfavorable prognosis due to the lack of effective therapies available. Vascular cell adhesion molecule-1 (VCAM-1) plays a vital role in coordinating the inflammatory response and recruitment of leukocytes in cardiac tissue, making it a potential target for developing novel therapies. MicroRNA-126 (miR-126) has been shown to downregulate VCAM-1 expression in endothelial cells, reducing leukocyte adhesion and exerting anti-inflammatory effects. Therefore, this work described a polysialic acid (PSA) modified ROS-responsive nanosystem to targeted co-delivery 1,8-Cineole and miR-126 for mitigating septic cardiac dysfunction. The nanosystem consists of 1,8-Cineole nanoemulsion (CNE) conjugated with PEI/miR126 complex by a ROS-sensitive linker, with PSA on its surface to facilitate targeted delivery via specific interactions with selectins on endothelial cells. CNE has demonstrated protective effects against inflammation in the cardiovascular system and synergistic anti-inflammatory effects when combined with miR-126. The targeted nanosystem successfully delivered miR-126 and 1,8-Cineole to the injured heart tissues and vessels, reducing inflammatory responses and improving cardiac function. In summary, this work provides a promising therapy for alleviating the inflammatory response in sepsis while boosting cardiovascular protection.

Alleviating visceral cancer pain in patients with pancreatic cancer using cryoablation and celiac plexus block.

Little is known about the effects of pancreas cryoablation (PCA) on abdominalgia in pancreatic cancer patients or its synergism with celiac plexus block (CPB). In patients without abdominalgia, to investigate the effects of PCA; in patients with abdominalgia, to investigate the pain-alleviating effects of PCA+CPB. Sixty-two patients were enrolled in this retrospective review; 12 without abdominalgia refused PCA, 15 without abdominalgia received PCA to reduce their tumor load and 35 with abdominalgia received PCA+CPB to reduce tumor load and alleviate pain. All PCA and PCA+CPB procedures were performed successfully. Some slight adverse effects (e.g. increased serum amylase, abdominal distension and nausea, abdominal bleeding) had disappeared by 3weeks, spontaneously or after symptomatic treatment. In patients without abdominalgia, pain occurred in one-third of cases (all with pancreatic head cancer) after PCA but had stopped 1-12days after treatment; in patients with abdominalgia before treatment, pain stopped immediately after PCA+CPB in 18 cases and 2-24days after treatment in 17 (all with pancreatic head cancer); a significant difference was found between pretreatment and post-treatment pain frequency (P=0.0019), regardless of the presence of advanced (P=0.0096) or metastatic (P=0.0072) cancer. The average time to pain relief was approximately 7days after both PCA and PCA+CPB, and abdominalgia did not recur for more than 8weeks. PCA may cause short-term pain in some pancreatic cancer patients. Combined PCA+CPB can alleviate cancer pain for more than 8weeks, without severe side effects.

Moderate altitude exposure impacts host fasting blood glucose and serum metabolome by regulation of the intestinal flora.

Moderate altitude exposure has shown beneficial effects on diabetes incidence but the underlying mechanisms are not understood. Our study aimed to investigate how the human gut microbiome impacted the serum metabolome and associated with glucose homeostasis in healthy Chinese individuals upon moderate-altitude exposure. Faecal microbiome composition was assessed using shotgun metagenomic sequencing. Serum metabolome was acquired by untargeted metabolomics technology, and amino acids (AAs) and propionic acid in serum were quantified by targeted metabolomics technology. The results indicated that the moderate-altitude exposed individuals presented lowered fasting blood glucose (FBG) and propionic acid, increased circulating L-Glutamine but decreased L-Glutamate and L-Valine, which correlated with enriched Bacteroidetes and decreased Proteobacteria. Additionally, the silico causality associations among gut microbiota, serum metabolome and host FBG were analyzed by mediation analysis. It showed that increased Bacteroides ovatus (B. ovatus) and decreased Escherichia coli (E. coli) were identified as the main antagonistic species driving the association between L-Glutamate and FBG in silico causality. Furthermore, the high-fat diet (HFD) fed mice subjected to faecal microbiota transplantation (FMT) were applied to validate the cause-in-fact effects of gut microbiota on the beneficial glucose response. We found that microbiome in the moderate-altitude exposed donor could predict the extent of the FBG response in recipient mice, which showed lowered FBG, L-Glutamate and Firmicutes/Bacteroidetes ratio. Our findings suggest that moderate-altitude exposure targeting gut microbiota and circulating metabolome, may pave novel avenues to counter dysglycemia.

