Faster both in operative time and functional recovery by the extraperitoneal daVinci SP-based robot-assisted radical prostatectomy: a propensity score matching analysis compared to transperitoneal multiport counterpart.

We aim to investigate the peri-operative outcomes after extraperitoneal single-port based robot-assisted radical prostatectomy (eSP-RARP) utilizing the da Vinci SP system compared to conventional transperitoneal multi-port counterparts (tMP-RARP), in an era when pelvic lymph node dissection (PNLD) was omitted for the node-negative case. With exclusion criteria of volume + 50 g, suspicious rectal invasion, and node-positive disease given relatively weak grasping power and limited range of motion from the current SP system, 50 consecutive patients (Since December 2021) with localized prostate cancer underwent eSP-RARP by a single urologist maintaining identical surgical technique for 100 consecutive tMP-RARP cases (Since December 2020). Given initial selection criteria, each group was matched to a 1:1 ratio based on the risk-stratification parameters and the prostate volume. The operative time, which was maintained in each group during the study period, was significantly faster in eSP-RARP groups than in tMP-RARP (149.2 vs. 163.2 min, p = 0.025), while the weight of the removed specimen (27.1 vs. 29.0 g, p = 0.420) and margin positivity (14.7% vs. 11.7% in pT2, p = 0.812) were similar. The gas-out (1.5 vs. 1.88 days, p = 0.003) and solid diet dates (2.26 vs. 3.22 days, p < 0.001) were faster in the eSP-RARP group. The single-pad continence dates (30.5 vs. 51.9 days, p = 0.145) and zero-pad continence dates (105.5 vs. 146.2 days, p = 0.210) were identical. 90-day single-pad continence rate was 92% vs. 82% (p = 0.142, 52% vs. 56% in zero-pad continence). Based on these, daVinci SP-based RARP restored bowel function faster with shorter operative time through an extraperitoneal approach than the conventional transperitoneal multi-port counterpart while maintaining similar incontinence outcomes in cases without a routine PNLD.

Comparative analysis of recurrence rates between intravesical gemcitabine and bacillus Calmette-Guérin induction therapy following transurethral resection of bladder tumors in patients with intermediate- and high-risk bladder cancer: A retrospective multicenter study.

PURPOSE: This study investigated the efficacy of intravesical gemcitabine as an alternative to bacillus Calmette-Guérin (BCG) therapy. MATERIALS AND METHODS: Data were retrospectively collected across seven institutions from February 1999 to May 2023. Inclusion criteria included patients with intermediate- or high-risk non-muscle invasive bladder cancer (NMIBC) who underwent transurethral resection of bladder tumors (TURBT) and received at least four sessions of intravesical gemcitabine or BCG induction therapy. Patient characteristics, complete remission (CR), occurrence, and progression rates were compared. RESULTS: In total, 149 patients were included in this study (gemcitabine, 63; BCG, 86). No differences were apparent between the two groups in baseline characteristics, except for the follow-up period (gemcitabine, 9.2±5.9 months vs. BCG, 43.9±41.4 months, p<0.001). There were no consistent significant differences observed between the two groups in the 3-month (gemcitabine, 98.4% vs. BCG, 95.3%; p=0.848), 6-month (94.9% vs. 90.0%, respectively; p=0.793) and 1-year CR rates (84.2% vs. 83.3%, respectively; p=0.950). Also, there was no significant statistical difference in progression-free survival between the two groups (p=0.953). The occurrence rates of adverse events were similar between the groups (22.2% vs. 22.1%; p=0.989); however, the rate of Clavien-Dindo grade 2 or higher was significantly higher in the BCG group (1.6% vs. 16.3%, respectively; p<0.001). CONCLUSIONS: Intravesical gemcitabine demonstrated efficacy comparable to BCG therapy for the first year in patients with intermediate- and high-risk NMIBC. However, long-term follow-up studies are warranted.

Fabrication of Protective Organic Layer Using Schiff-Base Metal Complex Responsible for Excellent Corrosion Performance: Experimental and Theoretical Perspectives.

