Targeting ROS in osteoclasts within the OA environment: A novel therapeutic strategy for osteoarthritis management.

This study investigated the therapeutic potential of a manganese dioxide-polymer dot (MnO2-PD)-incorporated hydrogel, designated as M-PD hydrogel, for modulating reactive oxygen species (ROS) within the osteoarthritis (OA) environment. Our research highlights the ability of the hydrogel to scavenge ROS, thereby influencing the differentiation of osteoclasts and protecting chondrocytes, offering a novel approach to osteoarthritis (OA) management. Our results indicated that the M-PD hydrogel increased electrical resistance and fluorescence recovery in the presence of osteoclasts, correlating with decreased ROS levels and suppressed expression of osteoclast differentiation markers. Coculture experiments revealed the protective effects of the hydrogel on chondrocytes by reducing the expression of matrix-degrading enzymes. In vivo application in burr holes and/or OA-induced mice revealed a significant reduction in osteoclast formation and cartilage destruction, suggesting the dual therapeutic action of the hydrogel in altering the joint microenvironment. These findings highlight the potential of targeting ROS in osteoclasts as a comprehensive therapeutic approach, offering not only symptomatic relief but also targeting the underlying mechanisms of disease progression in OA.

Imlunestrant, an oral selective estrogen receptor degrader, as monotherapy and combined with abemaciclib, in recurrent/advanced ER-positive endometrioid endometrial cancer: Results from the phase 1a/1b EMBER study.

OBJECTIVE: Imlunestrant is a next-generation oral selective estrogen receptor degrader designed to deliver continuous estrogen receptor (ER) target inhibition. EMBER is a phase 1a/b trial of imlunestrant, as monotherapy and combined with targeted therapy, in patients with ER+ advanced breast cancer or endometrioid endometrial cancer (EEC). This report focuses on patients with ER+ EEC. METHODS: EMBER used an i3 + 3 dose-escalation design to determine the recommended phase 2 dose (RP2D) followed by dose-expansion cohorts (1:1 randomization): imlunestrant monotherapy and imlunestrant plus abemaciclib (150 mg twice daily). Eligible patients had measurable disease and progression or recurrence after platinum-containing chemotherapy. Prior fulvestrant or aromatase inhibitor was not allowed. Secondary endpoints included safety, pharmacokinetics and antitumor activity. RESULTS: In total, 72 patients with a median of 2 prior anticancer therapies were treated. Among the 39 patients who received imlunestrant (400 mg [RP2D], n = 33; 800 mg, n = 6), the most common treatment-emergent adverse events (TEAEs) were grade 1-2 nausea (35.9 %), diarrhea (25.6 %), urinary tract infection (25.6 %), and abdominal pain (20.5 %). Overall response rate (ORR) was 10.3 %, clinical benefit rate (CBR) was 33.3 %, and median progression-free survival (mPFS) was 3.8 months (95 % CI, 1.8-6.7). Among the 33 patients who received imlunestrant (400 mg [RP2D], n = 29; 800 mg, n = 4) plus abemaciclib, the most common TEAEs were diarrhea (87.9 %), nausea (66.7 %), fatigue (48.5 %), and anemia (45.5 %). ORR was 18.2 %, CBR was 42.4 %, and mPFS was 6.8 months (95 % CI, 2.1-12). CONCLUSION: Imlunestrant, as monotherapy and combined with abemaciclib, has a manageable safety profile with preliminary evidence of antitumor activity in patients with ER+ EEC.

A phase Ib study of the combination of naporafenib with rineterkib or trametinib in patients with advanced and metastatic KRAS- or BRAF-mutant non-small cell lung cancer.