Self-assembled iRGD-R7-LAHP-M nanoparticle induced sufficient singlet oxygen and enhanced tumor penetration immunological therapy.

The generation of singlet oxygen (1O2) using photodynamic therapy (PDT) is limited by the hypoxia of the tumor microenvironment and the depth of external light penetration because it depends on the precise cooperation between the photosensitizers, oxygen, and light. Herein, we report a self-sufficient 1O2 nanoreactor with enhanced penetration into deep tumors for cancer therapy. Linoleic acid hydroperoxide (LAHP) is coordinated with transition metal ions (Cu2+/Fe3+) to prepare linoleic acid hydroperoxide metal complex nanoparticles (LAHP-M NPs). iRGD combined with R7 decoration endows the nanoparticles with tumor targeting and penetration ability. We show that the polypeptide carries the nanoparticles into deep tumors, and thereafter the nanoparticles are disassembled into LAHP and catalytical metal ions to produce 1O2 based on the Russell mechanism under the stimulation of acidic pH. The elevated ROS induces necrotic cell death in vitro and in vivo, and further causes immunogenic cell death (ICD). This study demonstrates the effectiveness of exploiting biochemical reactions as a spatial-temporal strategy to overcome the current limitations of photodynamic therapy.

Molecularly Imprinted Polymers with Enzymatic Properties Reduce Cytokine Release Syndrome.

A core-shell molecularly imprinted polymer nanoparticle with biological enzyme functional characteristics was developed by oxidative polymerization of template protein and polydopamine on the surface of protease-copper phosphate hybrid nanoflowers by molecular imprinting technology and enzyme immobilization technology. The obtained molecularly imprinted polymer showed specific binding characteristics with the template protein. It recognized and enriched the target molecules through the surface molecularly imprinted sites of the shell structure. In addition, the bound target molecules were further degraded into fragments by nanozymes with biological enzyme characteristics in the core. In this study, molecular imprinting technology and biotechnology were combined to obtain bifunctional molecularly imprinted polymer nanoparticles that can not only enrich template molecules but also degrade them into fragments. Herein, we selected interleukin 6 (IL-6), the target molecule of cytokine release syndrome (CRS), as a template molecule, and reported a molecularly imprinted polymer with degrading enzyme properties that can rapidly reduce IL-6 levels in vivo, including a molecularly imprinted layer that can recognize and bind IL-6 and nanozymes that can degrade IL-6 and deactivate it. It is used to clear the excessive secretion of IL-6 in CRS and reduce the level of IL-6 in the body to achieve the purpose of adjuvant treatment of CRS.

Exenatide-loaded inside-porous poly(lactic-co-glycolic acid) microspheres as a long-acting drug delivery system with improved release characteristics.

The glucagon-like peptide-1 receptor agonist exenatide (EXT) is an effective treatment for type 2 diabetes. However, this peptide has a short biological half-life and the delayed release characteristic of current formulations limit its clinical application. Herein, we prepared EXT-loaded inside-porous poly(d,l-lactic-co-glycolic acid (PLGA) microspheres with outside layers (EXT-PMS) using a W1/O/W2 emulsion method with a microfluidic technique and its fabrication and formulation conditions were systematically investigated. In vitro dissolution experiments showed that the PLGA concentration, proportion of drug and oil phase, and the number and size of pores strongly affected the release behaviors of EXT-PMS. In vitro, the optimized EXT-PMS with large internal pores exhibited rapid and stable release without a lag phase. In a rat model, subcutaneous administration of the product yielded plasma concentrations of EXT that was sustained for 30 days with low burst and no delayed-release effect. The preparation of inside-porous microspheres is lighting up the development of long-acting drug delivery systems for other drugs with favorable release characteristics.

