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1.
J Clin Anesth ; 97: 111519, 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38870700

ABSTRACT

STUDY OBJECTIVE: Elderly patients undergoing pathophysiological changes necessitate clinical tools for cerebral monitoring. This prospective randomized controlled study aimed to explore how cerebral monitoring using Δo2Hbi, ΔHHbi, and ΔcHbi manifests in elderly patients under either propofol or sevoflurane anesthesia. DESIGN: Single-center, prospective, randomization. SETTING: A single tertiary hospital (Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea). PATIENTS: Enrolled 100 patients scheduled for urologic surgery under general anesthesia. Inclusion criteria were (a) age 70-80 years, (b) American Society of Anesthesiologists (ASA) physical status I-II. INTERVENTION: Patients were double-blind randomized to receive propofol-based or sevoflurane anesthesia. Cerebral oximetry-related parameters were measured at 5, 10, 15, 20, and 30 min in a setting devoid of surgery-related factors. MEASUREMENTS: The primary outcome focused on the Δo2Hbi pattern in the left and right sides within the propofol and sevoflurane groups. MAIN RESULTS: We analyzed 100 patients, 50 patients in each group. In the propofol group, the left Δo2Hbi decreased from 1.4 (3.7) at 5 min to -0.1 (1.8) at 30 min (P < 0.0001), and the right Δo2Hbi decreased from 2.9 (4.2) at 5 min to -0.06 (2.3) at 30 min (P < 0.0001). In the sevoflurane group, the left Δo2Hbi decreased from 1.1 (3.4) at 5 min to -1.4 (4.4) at 30 min (P < 0.0001), and the right Δo2Hbi decreased from 2.0 (3.2) at 5 min to -1.2 (3.9) at 30 min (P < 0.0001). There were no significant differences between the two groups. ΔHHbi did not exhibit significant changes after an initial decrease at 5 min and showed no significant differences between the two groups. CONCLUSIONS: In cerebral oximetry, Δo2Hbi and ΔHHbi could emerge as a valuable approach for discerning changes in the underlying baseline status of the brain in elderly patients during anesthesia.

4.
Article in English | MEDLINE | ID: mdl-38848241

ABSTRACT

BACKGROUND: C3 glomerulopathy (C3G), which encompasses C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), results from dysregulation of the alternative complement pathway. Data on disease recurrence after kidney transplantation is limited, and details on histologic features of recurrent C3G are scarce. We aimed to evaluate C3G recurrence in the allograft, with a focus on histologic presentation and progression. METHODS: We retrospectively analyzed 18 patients with native kidney failure attributed to C3G (12 C3GN and six DDD) who received a kidney transplant from January 2016 to January 2023. Demographic, genetic, clinical, and histologic data were studied. The Nanostring 770 genes immune profiling panel was used for transcriptomic analysis. Disease recurrence was the primary outcome. RESULTS: During a median (IQR) follow-up period of 37 (18, 56) months, C3G recurrence occurred in 16 (89%) of patients (11 with C3GN and five with DDD), at a median (IQR) of 33 (13, 141) days post-transplantation. Over a third (38%) of recurrent cases were detected in protocol biopsies, and only 31% of patients presented with >300 mg/g of proteinuria. Recurrence in index biopsies was mainly established through a combination of immunofluorescence and electron microscopy findings, while it showed only subtle histologic alterations and no characteristic transcriptomic signals. Over time, histologic chronicity indices increased, but all allografts were functioning at the end of follow-up. Patients with recurrence of C3GN and DDD showed overlapping immunofluorescence and electron microscopy findings and had similar recurrence rate and time to recurrence. CONCLUSIONS: The majority of patients with native kidney failure attributed to C3G developed disease recurrence very early after kidney transplantation, usually with minimal proteinuria, mild histologic alterations, and favorable short-term allograft survival. Immunofluorescence and electron microscopy played a crucial role in detecting early, sub-clinical recurrence of C3GN and DDD, which showed significant overlapping features.