BACKGROUND: Genetic alterations activating the MAPK pathway are common in non-small cell lung cancer (NSCLC). Patients with NSCLC may benefit from treatment with the pan-RAF inhibitor naporafenib (LXH254) plus the ERK1/2 inhibitor rineterkib (LTT462) or MEK1/2 inhibitor trametinib. METHODS: This first-in-human phase 1b dose-escalation/dose-expansion study investigated the combinations of naporafenib (50-350 mg once daily [QD] or 300-600 mg twice daily [BID]) with rineterkib (100-300 mg QD) in patients with KRAS-/BRAF-mutant NSCLC and naporafenib (200 mg BID or 400 mg BID) with trametinib (0.5 mg QD, 1 mg QD or 1 mg QD 2 weeks on/2 weeks off) in patients with KRAS-/BRAF-mutant NSCLC and NRAS-mutant melanoma. The primary objectives were to identify the recommended dose for expansion (RDE) and evaluate tolerability and safety. Secondary objectives included antitumor activity and pharmacodynamics. RESULTS: Overall, 216 patients were treated with naporafenib plus rineterkib (NSCLC: n = 101) or naporafenib plus trametinib (NSCLC: n = 79; melanoma: n = 36). In total, 10 of 62 (16%) patients experienced at least one dose-limiting toxicity. The RDEs were established as naporafenib 400 mg BID plus rineterkib 200 mg QD, naporafenib 200 mg BID plus trametinib 1 mg QD and naporafenib 400 mg BID plus trametinib 0.5 mg QD. The most frequent grade ≥ 3 treatment-related adverse event was increased lipase (8/101 [7.9%] patients) for naporafenib plus rineterkib and rash (22/115 [19.1%] patients) for naporafenib plus trametinib. Among patients with NSCLC, partial response was observed in three patients (one with KRAS-mutant, two with BRAFnon-V600-mutant NSCLC) treated with naporafenib plus rineterkib and two patients (both with KRAS-mutant NSCLC) treated with naporafenib plus trametinib. On-treatment median reductions in DUSP6 mRNA levels from baseline were 45.5% and 76.1% with naporafenib plus rineterkib or trametinib, respectively. CONCLUSIONS: Both naporafenib combinations had acceptable safety profiles. Antitumor activity was limited in patients with NSCLC, despite the observed on-target pharmacodynamic effect. CLINICALTRIALS: gov identifier: NCT02974725.

Exploring 7ß-amino-6-nitrocholestens as COVID-19 antivirals: in silico, synthesis, evaluation, and integration of artificial intelligence (AI) in drug design: assessing the cytotoxicity and antioxidant activity of 3ß-acetoxynitrocholestane.

In light of the ongoing pandemic caused by SARS-CoV-2, effective and clinically translatable treatments are desperately needed for COVID-19 and its emerging variants. In this study, some derivatives, including 7ß-aminocholestene compounds, and 3ß-acetoxy-6-nitrocholesta-4,6-diene were synthesized, in quantitative yields from 7ß-bromo-6-nitrocholest-5-enes (1-3) with a small library of amines. The synthesized steroidal products were then thoroughly characterized using a range of physicochemical techniques, including IR, NMR, UV, MS, and elemental analysis. Next, a virtual screening based on structures using docking studies was conducted to investigate the potential of these synthesized compounds as therapeutic candidates against SARS-CoV-2. Specifically, we evaluated the compounds' binding energy of the reactants and their products with three SARS-CoV-2 functional proteins: the papain-like protease, 3C-like protease or main protease, and RNA-dependent RNA polymerase. Our results indicate that the 7ß-aminocholestene derivatives (4-8) display intermediate to excellent binding energy, suggesting that they interact strongly with the receptor's active amino acids and may be promising drug candidates for inhibiting SARS-CoV-2. Although the starting steroid derivatives; 7ß-bromo-6-nitrocholest-5-enes (1-3) and one steroid product; 3ß-acetoxy-6-nitrocholesta-4,6-diene (9) exhibited strong binding energies with various SARS-CoV-2 receptors, they did not meet the Lipinski Rule and ADMET properties required for drug development. These compounds showed either mutagenic or reproductive/developmental toxicity when assessed using toxicity prediction software. The findings based on structure-based virtual screening, suggest that 7ß-aminocholestaines (4-8) may be useful for reducing the susceptibility to SARS-CoV-2 infection. The docking pose of compound 4, which has a high score of -7.4 kcal mol-1, was subjected to AI-assisted deep learning to generate 60 AI-designed molecules for drug design. Molecular docking of these AI molecules was performed to select optimal candidates for further analysis and visualization. The cytotoxicity and antioxidant effects of 3ß-acetoxy-6-nitrocholesta-4,6-diene were tested in vitro, showing marked cytotoxicity and antioxidant activity. To elucidate the molecular basis for these effects, steroidal compound 9 was subjected to molecular docking analysis to identify potential binding interactions. The stability of the top-ranked docking pose was subsequently assessed using molecular dynamics simulations.

