Outcomes of Liver Resection and Transarterial Chemoembolization in Patients with Multinodular BCLC-A Hepatocellular Carcinoma.

Background: This study aimed to compare the outcomes of liver resection (LR) and transarterial chemoembolization (TACE) in patients with multinodular hepatocellular carcinoma (HCC) within the Milan criteria who were not eligible for liver transplantation. Methods: We retrospectively analyzed 483 patients with multinodular HCC within the Milan criteria, who underwent either LR or TACE as an initial therapy between 2013 and 2022. The overall survival (OS) in the entire population and recurrence-free survival (RFS) in patients who underwent LR and TACE and achieved a complete response were analyzed. Propensity score (PS) matching analysis was also used for a fair comparison of outcomes between the two groups. Results: Among the 483 patients, 107 (22.2%) and 376 (77.8%) underwent LR and TACE, respectively. The median size of the largest tumor was 2.0 cm, and 72.3% of the patients had two HCC lesions. The median OS and RFS were significantly longer in the LR group than in the TACE group (p <0.01 for both). In the multivariate analysis, TACE (adjusted hazard ratio [aHR], 1.81 and aHR, 2.41) and large tumor size (aHR, 1.43 and aHR, 1.44) were significantly associated with worse OS and RFS, respectively. The PS-matched analysis also demonstrated that the LR group had significantly longer OS and RFS than the TACE group (PS <0.05). Conclusion: In this study, LR showed better OS and RFS than TACE in patients with multinodular Barcelona Clinic Liver Cancer stage A HCC. Therefore, LR can be considered an effective treatment option for these patients.

Response to atezolizumab plus bevacizumab specific for lung and lymph node metastases affects survival of patients with HCC.

BACKGROUND & AIMS: Tumour microenvironment heterogeneity among different organs can influence immunotherapy responses. Here, we evaluated the impact of differential organ-specific responses on survival in patients with advanced-stage hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atezo/Bev). METHODS: We retrospectively analysed 366 consecutive patients with advanced-stage HCC treated with Atezo/Bev as first-line systemic treatment. Therapeutic response was assessed using RECIST v1.1. Patients were divided into an intention-to-treat (ITT) group (patients treated with ≥1 dose of Atezo/Bev) and a per-protocol (PP) analysis group (patients with at least one measurable lesion irrespective of location treated with ≥3 doses of Atezo/Bev). Overall response and organ-specific response at initial and best response were evaluated in the PP group. Responders were defined as patients achieving complete remission or partial response. Initial progressors were defined as patients with progressive disease after three doses of Atezo/Bev. RESULTS: The ITT and PP groups comprised 324 and 236 patients, respectively. In the PP group, the organ-specific response rate of lung and lymph node (LN) metastases at both initial and best responses were higher than those of intrahepatic lesions and macrovascular tumour thrombosis. Lung and LN-specific response rates were 21.1% and 23.5%, respectively, at initial response, and 24.7% and 31.4%, respectively, at best response. Both initial pulmonary and lymphatic progressors (adjusted hazard ratios [95% confidence intervals], 6.37 [2.10-19.3], and 8.36 [2.16-32.4], respectively) were independently associated with survival regardless of intrahepatic response. CONCLUSIONS: The response of metastatic HCC to the Atezo/Bev regimen may be used to determine whether to continue treatment or switch to second-line treatment at an early phase of therapy.

Inhibitory effects of Acanthopanax sessiliflorus Harms extract on the etiology of rheumatoid arthritis in a collagen-induced arthritis mouse model.

BACKGROUND: The biological function of Acanthopanax sessiliflorus Harm (ASH) has been investigated on various diseases; however, the effects of ASH on arthritis have not been investigated so far. This study investigates the effects of ASH on rheumatoid arthritis (RA). METHODS: Supercritical carbon dioxide (CO2) was used for ASH extract preparation, and its primary components, pimaric and kaurenoic acids, were identified using gas chromatography-mass spectrometer (GC-MS). Collagenase-induced arthritis (CIA) was used as the RA model, and primary cultures of articular chondrocytes were used to examine the inhibitory effects of ASH extract on arthritis in three synovial joints: ankle, sole, and knee. RESULTS: Pimaric and kaurenoic acids attenuated pro-inflammatory cytokine-mediated increase in the catabolic factors and retrieved pro-inflammatory cytokine-mediated decrease in related anabolic factors in vitro; however, they did not affect pro-inflammatory cytokine (IL-1ß, TNF-α, and IL-6)-mediated cytotoxicity. ASH effectively inhibited cartilage degradation in the knee, ankle, and toe in the CIA model and decreased pannus development in the knee. Immunohistochemistry demonstrated that ASH mostly inhibited the IL-6-mediated matrix metalloproteinase. Gene Ontology and pathway studies bridge major gaps in the literature and provide insights into the pathophysiology and in-depth mechanisms of RA-like joint degeneration. CONCLUSIONS: To the best of our knowledge, this is the first study to conduct extensive research on the efficacy of ASH extract in inhibiting the pathogenesis of RA. However, additional animal models and clinical studies are required to validate this hypothesis.