5.
Medicine (Baltimore) ; 103(26): e38718, 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38941413

ABSTRACT

I-gel has been used in various clinical situations. The study investigated alterations in respiratory parameters following a stepwise lung recruitment maneuver (LRM) using the i-gel. The research involved 60 patients classified as American Society of Anesthesiologists class I-II, aged 30 to 75 years, undergoing elective urologic surgery. Various respiratory parameters, including lung compliance, airway resistance, leak volume, airway pressure, and oxygen reserve index, were recorded at different time points: before LRM, immediately after LRM, and at 5, 15, and 30 minutes after LRM, as well as at the end of the surgery. The primary outcome was to assess an improvement in lung compliance. Dynamic lung compliance (mean ±â€…SD) was significantly increased from 49.2 ±â€…1.8 to 70.15 ±â€…3.2 mL/cmH2O (P < .05) after LRM. Static lung compliance (mean ±â€…SD) was increased considerably from 52.4 ±â€…1.7 to 65.0 ±â€…2.5 mL/cmH2O (P < .05) after the LRM. Both parameters maintained a statistically significant increased status for a certain period compared to baseline despite a decreased degree of increment. Airway resistance (mean ±â€…SD) was significantly reduced after the LRM from 12.05 ±â€…0.56 to 10.41 ±â€…0.64 L/cmH2O/s (P < .05). Stepwise LRM using i-gel may improve lung compliance and airway resistance. Repeated procedures could lead to prolonged improvements in respiratory parameters.


Subject(s)
Airway Resistance , Humans , Middle Aged , Prospective Studies , Male , Female , Aged , Lung Compliance/physiology , Adult , Airway Resistance/physiology , Positive-Pressure Respiration/methods
6.
J Control Release ; 372: 587-608, 2024 Jun 29.
Article in English | MEDLINE | ID: mdl-38942083

ABSTRACT

Tumor-associated macrophages (TAMs) constitute 50-80% of stromal cells in most solid tumors with high mortality and poor prognosis. Tumor-infiltrating dendritic cells (TIDCs) and TAMs are key components mediating immune responses within the tumor microenvironment (TME). Considering their refractory properties, simultaneous remodeling of TAMs and TIDCs is a potential strategy of boosting tumor immunity and restoring immunosurveillance. In this study, mannose-decorated poly(lactic-co-glycolic acid) nanoparticles loading with R848 (Man-pD-PLGA-NP@R848) were prepared to dually target TAMs and TIDCs for efficient tumor immunotherapy. The three-dimensional (3D) cell culture model can simulate tumor growth as influenced by the TME and its 3D structural arrangement. Consequently, cancer spheroids enriched with tumor-associated macrophages (TAMs) were fabricated to assess the therapeutic effectiveness of Man-pD-PLGA-NP@R848. In the TME, Man-pD-PLGA-NP@R848 targeted both TAMs and TIDCs in a mannose receptor-mediated manner. Subsequently, Man-pD-PLGA-NP@R848 released R848 to activate Toll-like receptors 7 and 8, following dual-reprograming of TIDCs and TAMs. Man-pD-PLGA-NP@R848 could uniquely reprogram TAMs into antitumoral phenotypes, decrease angiogenesis, reprogram the immunosuppressive TME from "cold tumor" into "hot tumor", with high CD4+ and CD8+ T cell infiltration, and consequently hinder tumor development in B16F10 tumor-bearing mice. Therefore, dual-reprograming of TIDCs and TAMs with the Man-pD-PLGA-NP@R848 is a promising cancer immunotherapy strategy.