Unmet medical needs and influencing factors among Korean police officers: a cross-sectional survey.

OBJECTIVES: South Korea grapples with a disproportionately high incidence of unmet medical needs, a concern that is particularly acute among police officers, who are exposed to significant occupational risks. Given the pivotal role of police officers in upholding democratic values and public safety, their well-being holds critical societal implications. This study aims to determine the incidence of unmet medical needs among police officers and identify the influencing factors. DESIGN: This is a retrospective and cross-sectional study. Applying the Andersen behavioural model and multiple logistic regression analysis, we explored factors impacting unmet medical needs. SETTING: The study took place in South Korea and involved its total force of police officers. PARTICIPANTS: Our analysis encompassed data from 6591 participants, representing 5.2% of South Korea's total police officers. OUTCOME MEASURES: Unmet medical needs. RESULTS: Our findings revealed several influencing factors. First, predisposing factors included sex, with women experiencing a higher incidence of unmet medical needs. Second, enabling factors highlighted the significance of job positions and reduced annual leave guarantees in influencing unmet medical needs. Finally, need factors demonstrated the substantial impact of chronic diseases, heightened levels of depression, reduced subjective health assessments, increased stress levels and exposure to rough physical activity on driving unmet medical needs. CONCLUSIONS: To mitigate and pre-empt the long-term health repercussions associated with unmet medical needs, intervention strategies should prioritise these identified factors. An integrated healthcare programme emerges as a critical necessity for addressing the healthcare challenges faced by police officers.

Spatially offset Raman scattering line-mapping as an adaptive tool ensuring accuracy for determination of component concentrations in tablets with different particle sizes.

Spatially offset Raman scattering (SORS) line-mapping was explored as a versatile tool to examine accuracy variations in compositional analyses of tablets with different particle sizes. SORS spectra collected near the laser irradiation were less representative of tablet composition due to the limited spectroscopic sampling volume, while the signal-to-noise (S/N) ratios of corresponding spectra were higher. On the other hand, SORS spectra at longer offset distances were better representative of tablet composition, while their S/N ratios were decreased considerably. Therefore, the use of only a certain portion of sliced (line-mapped) spectra balanced with the sample representation and S/N ratio could be advantageous to enhance accuracy. Moreover, a group of optimal slice spectra is expected to vary when the particle size of the tablet changes since the characteristics of internal photon propagation also would change. For the overall examination, SORS spectra of 30 Anaprox tablets (composed of 4 constituents including naproxen sodium) with 2 particle sizes (88.4 ± 11.8 µm and 118.9 ± 38.8 µm) were analyzed, and the concentrations of three components in these tablets were determined. A total of 6 cases (3 components and 2 particle sizes) were examined. When the average optimal slice spectra were employed in each case, the errors were lower compared to those using the average of all slice spectra. The demonstrated scheme was versatile to study the offset distance-dependent accuracy variations according to particle size and target component.

Higher mortality and longer length of stay in hospitalized patients with newly diagnosed diabetes.

AIMS: We investigated the association between diabetes status at admission and in-hospital outcomes in all hospitalized patients, regardless of the reason for admission. METHODS: All individuals aged 20 years or older who were admitted to Yongin Severance Hospital between March 2020 and February 2022 were included in study. Subjects were categorized into three groups: non-DM, known DM, and newly diagnosed DM, based on medical history, anti-diabetic medications use, and laboratory test. Hospitalization-related outcomes, including in-hospital mortality and length of hospital stay, were compared between groups. RESULTS: 33,166 participants were enrolled. At hospitalization, 6,572 (19.8 %) subjects were classified as known DM, and another 2,634 (7.9 %) subjects were classified as newly diagnosed DM. In-hospital mortality was highest in newly diagnosed DM (HR 1.89, 95% CI 1.58-2.26, p < 0.001) followed by known DM (HR 1.41, 95% CI 1.18-1.69, p < 0.001) compared to non-DM. Length of hospital stay was significantly longer in newly diagnosed DM (median [IQR] 9.0 [5.0-18.0],days) than known DM (median [IQR] 5.0 [3.0-10.0],days)(p < 0.001) and non-DM (median [IQR] 4.0 [2.0-7.0],days). After adjusting for multiple covariates, newly diagnosed diabetes was independently associated with increased in-hospital mortality (p < 0.001). CONCLUSIONS: Diabetes status at admission was closely linked to hospitalization-related outcomes. Notably, individuals with newly diagnosed diabetes demonstrated a higher risk of in-hospital mortality and a prolonged length of hospital stay.