Long-term sustained release Poly(lactic-co-glycolic acid) microspheres of asenapine maleate with improved bioavailability for chronic neuropsychiatric diseases.

Schizophrenia and bipolar disorder are severe chronic neuropsychiatric diseases, affecting hundreds of millions of people worldwide. Asenapine maleate (ASM) has been demonstrated as a safe and effective therapeutic agent under twice-daily administration. However, lower compliance is observed when patients are treated with ASM, which significantly limits its application in schizophrenia and bipolar disorder. Moreover, the low bioavailability of ASM caused by first-pass metabolism and poor aqueous solubility also impairs the treatment effect. A formulation of ASM with the property of long-term sustained release and improved bioavailability can be a solution to overcome these weaknesses. In this article, we prepared ASM-loaded poly(lactic-co-glycolic acid) (ASM-PLGA) microspheres through different techniques, including emulsification-solvent evaporation (ESE), Shirasu porous glass membrane emulsification (SPG-ME), and microfluidic method. In vitro and in vivo assessments demonstrated that uniform-sized microspheres generated by the microfluidic process sustainably released ASM throughout 40-days, showing low burst release and significantly improved bioavailability. The results suggest that ASM-PLGA microspheres prepared by the microfluidic method provide an efficient strategy to enhance the drug exposure of ASM as the treatment of chronic neuropsychiatric diseases. It is also evident that this microfluidic strategy has the potential to construct with other drugs, establishing long-acting formulations.

Propylene glycol-embodying deformable liposomes as a novel drug delivery carrier for vaginal fibrauretine delivery applications.

The purpose of this work was to develop and characterize the fibrauretine (FN) loaded propylene glycol-embodying deformable liposomes (FDL), and evaluate the pharmacokinetic behavior and safety of FDL for vaginal drug delivery applications. FDL was characterized for structure, particle size, zeta potential, deformability and encapsulation efficiency; the ability of FDL to deliver FN across vagina tissue in vitro and the distribution behavior of FN in rat by vaginal drug delivery were investigated, the safety of FDL to the vagina of rabbits and rats as well as human vaginal epithelial cells (VK2/E6E7) were also evaluated. Results revealed that: (i) the FDL have a closed spherical shape and lamellar structure with a homogeneous size of 185±19nm, and exhibited a negative charge of -53±2.7mV, FDL also have a good flexibility with a deformability of 92±5.6 (%phospholipids/min); (ii) the dissolving capacity of inner water phase and hydrophilicity of phospholipid bilayers of deformable liposomes were increased by the presence of propylene glycol, this may be elucidated by the fluorescent probes both lipophilic Nile red and hydrophilic calcein that were filled up the entire volume of the FDL uniformly, so the FDL with a high entrapment capacity (were calculated as percentages of total drug) for FN was 78±2.14%; (iii) the permeability of FN through vaginal mucosa was obviously improved by propylene glycol-embodying deformable liposomes, no matter whether the FN loaded in liposomes or not, although FN loaded in liposomes caused the highest permeability and drug reservoir in vagina; (iv) the FN mainly aggregated in the vagina and uterus, then the blood, spleen, liver, kidney, heart and lungs for vaginal drug delivery, this indicating vaginal delivery of FDL have a better 'vaginal local targeting effect'; and (v) the results of safety evaluation illustrate that the FDL is non-irritant and well tolerated in vivo, thereby establishing its vaginal drug delivery potential. These results indicate that the propylene glycol-embodying deformable liposomes may be a promising drug delivery carrier for vaginal delivery of fibrauretine.

Recurrent retroperitoneal extra-GIST with rhabdomyosarcomatous and chondrosarcomatous differentiations: a rare case and literature review.