7.
Dig Endosc ; 2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38872503

ABSTRACT

OBJECTIVES: The elapse time between the completion of bowel cleansing and colonoscopy is one of the important factors for proper bowel cleansing. Although several studies have reported that a short time interval resulted in a favorable bowel cleansing, no randomized controlled trial (RCT) has been conducted to determine the effect of the elapse time. Consequently, we performed an RCT to investigate the efficacy of bowel preparation of participants who underwent colonoscopy according to the different time intervals between the completion of bowel preparation and colonoscopy. METHODS: In this single-center RCT, study participants were randomized to complete bowel preparation either 2-4 h or 4-8 h before colonoscopy. The primary end-point was successful bowel preparation, rated using the Boston Bowel Preparation Scale (BBPS). RESULTS: A total of 504 individuals were included (2-4 h, 255; 4-8 h, 249). The rate of successful bowel preparation in the 2-4 h group showed noninferiority compared with that of the 4-8 h group (97.6% vs. 95.2%; rate difference, 2.5% [-0.8% to 5.7%]; Pfor noninferiority < 0.001, Pfor superiority = 0.136). The rate for perfect cleansing (a BBPS score of 9) was higher in the 2-4 h group (56.5% vs. 39.8%, P < 0.001). CONCLUSION: When bowel cleansing was finished 2-4 h before the start of colonoscopy, the overall bowel cleansing was noninferior, and perfect cleansing was superior, compared to that when cleansing was finished 4-8 h before colonoscopy.

8.
Angew Chem Int Ed Engl ; : e202410645, 2024 Jun 27.
Article in English | MEDLINE | ID: mdl-38935405

ABSTRACT

Photoacoustic imaging (PAI) is an emerging modality in biomedical imaging with superior imaging depth and specificity. However, PAI still has significant limitations, such as the background noise from endogenous chromophores. To overcome these limitations, we developed a covalent activity-based PAI probe, NOx-JS013, targeting NCEH1. NCEH1, a highly expressed and activated serine hydrolase in aggressive cancers, has the potential to be employed for the diagnosis of cancers. We show that NOx-JS013 labels active NCEH1 in live cells with high selectivity relative to other serine hydrolases. NOx-JS013 also presents its efficacy as a hypoxia-responsive imaging probe in live cells. Finally, NOx-JS013 successfully visualizes aggressive prostate cancer tumors in mouse models of PC3, while negligibly detected in tumors of non-aggressive LNCaP mouse models. These findings show that NOx-JS013 has the potential to be used to develop precision PAI reagents for detecting metastatic progression in various cancers.

9.
FEBS J ; 2024 May 07.
Article in English | MEDLINE | ID: mdl-38715400

ABSTRACT

Tauopathies exhibit a characteristic accumulation of misfolded tau aggregates in the brain. Tau pathology shows disease-specific spatiotemporal propagation through intercellular transmission, which is closely correlated with the progression of clinical manifestations. Therefore, identifying molecular mechanisms that prevent tau propagation is critical for developing therapeutic strategies for tauopathies. The various innate immune receptors, such as complement receptor 3 (CR3) and complement receptor 4 (CR4), have been reported to play a critical role in the clearance of various extracellular toxic molecules by microglia. However, their role in tau clearance has not been studied yet. In the present study, we investigated the role of CR3 and CR4 in regulating extracellular tau clearance. We found that CR4 selectively binds to tau fibrils but not to tau monomers, whereas CR3 does not bind to either of them. Inhibiting CR4, but not CR3, significantly reduces the uptake of tau fibrils by BV2 cells and primary microglia. By contrast, inhibiting CR4 has no effect on the uptake of tau monomers by BV2 cells. Furthermore, inhibiting CR4 suppresses the clearance of extracellular tau fibrils, leading to more seed-competent tau fibrils remaining in the extracellular space relative to control samples. We also provide evidence that the expression of CR4 is upregulated in the brains of human Alzheimer's disease patients and the PS19 mouse model of tauopathy. Taken together, our data strongly support that CR4 is a previously undescribed receptor for the clearance of tau fibrils in microglia and may represent a novel therapeutic target for tauopathy.

10.
Heliyon ; 10(9): e30837, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38774106

ABSTRACT

Infrapositioning of implants in the maxillary anterior region can cause esthetic complications, including soft tissue problems. These complications commonly occur in implants placed in young adults. However, there are many clinical reports of implant infrapositioning in the maxillary anterior region after the fourth decade of life. This clinical report describes a case of infrapositioning of the maxillary central incisor wherein esthetic results were obtained through surgical and prosthetic approaches. The surgical approach improved the gingiva shape using the tunnel technique, and the prosthetic approach increased gingiva thickness by adjusting the shape of the abutment, resulting in a shape similar to the natural teeth.