A comprehensive Exdia TRF-LFIA for simultaneous quantification of GFAP and NT-proBNP in distinguishing ischemic and hemorrhagic stroke.

The goal of this study is to create a highly sensitive time-resolved fluorescence lateral flow immunoassay (TRF-LFIA) capable of concurrently measuring glial fibrillary acidic protein (GFAP) and the N-terminal fragment of B-type natriuretic peptide precursor (NT-proBNP). This assay is designed as a diagnostic tool and aims to provide an algorithm for stroke management, specifically for distinguishing between Ischemic stroke (IS) and Hemorrhagic stroke (HS). However, LFIA to quantify simultaneous serum NT-proBNP and GFAP are not yet available. We have developed and validated a novel TRF-LFIA for the simultaneous quantitative detection of NT-proBNP and GFAP. The sensitivity and reproducibility of the immunoassay were significantly improved by employing specific monoclonal antibodies linked to europium nanoparticles (EuNPs) that specifically target NT-proBNP and GFAP. The detection area on the nitrocellulose membrane featured sandwich-style complexes containing two test lines for NT-proBNP and GFAP, and one Control line. The fluorescence intensity of these test lines and control line was measured using an in-house developed Exdia TRF-Plus analyzer. As proof-of-concept, we enrolled patients suspected of having a stroke who were admitted within a specific time frame (6 h). A small amount of clinical specimen (serum) was used. To optimize the LFIA, an EuNPs conjugated antibodies were investigated to improve the detection sensitivity and decrease the background signal as well shorten the detection time. The Exdia TRF-LFIA cartridge offers a wide linear dynamic detection range, rapid detection, high sensitivity, and specificity. The limit of detection was determined to be 98 pg/mL for NT-proBNP and 68 pg/mL for GFAP, with minimal cross-reactivity. There were 200 clinical human serum samples that were used to evaluate this platform with high correlation. By combining the results of NT-proBNP and GFAP, we formulated an algorithm for the clinical assessment of Ischemic Stroke (IS) and Hemorrhagic Stroke (HS). According to our proposed algorithm, the combination of GFAP and NT-proBNP emerged as the most effective biomarker combination for distinguishing between IS and HS. Exdia TRF-LFIA shows great potential as a supplemental method for in vitro diagnostics in the laboratory or in other point-of-care testing (POCT) applications. Its development substantially decreases the diagnosis time for IS and HS. The proposed algorithm not only minimizes treatment delays but also lowers medical costs for patients.

Extensional rheology of anode slurries for li-ion batteries containing natural and synthetic graphite.

Processing of electrode slurry, which is highly non-Newtonian fluid, is a critical step in the mass production of lithium-ion batteries (LIBs). While extensional flow plays an important role in the electrode slurry processes such as coating, most previous studies have focused only on the shear rheology, due to the lack of a reliable method to measure the extensional rheological properties of the slurry. Here, it is demonstrated that the extensional rheological properties of the anode slurries can be successfully characterized using the stop-flow-dripping-onto-substrate/capillary break-up rheometry (SF-DoS/CaBER). Using this system, it is observed that the extensional rheology of the anode slurry is significantly affected by the blend ratio of the natural and synthetic graphite, as well as the binder and conductive concentrations. Furthermore, the shear rheology-based model predicts much shorter pinch-off times than those measured experimentally, indicating that the yield-stress of the anode slurry is much larger in extensional flow than in shear flow.