The effectiveness of a copper(II) complex with a Schiff base derived from 2-amino-4-phenyl-5-methylthiazole and salicylaldehyde (APMS) as a corrosion inhibitor for XC18 steel in an HCl solution was investigated. Experimental findings indicated a slight negative correlation between inhibition efficiencies in 1 M HCl and temperature but a positive correlation with both inhibitor concentration and immersion time, respectively. The weight loss measurement revealed that APMS achieved a maximum inhibition rate of 92.07% at 303 K. A fitting analysis demonstrated that APMS adheres to the Langmuir adsorption isotherm. The electrochemical results revealed an enhanced inhibitive performance of APMS, with the efficiency increasing as concentrations increased, ultimately reaching a peak of 94.47% at 5 × 10-3 mol L-1. Potentiodynamic polarization measurements revealed that APMS acted as a mixed-type inhibitor without affecting the corrosion mechanism. Scanning electron microscopy investigations of the metal surfaces corroborated the presence of an adsorbed organic layer. Advanced theoretical calculations utilizing density functional theory and first-principles density-functional tight-binding were conducted to gain insights into the behavior of APMS on the metal surface. APMS derives its advantages from crucial inter- and intramolecular interactions, resulting in the formation of a resilient adsorption layer, in line with the experimental findings. It is found that the presence of the APMS-based inhibitor exhibits a significant synergistic corrosion inhibition effect. The current study offers a design direction for enhancing the structural characteristics of Schiff base metal complexes, laying the groundwork for multifunctional frameworks to minimize corrosion rates with considerations for real-world use and cost-efficiency. The ability to replace harmful, expensive constituents with sustainable, and cost-effective organic alternatives represents a significant outcome of this study.

Epigenome-wide Association Study for Tic Disorders in Children: A Preliminary Study in Korean Population.

Objective: : Tic disorders can affect the quality of life in both childhood and adolescence. Many factors are involved in the etiology of tic disorders, and the genetic and epigenetic factors of tic disorders are considered complex and heterogeneous. Methods: : In this study, the differentially methylated regions (DMRs) between normal controls (n = 24; aged 6-15; 7 females) and patients with tic disorders (n = 16; aged 6-15; 5 females) were analyzed. We performed an epigenome-wide association study of tic disorders in Korean children. The tics were assessed using Yale Global Tic Severity Scale. The DNA methylation data consisted of 726,945 cytosine phosphate guanine (CpG) sites, assessed using the Illumina Infinium MethylationEPIC (850k) BeadChip. The DNA methylation data of the 40 participants were retrieved, and DMRs between the four groups based on sex and tic disorder were identified. From 28 male and 16 female samples, 37 and 38 DMRs were identified, respectively. We analyzed the enriched terms and visualized the network, heatmap, and upset plot. Results: : In male, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed hypomethylated patterns in the ligand, receptor, and second signal transductors of the PI3K-Akt and MAPK signaling pathway (most cells were indicated as green color), and in female, the opposite patterns were revealed (most cells were indicated as red color). Five mental disorder-related enriched terms were identified in the network analysis. Conclusion: : Here, we provide insights into the epigenetic mechanisms of tic disorders. Abnormal DNA methylation patterns are associated with mental disorder-related symptoms.

FLRT2 prevents endothelial cell senescence and vascular aging by regulating the ITGB4/mTORC2/p53 signaling pathway.

The roles of fibronectin leucine-rich transmembrane protein 2 (FLRT2) in physiological and pathological processes are not well known. Here, we identify a potentially novel function of FLRT2 in preventing endothelial cell senescence and vascular aging. We found that FLRT2 expression was lower in cultured senescent endothelial cells as well as in aged rat and human vascular tissues. FLRT2 mediated endothelial cell senescence via the mTOR complex 2, AKT, and p53 signaling pathway in human endothelial cells. We uncovered that FLRT2 directly associated with integrin subunit beta 4 (ITGB4) and thereby promoted ITGB4 phosphorylation, while inhibition of ITGB4 substantially mitigated the induction of senescence triggered by FLRT2 depletion. Importantly, FLRT2 silencing in mice promoted vascular aging, and overexpression of FLRT2 rescued a premature vascular aging phenotype. Therefore, we propose that FLRT2 could be targeted therapeutically to prevent senescence-associated vascular aging.