High sucrose intake exacerbates airway inflammation through pathogenic Th2 and Th17 response in ovalbumin (OVA)-induced acute allergic asthma in C57BL/6 mice.

Asthma is an inflammatory disease characterized by chronic inflammation in lung tissues and excessive mucus production. High-fat diets have long been assumed to be a potential risk factor for asthma. However, to date, very few direct evidence indicating the involvement of high sucrose intake (HSI) in asthma progression exists. In this study, we investigate the effect of HSI on ovalbumin (OVA)-sensitized allergic asthma mice. We observed that HSI increased the expression of inflammatory genes (IL-1ß, IL-6, TNF-α) in adipose tissues and led to reactive oxygen species generation in the liver and lung. In addition, HSI accelerated the TLR4/NF-κB signaling pathway leading to MMP9 activation, which promotes the chemokines and TGF-ß secretion in the lungs of OVA-sensitized allergic asthma mice. More importantly, HSI significantly promoted the pathogenic Th2 and Th17 responses. The increase of IL-17A secretion by HSI increased the expression of chemokines (MCP-1, CXCL1, CXCL5, CXCL8). It resulted in eosinophil and mast cell infiltration in the lung and trachea. We also demonstrated that HSI increased mucus hypersecretion, which was validated by increased main mucin protein (MUC5AC) secreted in the lungs. Our findings suggest that HSI exacerbates the development of Th2/Th17-predominant asthma by upregulating the TLR4-mediated NF-κB pathway, leading to excessive MMP9 production.

Oral Administration of Sargassum horneri Suppresses Particulate Matter-Induced Oxidative DNA Damage in Alveolar Macrophages of Allergic Airway Inflammation: Relevance to PM-Mediated M1/M2 AM Polarization.

SCOPE: Particulate matter (PM) can cause cellular oxidative damage and promote respiratory diseases. It has recently shown that Sargassum horneri ethanol extract (SHE) containing sterols and gallic acid reduces PM-induced oxidative stress in mice lung cells through ROS scavenging and metal chelating. In this study, the role of alveolar macrophages (AMs) is identified that are particularly susceptible to DNA damage due to PM-triggered oxidative stress in lungs of OVA-sensitized mice exposed to PM. METHODS AND RESULTS: The study scrutinizes if PM exposure causes oxidative DNA damage to AMs differentially depending on their type of polarization. Further, SHE's potential is investigated in reducing oxidative DNA damage in polarized AMs and restoring AM polarization in PM-induced allergic airway inflammation. The study discovers that PM triggers prolonged oxidative stress to AMs, leading to lipid peroxidation in them and alveolar epithelial cells. Particularly, AMs are polarized to M2 phenotype (F4/80+ CD206+ ) with enhanced oxidative DNA damage when subject to PM-induced oxidative stress. However, SHE repairs oxidative DNA damage in M1- and M2-polarized AMs and reduces AMs polarization imbalance due to PM exposure. CONCLUSION: These results suggest the possibility of SHE as beneficial foods against PM-induced allergic airway inflammation via suppression of AM dysfunction.

MRI-negative myelitis associated with MOG-IgG antibody: A case report and literature reviews.

According to few case reports, myelin oligodendrocyte glycoprotein-associated disease (MOGAD) could present as myelitis subtype with normal spine MRI, though it is rare. Herein, we report a case of clinically myelitis but MRI was normal, with strongly positive anti-MOG-IgG antibody in the sera. The patient showed a rapid improvement following a high dose methylprednisolone treatment.

Quantitative Thermal Stimulation Using Therapeutic Ultrasound to Improve Cerebral Blood Flow and Reduce Vascular Stiffness.