11.
Proc Natl Acad Sci U S A ; 121(19): e2319937121, 2024 May 07.
Article in English | MEDLINE | ID: mdl-38696469

ABSTRACT

Subtropical oceans contribute significantly to global primary production, but the fate of the picophytoplankton that dominate in these low-nutrient regions is poorly understood. Working in the subtropical Mediterranean, we demonstrate that subduction of water at ocean fronts generates 3D intrusions with uncharacteristically high carbon, chlorophyll, and oxygen that extend below the sunlit photic zone into the dark ocean. These contain fresh picophytoplankton assemblages that resemble the photic-zone regions where the water originated. Intrusions propagate depth-dependent seasonal variations in microbial assemblages into the ocean interior. Strikingly, the intrusions included dominant biomass contributions from nonphotosynthetic bacteria and enrichment of enigmatic heterotrophic bacterial lineages. Thus, the intrusions not only deliver material that differs in composition and nutritional character from sinking detrital particles, but also drive shifts in bacterial community composition, organic matter processing, and interactions between surface and deep communities. Modeling efforts paired with global observations demonstrate that subduction can flux similar magnitudes of particulate organic carbon as sinking export, but is not accounted for in current export estimates and carbon cycle models. Intrusions formed by subduction are a particularly important mechanism for enhancing connectivity between surface and upper mesopelagic ecosystems in stratified subtropical ocean environments that are expanding due to the warming climate.


Subject(s)
Bacteria , Oceans and Seas , Seawater , Seawater/microbiology , Seawater/chemistry , Bacteria/metabolism , Carbon/metabolism , Carbon Cycle , Chlorophyll/metabolism , Ecosystem , Phytoplankton/metabolism , Seasons , Biomass , Microbiota/physiology , Oxygen/metabolism
12.
Mol Ther ; 32(6): 1817-1834, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38627969

ABSTRACT

Cellular therapies for the treatment of human diseases, such as chimeric antigen receptor (CAR) T and natural killer (NK) cells have shown remarkable clinical efficacy in treating hematological malignancies; however, current methods mainly utilize viral vectors that are limited by their cargo size capacities, high cost, and long timelines for production of clinical reagent. Delivery of genetic cargo via DNA transposon engineering is a more timely and cost-effective approach, yet has been held back by less efficient integration rates. Here, we report the development of a novel hyperactive TcBuster (TcB-M) transposase engineered through structure-guided and in vitro evolution approaches that achieves high-efficiency integration of large, multicistronic CAR-expression cassettes in primary human cells. Our proof-of-principle TcB-M engineering of CAR-NK and CAR-T cells shows low integrated vector copy number, a safe insertion site profile, robust in vitro function, and improves survival in a Burkitt lymphoma xenograft model in vivo. Overall, TcB-M is a versatile, safe, efficient and open-source option for the rapid manufacture and preclinical testing of primary human immune cell therapies through delivery of multicistronic large cargo via transposition.


Subject(s)
Burkitt Lymphoma , Genetic Vectors , Immunotherapy, Adoptive , Receptors, Chimeric Antigen , Transposases , Humans , Transposases/genetics , Transposases/metabolism , Animals , Receptors, Chimeric Antigen/genetics , Receptors, Chimeric Antigen/metabolism , Immunotherapy, Adoptive/methods , Mice , Genetic Vectors/genetics , Genetic Vectors/administration & dosage , Burkitt Lymphoma/therapy , Burkitt Lymphoma/genetics , Xenograft Model Antitumor Assays , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Cell Line, Tumor , DNA Transposable Elements , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Transgenes
13.
ACS Biomater Sci Eng ; 10(4): 2477-2485, 2024 04 08.
Article in English | MEDLINE | ID: mdl-38483467