Predictive value of plaque characteristics for identification of lesions causing ischemia.

BACKGROUND: Functional assessment using fractional flow reserve (FFR) and anatomical assessment using optical coherence tomography (OCT) are used in clinical practice for patients with intermediate coronary stenosis. Moreover, coronary computed tomography angiography (CTA) is a common noninvasive imaging technique for evaluating suspected coronary artery disease before being referred for angiography. This study aimed to investigate the association between FFR and plaque characteristics assessed using coronary CTA and OCT for intermediate coronary stenosis. METHODS: Based on a prospective multicenter registry, 159 patients having 339 coronary lesions with intermediate stenosis were included. All patients underwent coronary CTA before being referred for coronary angiography, and both FFR measurements and OCT examinations were performed during angiography. A stenotic lesion identified with FFR ≤0.80 was deemed diagnostic of an ischemia-causing lesion. The predictive value of plaque characteristics assessed using coronary CTA and OCT for identifying lesions causing ischemia was analyzed. RESULTS: Stenosis severity and plaque characteristics on coronary CTA and OCT differed between lesions that caused ischemia and those that did not. In multivariate analysis, low attenuation plaque on coronary CTA (odds ratio [OR]=2.78; P=0.038), thrombus (OR=5.13; P=0.042), plaque rupture (OR=3.25; P=0.017), and intimal vasculature on OCT (OR=2.57; P=0.012) were independent predictors of ischemic lesions. Increasing the number of these plaque characteristics offered incremental improvement in predicting the lesions causing ischemia. CONCLUSIONS: Comprehensive anatomical evaluation of coronary stenosis may provide additional supportive information for predicting the lesions causing ischemia.

Extrinsic hydrophobicity-controlled silver nanoparticles as efficient and stable catalysts for CO2 electrolysis.

To realize economically feasible electrochemical CO2 conversion, achieving a high partial current density for value-added products is particularly vital. However, acceleration of the hydrogen evolution reaction due to cathode flooding in a high-current-density region makes this challenging. Herein, we find that partially ligand-derived Ag nanoparticles (Ag-NPs) could prevent electrolyte flooding while maintaining catalytic activity for CO2 electroreduction. This results in a high Faradaic efficiency for CO (>90%) and high partial current density (298.39 mA cm‒2), even under harsh stability test conditions (3.4 V). The suppressed splitting/detachment of Ag particles, due to the lipid ligand, enhance the uniform hydrophobicity retention of the Ag-NP electrode at high cathodic overpotentials and prevent flooding and current fluctuations. The mass transfer of gaseous CO2 is maintained in the catalytic region of several hundred nanometers, with the smooth formation of a triple phase boundary, which facilitate the occurrence of CO2RR instead of HER. We analyze catalyst degradation and cathode flooding during CO2 electrolysis through identical-location transmission electron microscopy and operando synchrotron-based X-ray computed tomography. This study develops an efficient strategy for designing active and durable electrocatalysts for CO2 electrolysis.

Federated Learning with Pareto Optimality for Resource Efficiency and Fast Model Convergence in Mobile Environments.

Federated learning (FL) is an emerging distributed learning technique through which models can be trained using the data collected by user devices in resource-constrained situations while protecting user privacy. However, FL has three main limitations: First, the parameter server (PS), which aggregates the local models that are trained using local user data, is typically far from users. The large distance may burden the path links between the PS and local nodes, thereby increasing the consumption of the network and computing resources. Second, user device resources are limited, but this aspect is not considered in the training of the local model and transmission of the model parameters. Third, the PS-side links tend to become highly loaded as the number of participating clients increases. The links become congested owing to the large size of model parameters. In this study, we propose a resource-efficient FL scheme. We follow the Pareto optimality concept with the biased client selection to limit client participation, thereby ensuring efficient resource consumption and rapid model convergence. In addition, we propose a hierarchical structure with location-based clustering for device-to-device communication using k-means clustering. Simulation results show that with prate at 0.75, the proposed scheme effectively reduced transmitted and received network traffic by 75.89% and 78.77%, respectively, compared to the FedAvg method. It also achieves faster model convergence compared to other FL mechanisms, such as FedAvg and D2D-FedAvg.