Preparation of a Pt(II)-3-Hydroxy-2-tolyl-4H-chromen-4-one Complex Having Antimicrobial, Anticancerous, and Radical Scavenging Activities with Related Computational Studies.

A novel benzopyran-based platinum (II)-3-hydroxy-2-tolyl-4H-chromen-4-one (HToC) complex has been prepared and studied by UV-visible spectrophotometry. The study is based on the colored complexation between Pt(II) and HToC in the pH range of 8.92-9.21, resulting in the formation of a stable binary yellow complex exhibiting λmax at 509-525 nm. The formed complex maintains linearity between 0.0 and 1.8 µg Pt(II) mL-1. The well-known qualitative analytical methods, including Job's method of continuous variations and the mole ratio approach, have both proven that the stoichiometry of the complex is 1:2 [Pt(II)/HToC]. Hence, the analytical results suggest that the formed platinum complex exhibits a square planar geometry. The values of various attributes corresponding to spectrophotometric studies and statistical calculations, such as the molar extinction coefficient (6.790 × 104 L mol-1 cm-1), Sandell's sensitivity (0.0029 µg Pt(II) cm-2), standard deviation (± 0.0011), RSD (0.317%), limit of detection (0.0147 µg mL-1) and correlation coefficient (0.9999), show that the performed study satisfies all of the criteria for good sensitivity, versatility, and cost-effectiveness. In order to have an apprehension of the molecular geometry and other structural specifics of the complex, DFT studies have been carried out. The in vitro anticancer potential of the ligand and its platinum complex in the human breast cancer cell line (T-27D), as determined by the MTT assay, reveals that the complex has better antiproliferative potential than the ligand. The antimicrobial potential of the complex has been successfully tested against both Gram-positive and -negative bacteria. Antioxidant capacity results suggest the better radical scavenging capacity of the complex than that of the ligand.

Disseminated Histoplasmosis in an Indigenous Child With Malnutrition: A Case Report.

Histoplasmosis is a mycosis caused by Histoplasma capsulatum, a dimorphic fungus endemic to areas with nitrogen-rich soil, like the one contaminated with bird and bat excrement. Patients with a deficient immune response are especially at risk for developing invasive infections, such as disseminated histoplasmosis, and secondary immunodeficiency can be a consequence of malnutrition. This case report presents a 15-month-old male infant with malnutrition who presented with signs and symptoms of disseminated histoplasmosis, including fever, malaise, weight loss, cough, and diarrhea. The infant came from a geographic area where histoplasmosis is endemic, and he was a member of a cultural group with a higher prevalence of histoplasmosis than the general population. On physical examination, hepatosplenomegaly, lymphadenopathy, and lung crackles were found, which are common in most patients with histoplasmosis. The keystone of diagnosis of H. capsulatum infection is antigen detection, but the criterion standard is isolation of the organism from body specimens through laboratory culture. Histological diagnosis is especially useful for rapid diagnosis. Treatment of disseminated histoplasmosis in the pediatric population consists of deoxycholate amphotericin B for four to six weeks followed by itraconazole to complete a total of three months of treatment. Despite the involvement of multiple organ systems, the patient recovered satisfactorily after the completion of amphotericin B treatment for one month and the resolution of his malnourishment.

Recent advances in microbial production of medium chain fatty acid from renewable carbon resources: A comprehensive review.

Microbial production of medium chain length fatty acids (MCFAs) from renewable resources is becoming increasingly important in establishing a sustainable and clean chemical industry. This review comprehensively summarizes current advances in microbial MCFA production from renewable resources. Detailed information is provided on two major MCFA production pathways using various renewable resources and other auxiliary pathways supporting MCFA production to help understand the fundamentals of bio-based MCFA production. In addition, conventional and well-studied MCFA producers are classified into two categories, natural and synthetic producers, and their characteristics on MCFA production are outlined. Moreover, various engineering strategies employed to achieve the highest MCFAs production up to date are showcased together with key enzymes suggested for MCFA overproduction. Finally, future challenges and perspectives are discussed towards more efficient production of bio-based MCFA production.

Numerical simulation and biomechanical analysis of locking screw caps on clavicle locking plates.