ABSTRACT

Examining tumor heterogeneity is essential for selecting an appropriate anticancer treatment for an individual. This study aimed to distinguish low- and high-aggressive tumor cells by analyzing the formation patterns of spheroids. The droplet-based microfluidic system was employed for the formation of each spheroid from four different subtypes of breast tumor cells. Additionally, heterotypic spheroids with T lymphocytes and cancer-associated fibroblasts (CAFs) were produced, and distinctions between low- and high-aggressive tumor cells were explored through the analysis of formation patterns using circularity, convexity, and cell distributions. In both homotypic spheroids and heterotypic spheroids with T lymphocytes, spheroids formed from low-aggressive tumor cells exhibited high circularity and convexity. On the other hand, spheroids formed from high-aggressive tumor cells had relatively low circularity and convexity. In the case of heterotypic spheroids with CAFs, circularity and convexity did not exhibit clear differences between low- and high-aggressive tumor cells, but distinct variations were observed in cell distributions. CAFs and low-aggressive tumor cells were evenly distributed, whereas the CAFs were predominantly located in the inner layer, and high-aggressive tumor cells were primarily located in the outer layer. This finding can offer valuable insights into predicting the aggressiveness of unknown tumor cells.


Subject(s)
Microfluidics , Spheroids, Cellular
14.
J Clin Med ; 13(6)2024 Mar 12.
Article in English | MEDLINE | ID: mdl-38541842

ABSTRACT

(1) Background: The relationship between nonalcoholic fatty liver disease (NAFLD) and incident chronic kidney disease (CKD) is unclear, and long-term follow-up data are limited. Therefore, this study aimed to evaluate whether NAFLD, as assessed by the fatty liver index (FLI), could predict the development of CKD in a community-based Korean cohort over 16 years. (2) Methods: Among the 10,030 total participants, 7778 patients without CKD were selected from the Korean Genome and Epidemiology Study (KoGES). The FLI grade ranged from 0 to 100 and was divided into three groups: low (FLI, <30), intermediate (FLI, 30-59), and high (FLI, ≥60). An estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2 or the development of proteinuria was considered to indicate incident CKD. (3) Results: During the 16-year follow-up period, 919 individuals (11.8%) developed CKD. The HRs of incident CKD in the intermediate FLI group (30-59) and high FLI group (≥60) increased compared with the reference low FLI group (<30) after adjusting for potentially confounding variables. NAFLD, as assessed by the FLI, was an independent risk factor for CKD. (4) Conclusions: Our findings suggest that the FLI, a simple surrogate biomarker of fatty liver disease, may be used to identify people at high risk of incident CKD in clinical practice.

15.
Redox Biol ; 71: 103097, 2024 May.
Article in English | MEDLINE | ID: mdl-38442648

ABSTRACT

Phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] is implicated in various processes, including hormone-induced signal transduction, endocytosis, and exocytosis in the plasma membrane. However, how H2O2 accumulation regulates the levels of PtdIns(4,5)P2 in the plasma membrane in cells stimulated with epidermal growth factors (EGFs) is not known. We show that a plasma membrane PtdIns(4,5)P2-degrading enzyme, synaptojanin (Synj) phosphatase, is inactivated through oxidation by H2O2. Intriguingly, H2O2 inhibits the 4-phosphatase activity of Synj but not the 5-phosphatase activity. In EGF-activated cells, the oxidation of Synj dual phosphatase is required for the transient increase in the plasma membrane levels of phosphatidylinositol 4-phosphate [PtdIns(4)P], which can control EGF receptor-mediated endocytosis. These results indicate that intracellular H2O2 molecules act as signaling mediators to fine-tune endocytosis by controlling the stability of plasma membrane PtdIns(4)P, an intermediate product of Synj phosphoinositide dual phosphatase.