Glucose Metabolism as a Potential Therapeutic Target in Cytarabine-Resistant Acute Myeloid Leukemia.

Altered glycolytic metabolism has been associated with chemoresistance in acute myeloid leukemia (AML). However, there are still aspects that need clarification, as well as how to explore these metabolic alterations in therapy. In the present study, we aimed to elucidate the role of glucose metabolism in the acquired resistance of AML cells to cytarabine (Ara-C) and to explore it as a therapeutic target. Resistance was induced by stepwise exposure of AML cells to increasing concentrations of Ara-C. Ara-C-resistant cells were characterized for their growth capacity, genetic alterations, metabolic profile, and sensitivity to different metabolic inhibitors. Ara-C-resistant AML cell lines, KG-1 Ara-R, and MOLM13 Ara-R presented different metabolic profiles. KG-1 Ara-R cells exhibited a more pronounced glycolytic phenotype than parental cells, with a weaker acute response to 3-bromopyruvate (3-BP) but higher sensitivity after 48 h. KG-1 Ara-R cells also display increased respiration rates and are more sensitive to phenformin than parental cells. On the other hand, MOLM13 Ara-R cells display a glucose metabolism profile similar to parental cells, as well as sensitivity to glycolytic inhibitors. These results indicate that acquired resistance to Ara-C in AML may involve metabolic adaptations, which can be explored therapeutically in the AML patient setting who developed resistance to therapy.

Calcium Chloride as a Novel Stabilizer for Foot-and-Mouth Disease Virus and Its Application in the Vaccine Formulation.

The thermal stability of the in-house-developed foot-and-mouth disease (FMD) type O and A viruses was evaluated, and the O Jincheon virus was found to exhibit the lowest thermal stability. To overcome this instability, we proposed a novel stabilizer, calcium chloride. The thermal stability of FMDVs increased up to a CaCl2 concentration of 10 mM, and it had a decreasing trend at >30 mM. The O Jincheon virus showed a significant decrease in the amount of antigen over time at 4 °C. In contrast, the samples treated with CaCl2 showed stable preservation of the virus without significant antigen loss. After the CaCl2-formulated vaccine was administered twice to pigs, the virus neutralization titer reached approximately 1:1000, suggesting that the vaccine could protect pigs against the FMDV challenge. In summary, the O Jincheon virus is difficult to utilize as a vaccine given its low stability during storage after antigen production. However, following its treatment with CaCl2, it can be easily utilized as a vaccine. This study evaluated CaCl2 as a novel stabilizer in FMD vaccines and may contribute to the development of stable vaccine formulations, especially for inherently unstable FMDV strains.

The adjunctive effect of polydeoxyribonucleotide on bone formation in alveolar ridge preservation: A pre-clinical in vivo study.

AIM: This study investigated the adjunctive effect of polydeoxyribonucleotide (PDRN) on bone formation in alveolar ridge preservation (ARP) sockets. MATERIALS AND METHODS: Both mandibular second, third and fourth premolars of eight beagle dogs were randomly divided into ARP and ARP/PDRN groups. Following tooth extraction, ARP procedures were conducted using collagenized alloplastic graft material and bilayer collagen membrane soaked with normal saline (ARP group) or PDRN (ARP/PDRN group) for 10 min before application. Both groups were also randomly allocated to 2-, 4- or 12-week healing subgroups. The primary endpoint of this study was to compare histomorphometric differences between ARP and ARP/PDRN. The secondary endpoints of this study were to compare micro-CT analysis and three-dimensional volumetric measurement between the two groups. RESULTS: In the histomorphometric analysis, the ARP/PDRN group exhibited greater new bone formation at coronal, middle and total position compared with the ARP group at 2-week healing. The number of newly formed blood vessels was higher in the ARP/PDRN group than in the ARP group at 2- and 4-week healing. In micro-CT analysis, the mean new bone volume/total bone volume between ARP and ARP/PDRN was statistically significant at 2-week healing. Ridge volume alterations were significantly decreased in the ARP/PDRN group during entire healing time compared with the ARP group, especially on the buccal side. CONCLUSIONS: The application of PDRN in ARP might provide additional benefits for early bone regeneration and maintenance of buccal ridge volume.