It is important to improve cerebrovascular health before the occurrence of cerebrovascular disease, as it has various aftereffects and a high recurrence rate, even with appropriate treatment. Various medical recommendations for preventing cerebrovascular diseases have been introduced, including smoking cessation, exercise, and diet. However, the effectiveness of these methods varies greatly from person to person, and their effects cannot be confirmed unless they are practiced over a long period. Therefore, there is a growing need to develop more quantitative methods that are applicable to the public to promote cerebrovascular health. Thus, in this study, we aimed to develop noninvasive and quantitative thermal stimulation techniques using ultrasound to improve cerebrovascular health and prevent cerebrovascular diseases. This study included 27 healthy adults in their 20s (14 males, 13 females). Thermal stimulation using therapeutic ultrasound at a frequency of 3 MHz was applied to the right sternocleidomastoid muscle in the supine posture for 2 min at four intensities (2.4, 5.1, 7.2, and 10.2 W/cm2). Diagnostic ultrasound was used to measure the peak systolic velocity (PSV), heart rate (HR), and pulse wave velocity (PWV) in the right common carotid artery (CCA), and the physiological changes were compared between intervention intensities. Compared to pre-intervention (preI), the PSV showed a significant increase during intervention (durI) at intensities of 7.2 W/cm2 and 10.2 W/cm2 (p = 0.010 and p = 0.021, respectively). Additionally, PWV showed a significant decrease for post-intervention (postI) at 7.2 W/cm2 and 10.2 W/cm2 (p = 0.036 and p = 0.035, respectively). However, the HR showed no significant differences at any of the intensities. The results demonstrate that an intervention at 3 MHz with an intensity of 7.2 W/cm2 or more can substantially increase cerebral blood flow and reduce arterial stiffness. Therefore, the use of therapeutic ultrasound of appropriate intensity is expected to improve the cerebral blood flow and reduce vascular stiffness to maintain cerebral blood flow at a certain level, which is closely related to the prevention and treatment of cerebrovascular diseases, thereby improving cerebrovascular health.

High-Sucrose Diet Accelerates Arthritis Progression in a Collagen-Induced Rheumatoid Arthritis Model.

SCOPE: High dietary sugar and sweeteners are suspected to cause the development of rheumatoid arthritis (RA) symptoms through the induction of proinflammatory cytokine release. However, the mechanisms by which increased dietary sugar affects RA etiology are not yet fully understood. The study uses a mouse model of collagen-induced RA (CIA) to investigate the relationship between excessive sugar consumption and RA risk. METHODS AND RESULTS: RA-associated pathological features are assessed in the nonimmunized (NI) control group, the CIA-positive control group, and the CIA + high-sucrose diet (CIA+HS, 63% calories from sucrose) group. Compared with the CIA group, the CIA+HS group shows a greater increase in paw thickness and clinical scores, as well as, a higher degree of pannus formation and inflammation in the knee, ankle, and sole tissues. Moreover, the infiltration of immune cells is increased in the CIA+HS group. Although the expression of hepatic lipogenic genes, is not altered, that of toll-like receptor (TLR4) and IL-1ß is considerably elevated in the CIA+HS group. CONCLUSIONS: These findings suggest that excessive sucrose consumption causes hepatic fibrosis and inflammation, contributing to the pathophysiology of RA.

Simultaneous evaluation of treatment efficacy and toxicity for bispecific T-cell engager therapeutics in a humanized mouse model.

Immuno-oncology (IO)-based therapies such as checkpoint inhibitors, bi-specific antibodies, and CAR-T-cell therapies have shown significant success in the treatment of several cancer indications. However, these therapies can result in the development of severe adverse events, including cytokine release syndrome (CRS). Currently, there is a paucity of in vivo models that can evaluate dose-response relationships for both tumor control and CRS-related safety issues. We tested an in vivo PBMC humanized mouse model to assess both treatment efficacy against specific tumors and the concurrent cytokine release profiles for individual human donors after treatment with a CD19xCD3 bispecific T-cell engager (BiTE). Using this model, we evaluated tumor burden, T-cell activation, and cytokine release in response to bispecific T-cell-engaging antibody in humanized mice generated with different PBMC donors. The results show that PBMC engrafted NOD-scid Il2rgnull mice lacking expression of mouse MHC class I and II (NSG-MHC-DKO mice) and implanted with a tumor xenograft predict both efficacy for tumor control by CD19xCD3 BiTE and stimulated cytokine release. Moreover, our findings indicate that this PBMC-engrafted model captures variability among donors for tumor control and cytokine release following treatment. Tumor control and cytokine release were reproducible for the same PBMC donor in separate experiments. The PBMC humanized mouse model described here is a sensitive and reproducible platform that identifies specific patient/cancer/therapy combinations for treatment efficacy and development of complications.

Low Level of Hepatitis B Viremia Compared With Undetectable Viremia Increases the Risk of Hepatocellular Carcinoma in Patients With Untreated Compensated Cirrhosis.