BACKGROUND: The risk of displaced and comminuted midshaft clavicle fractures is increased in high-energy traumas such as sport injuries and traffic accidents. Open reduction and plate fixation have been widely used for midshaft clavicle fractures. Among various plates for clavicle shaft fractures, superior locking compression plates (LCPs) have been mostly used. In plate fixation, nonunion caused by implant failure is the most difficult complication. The most common reasons for metal plate failure are excessive stress and stress concentration caused by cantilever bending. These causes were easily addressed using a locking screw cap (LSC). METHODS: The clavicle 3-dimensional image was made from a computed tomography scan, and the clavicle midshaft fracture model was generated with a 10-mm interval. The fracture model was fixed with a superior LCP, and finite element analysis was conducted between the presence (with LSC model) and absence (without LSC model) of an LSC on the site of the fracture. The stresses of screw holes in models with and without LSCs were measured under 3 forces: 100 N cantilever bending force, 100 N axial compression force, and 1 N·m axial torsion force. After the finite element analysis, a validation test was conducted on the cantilever bending force known as the greatest force applied to superior locking plates. RESULTS: The mean greatest stress under the cantilever bending force was significantly greater than other loading forces. The highest stress site was the screw hole edge on the fracture site in both models under the cantilever bending and axial compression forces. Under the axial torsional force, the maximum stress point was the lateral first screw hole edge. The ultimate plate stress of the with LSC model is completely lower than that of the without LSC model. According to the validation test, the stiffness, ultimate load, and yield load of the with LSC model were higher than those of the without LSC model. CONCLUSIONS: Therefore, inserting an LSC into an empty screw hole in the fracture area reduces the maximum stress on an LCP and improves biomechanical stability.

Screening of biosynthesized zinc oxide nanoparticles for their effect on Daucus carota pathogen and molecular docking.

Herein, we investigate the phytogenic synthesis of zinc oxide nanoparticles (ZnO-NPs) by using aqueous extract of seed coat of almond as a novel resource which can acts as a stabilizing and reducing agents. Successful biosynthesis of ZnO-NPs was observed by Ultraviolet-visible spectroscopy (UV-vis) showing peak at ~272 nm. The scanning electron microscopy (SEM) and transmission electron microscopy (TEM) techniques confirm the circular shape with an average size of ~20 nm. Applications of ZnO-NPs were observed on carrot (Daucus carota) plant infected with pathogenic fungus Rhizoctonia solani. Spray with 50 ppm and 100 ppm ZnO-NPs caused significant increase in plant growth attributes and photosynthetic pigments of carrot plants. It has been reported that the synthesized ZnO-NPs demonstrated an inhibitory activity against plant pathogenic fungus R. solani and reduces disease in carrot plants. Scanning electron microscopy and confocal microscopy indicated adverse effect of ZnO-NPs on pathogens. Antifungal efficiency of ZnO-NPs was further explained with help of molecular docking analysis. Conformation with highest negative binding energy was used to predict binding site of receptor with NPs to know mechanistic approach. ZnO-NPs are likely to interact with the pathogens by mechanical enfolding which may be one of the major toxicity actions against R. solani by ZnO-NPs. RESEARCH HIGHLIGHTS: ZnO nanoparticles were synthesized using waste material from the coat of almond seeds. Images from SEM, TEM, and related techniques like EDS and SAED revealed the irregularity of the ZnO NPs as well as their atom composition. FTIR and XRD analyses confirmed the formation and the presence of crystalline ZnO NPs in nature. Biogenic ZnONPs were found to be effective against the plant pathogenic fungus R. solani. A spray of 50 ppm and 100 ppm ZnO-NPs significantly increased carrot plant growth characteristics and photosynthetic pigments.

Synthesis, Spectroscopic Characterization, Single-Crystal Structure, Hirshfeld Surface Analysis, and Antimicrobial Studies of 3-Acetoxy-2-methylbenzoic Anhydride.