Calcium Chloride Treatment Enhances Antigen Production in Foot-and-Mouth Disease Vaccines for Serotypes SAT1 and SAT3.

Foot-and-mouth disease (FMD) is a highly contagious viral infection causing acute and severe vesicular lesions in cattle and pigs, which has prompted global vaccination policies. This study presents a technique for enhancing antigen yield in SAT1 BOT and SAT3 ZIM by treatment with calcium chloride (CaCl2). We tested changes in cell viability in BHK-21 suspension cells treated with varying concentrations of CaCl2. The optimal CaCl2 concentration was determined based on antigen yield. The timing of CaCl2 supplementation relative to FMD virus inoculation was tested. Finally, the optimal medium for antigen production was identified. We observed a concentration-dependent decrease in BHK-21 cell viability at >7.5 mM CaCl2. A CaCl2 concentration of 3 mM yielded the most antigens. CaCl2 supplementation relative to FMD virus infection was optimal 2 h before or with viral inoculation. CD-BHK 21 medium supplemented with CaCl2 was the most productive medium. Specifically, SAT1 BOT and SAT3 ZIM showed improved antigen production in CD-BHK 21 medium with 3 mM CaCl2, while Provero-1 and Cellvento BHK-200 media showed no significant enhancement. Overall, CaCl2 supplementation enhanced FMD antigen productivity. This study provides a useful framework for enhancing antigen production efficiently in the FMD vaccine industry.

Determination of Optimal Antigen Yield and Virus Inactivation Conditions for the Production of the Candidate Foot-and-Mouth Disease Recombinant Vaccine Strain Asia1 Shamir-R in a Bioreactor.

Since the foot-and-mouth disease (FMD) outbreak in South Korea in 2010-2011, vaccination policies utilizing inactivated FMD vaccines composed of types O and A have been implemented nationwide. However, because type Asia1 occurred in North Korea in 2007 and intermittently in neighboring countries, the risk of type Asia1 introduction cannot be ruled out. This study evaluated the antigen yield and viral inactivation kinetics of the recombinant Asia1 Shamir vaccine strain (Asia1 Shamir-R). When Asia1 Shamir-R was proliferated in shaking flasks (1 L), a 2 L bioreactor (1 L), and a wave bioreactor (25 L), the antigen yields were 7.5 µg/mL, 5.2 µg/mL, and 3.8 µg/mL, respectively. The optimal FMDV inactivation conditions were 2 mM BEI at 26 °C and 1.0 mM BEI at 37 °C. There was no antigen loss due to BEI treatment, and only a decrease in antigen levels was observed during storage. The sera from pigs immunized with antigen derived from a bioreactor exhibited a neutralizing antibody titer of approximately 1/1000 against Asia1 Shamir and Asia1/MOG/05 viruses; therefore, Asia1 Shamir-R is expected to provide sufficient protection against both viruses. If an FMD vaccine production facility is established, this Asia1 Shamir-R can be employed for domestic antigen banks in South Korea.

Significant CO2 emission in the shallow inshore waters of the southeastern Yellow Sea in 2020.