Subject(s)
Hydrogen Peroxide , Nerve Tissue Proteins , Phosphatidylinositols , Hydrogen Peroxide/metabolism , Phosphatidylinositol 4,5-Diphosphate/metabolism , Phosphoric Monoester Hydrolases/metabolism , Cell Membrane/metabolism , Signal Transduction , Endocytosis
16.
Cancers (Basel) ; 16(5)2024 Feb 26.
Article in English | MEDLINE | ID: mdl-38473306

ABSTRACT

BACKGROUND: Little is known about the characteristics of early pancreatic cancer. We aimed to identify the characteristics, clues for early detection, and prognostic factors for early pancreatic cancer by analyzing a large number of patients with stage 1 pancreatic cancer. METHODS: A clinical data warehouse that includes databases of all the medical records of eight academic institutions was used to select and analyze patients with pancreatic cancer that had been diagnosed from January 2010 to May 2023. RESULTS: In total, 257 stage 1 pancreatic cancer patients were included. There were 134 men (52%), and the average age was 67.2 ± 9.9 years. Compared to patients with stage 1B pancreatic cancer (2-4 cm), patients with stage 1A pancreatic cancer (≤2 cm) had more tumors in the body and tail than in the head (p = 0.028), more new-onset diabetes and less old diabetes (p = 0.010), less jaundice (p = 0.020), more follow-up of IPMN (intraductal papillary mucinous neoplasm, p = 0.029), and more histories of acute pancreatitis (p = 0.013). The pathological findings showed that stage 1A pancreatic cancer involved more IPMNs (p < 0.001) and lower pancreatic intraepithelial neoplasia (p = 0.004). IPMN was present in all 13 pancreatic tumors that were smaller than 1 cm. In multivariate analysis, positive resection margin (odds ratio [OR] 1.536, p = 0.040), venous invasion (OR 1.710, p = 0.010), and perineural invasion (OR 1.968, p = 0.002) were found to be risk factors affecting disease-free survival, while old diabetes (odds ratio [OS] 1.981, p = 0.003) and perineural invasion (OR 2.270, p = 0.003) were found to be risk factors affecting overall survival. CONCLUSIONS: IPMN is closely associated with early pancreatic cancer and may provide an opportunity for early detection. The presence of perineural invasion was a crucial prognostic factor for both overall and disease-free survival in patients with stage 1 pancreatic cancer.

17.
Eur Thyroid J ; 13(2)2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38484463

ABSTRACT

Objective: Active surveillance (AS) is generally accepted as an alternative to immediate surgery for papillary thyroid carcinoma (PTC) measuring ≤1.0 cm (cT1a) without risk factors. This study investigated the clinicopathologic characteristics of PTCs measuring ≤2.0 cm without cervical lymph node metastasis (cT1N0) by tumor size group to assess the feasibility of AS for PTCs between 1.0 cm and 1.5 cm (cT1b≤1.5). Design: This study enrolled clinically T1N0 patients with preoperative ultrasonography information (n= 935) from a cohort of 1259 patients who underwent lobectomy and were finally diagnosed with PTC from June 2020 to March 2022. Results: The cT1b≤1.5 group (n = 171; 18.3 %) exhibited more lymphatic invasion and occult central lymph node (LN) metastasis with a higher metastatic LN ratio than the cT1a group (n = 719; 76.9 %). However, among patients aged 55 years or older, there were no significant differences in occult central LN metastasis and metastatic LN ratio between the cT1a, cT1b≤1.5, and cT1b>1.5 groups. Multivariate regression analyses revealed that occult central LN metastasis was associated with age, sex, tumor size, extrathyroidal extension, and lymphatic invasion in patients under 55, while in those aged 55 or older, it was associated only with age and lymphatic invasion. Conclusion: For PTC patients aged 55 years or older with cT1b≤1.5, AS could be a viable option due to the absence of a significant relationship between tumor size and occult central LN.