We report a novel anhydride derivative, 3-acetoxy-2-methylbenzoic anhydride (AMA), obtained from the interaction of 3-acetoxy-2-methylbenzoyl chloride with 3-acetoxy-2-methylbenzoic acid. The synthesized compound was characterized by elemental analysis, IR, 1H NMR, and 13C NMR spectroscopic studies and single-crystal X-ray crystallography which revealed the crystallization of AMA as monoclinic with space group P21/c. A Hirshfeld surface analysis was performed to record various intermolecular interactions, indicating the stabilization of the AMA structure by the intermolecular weak C-H···O hydrogen bonds and π···π interactions. The title compound was screened for antibacterial and antifungal activities using a serial dilution technique under aseptic conditions. The results indicate that the title compound has significant antibacterial properties but showed no antifungal behavior.

A novel thermosensitive poloxamer-hyaluronic acid- kappa-carrageenan-based hydrogel anti-adhesive agent loaded with 5-fluorouracil: A preclinical study in Sprague-Dawley rats.

Although the first-choice treatment for colorectal cancer is cytoreductive surgery combined with chemotherapy, post-surgical peritoneal adhesion and extant malignancy can cause fatal complications. Studies examining hydrogel-based postoperative anti-adhesion treatments are still limited. In this study, several formulations of 5-fluorouracil (5-FU) loaded into hyaluronic acid (HA) and kappa-carrageenan (kCGN)-poloxamer 407 (P407)-based cross-linked hydrogels were prepared and evaluated in vitro and in vivo for their efficacy in preventing adhesion. These hydrogels met a set of desired specifications such as thermosensitive behavior, strong elasticity at body temperature (tan δ < 1.0 at 37 °C), and ability to encapsulate hydrophilic drug and deliver it in a sustained released manner. Our secondary purpose is to provide in situ 5-FU for additional local antitumor effect when the anti-adhesion agent is spread over the tumor site. Over 60% of the total loaded drug was released within 4 h, and about 80% of 5-FU was released after three days. Both the Higuchi and Korsmeyer-Peppas models showed that the mechanism of sustained drug release involved diffusion. The constructed hydrogels were evaluated for in vivo intra-abdominal anti-adhesion barrier efficiency; the HA/kCGN 1%/3% w/v hydrogel formulation showed the best anti-adhesion effect in this preclinical study using Sprague-Dawley rat models.

Salvage living donor liver transplantation versus repeat liver resection for patients with recurrent hepatocellular carcinoma and Child-Pugh class A liver cirrhosis: A propensity score-matched comparison.

Following curative liver resection (LR), resectable tumor recurrence in patients with preserved liver function leads to deciding between a repeat LR and a salvage liver transplantation (LT), if a donor's liver is available. This retrospective study compared survival outcomes and recurrence pattern following salvage living donor LT (LDLT) and repeat LR in patients with recurrent hepatocellular carcinoma (HCC). We reviewed the medical records of patients who underwent repeat LR (n = 163) or LDLT (n = 84) for recurrent HCC following curative resections, between January 2005 and December 2017 at a single institution. A 1:1 propensity score matching led to 42 patients per group. Disease-specific and recurrence-free survival were significantly better in the salvage LDLT group than in the repeat LR group (p = .042; HR = 2.40; 95% CI, 0.69-6.00 and p < .001; HR = 4.23; 95% CI, 2.05-8.71, respectively). Despite significant differences in recurrence patterns between the two groups (p = .019), the patient death rates, after recurrence, were similar for both groups (p = .760). This study indicates that salvage LDLT is superior to repeat LR for treating patients with transplantable, intrahepatic HCC recurrence, even in patients with Child-Pugh class A liver cirrhosis.

Asbestosis diagnosis algorithm combining the lung segmentation method and deep learning model in computed tomography image.

BACKGROUND: Early detection of asbestosis is important; hence, quick and accurate diagnostic tools are essential. This study aimed to develop an algorithm that combines lung segmentation and deep learning models that can be utilized as a clinical decision support system (CDSS) for diagnosing patients with asbestosis in segmented computed tomography (CT) images. METHODS: We accurately segmented the lungs in CT images of patients examined at Seoul St. Mary's Hospital using a threshold-based method. Lungs with asbestosis and normal lungs were classified by applying the segmented image to the long-term recurrent convolutional network deep learning model. Performance was evaluated using the area under the receiver operating characteristic curve (AUROC) and F1 score from the test data. RESULTS: The algorithm developed using the DenseNet201pre-trained model showed excellent performance, with a sensitivity of 0.962, specificity of 0.975, accuracy of 0.970, AUROC of 0.968, and F1 score of 0.961. CONCLUSIONS: We developed an algorithm with significantly better diagnostic accuracy than a radiologist (0.970 vs. 0.73-0.79). Our developed algorithm is expected to be an excellent support tool if used as a CDSS to diagnose asbestosis using CT images.