This study investigated the carbonate system and air-sea CO2 exchange in the inshore waters along South Korea's western coastline in 2020. Overlooking these waters might introduce significant errors in estimating air-sea CO2 fluxes of the southeastern Yellow Sea, given their interaction with land, offshore regions, and sediments. During periods other than summer, seasonal variations in seawater CO2 partial pressure (pCO2) could be generally explained by thermal effects. Tidal mixing and shallow depths resulted in weaker stratification-induced carbon export compared to offshore regions. However, during summer, inshore waters exhibited high spatial variability in pCO2, ranging from approximately 185 to 1000 µatm. In contrast to offshore waters that modestly absorbed CO2, inshore waters shallower than 20 m emitted ∼100 Gg C yr-1 to the atmosphere. However, considering the high heterogeneity of the study area, additional observations with high spatial and temporal resolution are required to refine estimates of air-sea CO2 exchange.

Optimizing long-term stability of siRNA using thermoassemble ionizable reverse pluronic-Bcl2 micelleplexes.

Thermosassemble Ionizable Reverse Pluronic (TIRP) platform stands out for its distinctive combination of thermoassemble and ionizable features, effectively overcoming challenges in previous siRNA delivery systems. This study opens up a formation for long-term stabilization, and high loading of siRNA, specifically crafted for targeting oncogenic pathways. TIRP-Bcl2 self-assembles into a unique micelle structure with a nanodiameter of 75.8 ± 5.7 nm, efficiently encapsulating Bcl2 siRNA while maintaining exceptional colloidal stability at 4 °C for 8 months, along with controlled release profiles lasting 180 h. The dual ionizable headgroup enhance the siRNA loading and the revers pluronic unique structural orientation enhance the stability of the siRNA. The thermoassemble of TIRP-Bcl2 facilitates flexi-rigid response to mild hyperthermia, enhancing deep tissue penetration and siRNA release in the tumor microenvironment. This responsive behavior improves intracellular uptake and gene silencing efficacy in cancer cells. TIRP, with its smaller particle size and reverse pluronic nature, efficiently transports siRNA across the blood-brain barrier, holding promise for revolutionizing glioblastoma (GBM) treatment. TIRP-Bcl2 shows significant potential for precise, personalized therapies, promising prolonged siRNA delivery and in vitro/in vivo stability. This research opens avenues for further exploration and clinical translation of this innovative nanocarrier system across different cancers.

Biodegradable Honeycomb-Mimic Scaffolds Consisting of Nanofibrous Walls.

The scaffold is a porous three-dimensional (3D) material that supports cell growth and tissue regeneration. Such 3D structures should be generated with simple techniques and nontoxic ingredients to mimic bio-environment and facilitate tissue regeneration. In this work, simple but powerful techniques are demonstrated for the fabrication of lamellar and honeycomb-mimic scaffolds with poly(L-lactic acid). The honeycomb-mimic scaffolds with tunable pore size ranging from 70 to 160 µm are fabricated by crystal needle-guided thermally induced phase separation in a directional freezing apparatus. The compressive modulus of the honeycomb-mimic scaffold is ≈4 times higher than that of scaffold with randomly oriented pore structure. The fabricated honeycomb-mimic scaffold exhibits a hierarchical structure from nanofibers to micro-/macro-tubular structures. Pre-osteoblast MC3T3-E1 cells cultured on the honeycomb-mimic nanofibrous scaffolds exhibit an enhanced osteoblastic phenotype, with elevated expression levels of osteogenic marker genes, than those on either porous lamellar scaffolds or porous scaffolds with randomly oriented pores. The advanced techniques for the fabrication of the honeycomb-mimic structure may potentially be used for a wide variety of advanced functional materials.

A Novel Coating System Based on Layered Double Hydroxide/HQS Hierarchical Structure for Reliable Protection of Mg Alloy: Electrochemical and Computational Perspectives.

Growing research activity on layered double hydroxide (LDH)-based materials for novel applications has been increasing; however, promoting LDH layer growth and examining its morphologies without resorting to extreme pressure conditions remains a challenge. In the present study, we enhance LDH growth and morphology examination without extreme pressure conditions. By synthesizing Mg-Al LDH directly on plasma electrolytic oxidation (PEO)-treated Mg alloy surfaces and pores at ambient pressure, the direct synthesis was achieved feasibly without autoclave requirements, employing a suitable chelating agent. Additionally, enhancing corrosion resistance involved incorporating electron donor-acceptor compounds into a protective layer, with 8-Hydroxyquinoline-5-sulfonic acid (HQS) that helps in augmenting Mg alloy corrosion resistance through the combination of LDH ion-exchange ability and the organic layer. DFT simulations were used to explain the mutual interactions in the LDH system and provide a theoretical knowledge of the interfacial process at the molecular level.