Subject(s)
Carcinoma, Papillary , Thyroid Neoplasms , Humans , Thyroid Cancer, Papillary/diagnostic imaging , Thyroid Neoplasms/diagnostic imaging , Feasibility Studies , Watchful Waiting , Carcinoma, Papillary/diagnostic imaging , Lymphatic Metastasis/diagnostic imaging , Ultrasonography
18.
ACS Nano ; 18(11): 8392-8410, 2024 Mar 19.
Article in English | MEDLINE | ID: mdl-38450656

ABSTRACT

Therapeutic antibodies that block vascular endothelial growth factor (VEGF) show clinical benefits in treating nonsmall cell lung cancers (NSCLCs) by inhibiting tumor angiogenesis. Nonetheless, the therapeutic effects of systemically administered anti-VEGF antibodies are often hindered in NSCLCs because of their limited distribution in the lungs and their adverse effects on normal tissues. These challenges can be overcome by delivering therapeutic antibodies in their mRNA form to lung endothelial cells, a primary target of VEGF-mediated pulmonary angiogenesis, to suppress the NSCLCs. In this study, we synthesized derivatives of poly(ß-amino esters) (PBAEs) and prepared nanoparticles to encapsulate the synthetic mRNA encoding bevacizumab, an anti-VEGF antibody used in the clinic. Optimization of nanoparticle formulations resulted in a selective lung transfection after intravenous administration. Notably, the optimized PBAE nanoparticles were distributed in lung endothelial cells, resulting in the secretion of bevacizumab. We analyzed the protein corona on the lung- and spleen-targeting nanoparticles using proteomics and found distinctive features potentially contributing to their organ-selectivity. Lastly, bevacizumab mRNA delivered by the lung-targeting PBAE nanoparticles more significantly inhibited tumor proliferation and angiogenesis than recombinant bevacizumab protein in orthotopic NSCLC mouse models, supporting the therapeutic potential of bevacizumab mRNA therapy and its selective delivery through lung-targeting nanoparticles. Our proof-of-principle results highlight the clinical benefits of nanoparticle-mediated mRNA therapy in anticancer antibody treatment in preclinical models.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Animals , Mice , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Bevacizumab/pharmacology , Bevacizumab/therapeutic use , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism , Endothelial Cells/metabolism , Nanomedicine , RNA, Messenger/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Vascular Endothelial Growth Factors , Polymers/therapeutic use , Lung/metabolism , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/therapeutic use
19.
Front Microbiol ; 15: 1357797, 2024.
Article in English | MEDLINE | ID: mdl-38463486

ABSTRACT

Plant microbiomes are known to serve several important functions for their host, and it is therefore important to understand their composition as well as the factors that may influence these microbial communities. The microbiome of Thalassia testudinum has only recently been explored, and studies to-date have primarily focused on characterizing the microbiome of plants in a single region. Here, we present the first characterization of the composition of the microbial communities of T. testudinum across a wide geographical range spanning three distinct regions with varying physicochemical conditions. We collected samples of leaves, roots, sediment, and water from six sites throughout the Atlantic Ocean, Caribbean Sea, and the Gulf of Mexico. We then analyzed these samples using 16S rRNA amplicon sequencing. We found that site and region can influence the microbial communities of T. testudinum, while maintaining a plant-associated core microbiome. A comprehensive comparison of available microbial community data from T. testudinum studies determined a core microbiome composed of 14 ASVs that consisted mostly of the family Rhodobacteraceae. The most abundant genera in the microbial communities included organisms with possible plant-beneficial functions, like plant-growth promoting taxa, disease suppressing taxa, and nitrogen fixers.

20.
Biomol Ther (Seoul) ; 32(2): 171-182, 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-38346909

ABSTRACT

All cells are equipped with intricate signaling networks to meet the energy demands and respond to the nutrient availability in the body. AMP-activated protein kinase (AMPK) is among the most potent regulators of cellular energy balance. Under ATP -deprived conditions, AMPK phosphorylates substrates and affects various biological processes, such as lipid/glucose metabolism and protein synthesis. These actions further affect the cell growth, death, and functions, altering the cellular outcomes in energy-restricted environments. AMPK plays vital roles in maintaining good health. AMPK dysfunction is observed in various chronic diseases, making it a promising target for preventing and alleviating such diseases. Herein, we highlight the different AMPK functions, especially in allergy, aging, and cancer, to facilitate the development of new therapeutic approaches in the future.

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