Association between nonalcoholic fatty liver disease and cardiovascular disease revealed after comprehensive control of metabolic risk factors: a nationwide population-based study in Korea.

OBJECTIVES: Previous epidemiological studies have limitations in revealing whether cardiovascular disease (CVD) incidence is mediated by interim occurrence of other metabolic diseases in otherwise healthy nonalcoholic fatty liver disease (NAFLD) patients. METHODS: The study population consisted of 334 280 healthy subjects who had had the National Health check-ups in South Korea from 2009 to 2014. The fatty liver index (FLI) was used to identify subjects with NAFLD. CVD was defined as occurrence of a composite of cardiovascular death, myocardial infarction, ischemic stroke, or coronary revascularization. The association between FLI and CVD incidence was analyzed using time-dependent Cox regression analyses. RESULTS: The study population was categorized into quartile groups according to FLI (range: Q1, 0-4.9; Q2, 5.0-12.5; Q3, 12.6-31.0; Q4, >31.0). The median follow-up duration was 5.4 years, during which subjects with higher FLIs experienced CVD more frequently than did those with lower FLIs [Q1, 215 (0.3%); Q2, 498 (0.6%); Q3, 753 (0.9%); Q4, 981 (1.2%); P < 0.001]. Adjustment of baseline characteristics revealed that a higher FLI was independently associated with an increased risk for CVD [hazard ratio between Q4 and Q1, 1.86; 95% confidence interval (CI), 1.59-2.17; P < 0.001]. The association between them remained statistically significant (hazard ratio between Q4 and Q1, 1.92; 95% CI, 1.63-2.25; P < 0.001) after further adjustment for the interim events (diabetes, hypertension, heart failure, and atrial fibrillation). CONCLUSIONS: Otherwise healthy NAFLD patients progressed to develop CVD independently of the interim occurrence of other metabolic diseases, which emphasizes the importance of NAFLD as a potential therapeutic target for prevention of CVD.

Common and different alterations of bone marrow mesenchymal stromal cells in myelodysplastic syndrome and multiple myeloma.

OBJECTIVE: The objective of this study was to explore characteristics of bone marrow mesenchymal stromal cells (BM-MSCs) derived from patients with myelodysplastic syndrome (MDS) and multiple myeloma (MM). METHODS: BM-MSCs were recovered from 17 of MDS patients, 23 of MM patients and 9 healthy donors and were passaged until proliferation stopped. General characteristics and gene expression profiles of MSCs were analysed. In vitro, ex vivo coculture, immunohistochemistry and knockdown experiments were performed to verify gene expression changes. RESULTS: BM-MSCs failed to culture in 35.0% of patients and 50.0% of recovered BM-MSCs stopped to proliferate before passage 6. MDS- and MM-MSCs shared characteristics including decreased osteogenesis, increased angiogenesis and senescence-associated molecular pathways. In vitro and ex vivo experiments showed disease-specific changes such as neurogenic tendency in MDS-MSCs and cardiomyogenic tendency in MM-MSCs. Although the age of normal control was younger than patients and telomere length was shorter in patient's BM-MSCs, they were not different according to disease category nor degree of proliferation. Specifically, poorly proliferation BM-MSCs showed CDKN2A overexpression and CXCL12 downregulation. Immunohistochemistry of BM biopsy demonstrated that CDKN2A was intensely accumulation in perivascular BM-MSCs failed to culture. Interestingly, patient's BM-MSCs revealed improved proliferation activity after CDKN2A knockdown. CONCLUSION: These results collectively indicate that MDS-MSCs and MM-MSCs have common and different alterations at various degrees. Hence, it is necessary to evaluate their alteration status using representative markers such as CDKN2A expression.