CM1, a Chrysin Derivative, Protects from Endotoxin-Induced Lethal Shock by Regulating the Excessive Activation of Inflammatory Responses.

Sepsis, a leading cause of death worldwide, is a harmful inflammatory condition that is primarily caused by an endotoxin released by Gram-negative bacteria. Effective targeted therapeutic strategies for sepsis are lacking. In this study, using an in vitro and in vivo mouse model, we demonstrated that CM1, a derivative of the natural polyphenol chrysin, exerts an anti-inflammatory effect by inducing the expression of the ubiquitin-editing protein TNFAIP3 and the NAD-dependent deacetylase sirtuin 1 (SIRT1). Interestingly, CM1 attenuated the Toll-like receptor 4 (TLR4)-induced production of inflammatory cytokines by inhibiting the extracellular-signal-regulated kinase (ERK)/MAPK and nuclear factor kappa B (NF-κB) signalling pathways. In addition, CM1 induced the expression of TNFAIP3 and SIRT1 on TLR4-stimulated primary macrophages; however, the anti-inflammatory effect of CM1 was abolished by the siRNA-mediated silencing of TNFAPI3 or by the genetic or pharmacologic inhibition of SIRT1. Importantly, intravenous administration of CM1 resulted in decreased susceptibility to endotoxin-induced sepsis, thereby attenuating the production of pro-inflammatory cytokines and neutrophil infiltration into the lung compared to control mice. Collectively, these findings demonstrate that CM1 has therapeutic potential for diverse inflammatory diseases, including sepsis.

SOX2 and OCT4 mediate radiation and drug resistance in pancreatic tumor organoids.

Pancreatic cancer has a five-year survival rate of only 10%, mostly due to late diagnosis and limited treatment options. In patients with unresectable disease, either FOLFIRINOX, a combination of 5-fluorouracil (5-FU), oxaliplatin and irinotecan, or gemcitabine plus nab-paclitaxel combined with radiation are frontline standard regimens. However, chemo-radiation therapy has shown limited success because patients develop resistance to chemotherapy and/or radiation. In this study, we evaluated the role of pancreatic cancer stem cells (CSC) using OCT4 and SOX2, CSC markers in mouse pancreatic tumor organoids. We treated pancreatic tumor organoids with 4 or 8 Gy of radiation, 10 µM of 5-FU (5-Fluorouracil), and 100 µM 3-Bromopyruvate (3BP), a promising anti-cancer drug, as a single treatment modalities, and in combination with RT. Our results showed significant upregulation of, OCT4, and SOX2 expression in pancreatic tumor organoids treated with 4 and 8 Gy of radiation, and downregulation following 5-FU treatment. The expression of CSC markers with increasing treatment dose exhibited elevated upregulation levels to radiation and downregulation to 5-FU chemotherapy drug. Conversely, when tumor organoids were treated with a combination of 5-FU and radiation, there was a significant inhibition in SOX2 and OCT4 expression, indicating CSC self-renewal inhibition. Noticeably, we also observed that human pancreatic tumor tissues exhibited heterogeneous and aberrant OCT4 and SOX2 expression as compared to normal pancreas, indicating their potential role in pancreatic cancer growth and therapy resistance. In addition, the combination of 5-FU and radiation treatment exhibited significant inhibition of the ß-catenin pathway in pancreatic tumor organoids, resulting in sensitization to treatment and organoid death. In conclusion, our study emphasizes the crucial role of CSCs in therapeutic resistance in PC treatment. We recommend using tumor organoids as a model system to explore the impact of CSCs in PC and identify new therapeutic targets.