Selective tyrosine kinase inhibitor (TKI) targeting KIT and PDGFRA is the frontline therapy for metastatic and unresectable GIST patients. Some initially responsive patients experience tumor progress because of secondary drug resistance, and some cases can develop heterogeneous differentiation. Here we report a rare case of recurrent retroperitoneal extra-GIST with rhabdomyosarcomatous and chondrosarcomatous differentiation with TKI therapy after surgical tumorectomy. Histology, immunohistochemistry, and mutational analysis were performed on primary and recurrent samples. The current case represents the first report of a recurrent retroperitoneal extra-GIST harboring mixed morphologic phenotypes of rhabdomyosarcoma and chondrosarsoma after TKI treatment. The dual differentiation can represent diagnostic pitfall.

Input-to-state stability of switched nonlinear systems with time delays under asynchronous switching.

This paper is concerned with analyzing input-to-state stability (ISS) for a class of switched nonlinear systems with time delays under asynchronous switching. Due to the existence of switching delay, the switching of the controller does not coincide accurately with the switching of the system.When the subsystem is stabilized with the matched controller, the subsystem is ISS; otherwise, the subsystem may be not ISS. We establish efficient condition, in terms of an upper bound on the switching delay, and in terms of a lower bound on the matched time intervals for the subsystem and the controller, which ensures ISS for the whole switched nonlinear system. Finally, an illustrative example is presented to demonstrate the efficacy of the results.

Essential oil composition analysis of three cultivars seeds of Resina ferulae from Xinjiang, China.

OBJECTIVE: Three cultivars seeds of Resina ferulae were analyzed for essential oil composition, Ferula sinkiangensis K. M. Shen, Ferula fukangensis K. M. Shen, and Ferula ovina, investigated differences among different genera of medicinal R. ferulae. MATERIALS AND METHODS: The essential oils were extracted by the method of hydrodistillation and analyzed by gas chromatography-mass spectrometry (GC-MS), using normalization method to calculate relative amount. RESULTS: Twenty-six compounds were identified in F. sinkiangensis K. M. Shen, comprised 99.001% of total essential oil; 21 compounds were identified in F. fukangensis K. M. Shen, comprised 100% of total essential oil; 25 compounds were identified in F. ovina, comprised 99.459% of total essential oil. n-Propyl sec-butyl disulfide is the main component in three cultivars seeds of R. ferulae, accounting for 55.875%, 49.797%, 53.781%, respectively. CONCLUSION: Little diversity among three cultivars seeds of R. ferulae from Xinjiang.

New cut angle quartz crystal microbalance with low frequency-temperature coefficients in an aqueous phase.

In a traditional quartz crystal microbalance (QCM), an AT-cut (cut angle phi=35.25 degrees in yxl orientation) quartz wafer is employed because it has low frequency-temperature coefficients (dF/dT) at room temperature region. But when a QCM is in contact with a liquid phase, its frequency is also related to the properties of the liquid, which are temperature dependent. The value of dF/dT is about 20 Hz/ degrees C for a 9 MHz AT-cut QCM with one side facing water. In this work, a group of QCMs in new cut angles were prepared. The influence of the cut angle on the frequency-temperature characteristic, response sensitivities to surface mass loading and viscodensity of liquid were investigated. An intrinsically temperature-compensated QCM sensor that possesses low dF/dT values in aqueous solution was reported. When a 9 MHz QCM with phi=35.65 degrees was contacted with water with one side, its dF/dT value is close to zero at ca. 25 degrees C and its averaged value of |dF/dT| is only 0.6 Hz/ degrees C in the temperature range of 23-27 degrees C. The frequency responses to surface mass loading and viscodensity of liquid phase are very close among the QCMs with the cut angles in the range of 35.15-35.7 degrees . The intrinsically temperature-compensated QCM was applied to investigate the alternate adsorption processes of cationic polyelectrolyte and silica nanoparticle.