INTRODUCTION: The initiation of antiviral treatment in patients with chronic hepatitis B with compensated cirrhosis and low-level viremia (LLV; HBV DNA 15-2,000 IU/mL) remains controversial. We sought to compare the long-term outcomes of these untreated patients according to their viremic status. METHODS: Six hundred twenty-seven untreated patients with chronic hepatitis B with compensated cirrhosis were analyzed retrospectively. The risk of hepatocellular carcinoma (HCC) and liver-related clinical events, including hepatic decompensation, were compared between patients with LLV and undetectable HBV DNA. Patients who received antiviral treatment were censored during treatment initiation. RESULTS: The mean age of the patients was 54.7 years, 64.4% of whom were male. During the study period, 59 patients developed HCC (20 and 39 in the undetectable and LLV groups, respectively) with an annual incidence of 2.44/100 person-years. Multivariable analysis revealed that the LLV group was associated with a significantly higher risk of HCC (adjusted hazard ratio: 2.36, P = 0.002) than the undetectable group. In the 204 propensity score-matched cohort, the LLV group had a 2.16-fold greater risk of HCC than the undetectable group ( P = 0.014). Liver-related clinical events occurred in 121 patients with an annual incidence of 5.25/100 person-years. Despite not reaching statistical significance, the LLV group tended to have a higher risk of liver-related events in the propensity score-matched cohort (hazard ratio: 1.14, P = 0.50). DISCUSSION: Compared with patients with undetectable HBV DNA, those with compensated cirrhosis and LLV had a significantly higher risk of HCC. Antiviral treatment should be advised for these patients.

Formulation of Glycyrrhizic Acid-based Nanocomplexes for Enhanced Anti-cancer and Anti-inflammatory Effects of Curcumin.

In this study, nanocomplexes composed of glycyrrhizic acid (GA) derived from the root of the licorice plant (Glycyrrhiza glabra) were formulated for the delivery of curcumin (CUR). Sonication of amphiphilic GA solution with hydrophobic CUR resulted in the production of nanosized complexes with a size of 164.8 ± 51.7 nm, which greatly enhanced the solubility of CUR in aqueous solution. A majority of the CURs were released from these GA/ CUR nanocomplexes within 12 h. GA/CUR nanocomplexes exhibited excellent intracellular uptake in human breast cancer cells (Michigan cancer foundation-7/multi-drug resistant cells), indicating enhanced anti-cancer effects compared to that of free CUR. In addition, GA/CUR nanocomplexes demonstrated high intracellular uptake into macrophages (RAW264.7 cells), consequently reducing the release of the pro-inflammatory cytokine tumor necrosis factor-α. Furthermore, GA/CUR nanocomplexes successfully reduced the levels of serum pro-inflammatory cytokines and splenomegaly in a rheumatoid arthritis model.

Chronic infrared-A irradiation-induced photoaging of human dermal fibroblasts from different donors at physiological temperature.

BACKGROUND: In this study, we examined cellular responses to acute and chronic IRA irradiation at mild and natural levels of exposure in two types of human fibroblasts, each isolated from a different donor, at physiological temperature (34°C). METHOD: Two types of human dermal fibroblasts (derived from a 20- and 50-year-old women, respectively) were exposed to different repeat numbers of IRA exposure (3, 6, 10, and 14 times; 42 mW/cm2 ) at a frequency of 3-4 times per week (4 h per irradiation). Cellular responses to acute and chronic IRA irradiation were examined by reactive oxygen species (ROS) level, apoptotic signals, cellular morphology, and collagen level. RESULTS: We demonstrated that chronic IRA irradiation-induced severe cellular damage, including prolonged cell proliferation, increased intracellular ROS levels, activated cellular apoptosis, and elongated cell morphology, whereas acute IRA irradiation had negligible effects at 34°C. In addition, it was evident that the degree of cellular damage due to IRA irradiation differed according to the type of fibroblasts. CONCLUSIONS: Considering the severe cellular damage induced by chronic IRA irradiation without heat, continuous exposure of skin to IRA irradiation during daily life may be harmful enough to induce photoaging.

Severity Evaluation of Regional Cerebrovascular Reactivity in Acute Stroke Patients Using SPECT.

BACKGROUND: Cerebrovascular Reactivity (CVR), as measured using perfusion Single Photon Emission Computed Tomography (SPECT), is an important indicator for the treatment and prognosis of cerebrovascular disease, but there are a few studies on acute stroke or small vascular disease using SPECT. OBJECTIVE: This study evaluated the regional severity with quantitatively determined CVR in patients with acute stroke. METHODS: Fifty-eight patients who took brain SPECT images were selected to localize quantitative CVR values. The severity of the disease (Grade 1 to 4) was determined through image-based clinical assessment in the absence and presence of a CVR map, and their results were compared. RESULTS: In 1st diagnosis without the map, the mean CVR values of Grades 2 and 3 were -6.07 % and -9.12 %, respectively (P=0.034), while they were -4.78 % and -12.34 % in 2nd diagnosis with the map, respectively (P<0.001), suggesting that the CVR difference with the map was much more pronounced than without the map. Furthermore, in the ROC analysis, the diagnostic sensitivity between Grades 2 and 3 in the 2nd diagnosis (AUC=0.899, P<0.001) was substantially greater than the 1st diagnosis (AUC=0.646, P=0.048). CONCLUSION: This study demonstrated that the quantitative CVR maps could reinforce the clinical evaluation of cerebral severity by showing that they can provide statistically significant results between severity and CVR. Furthermore, this study was the first to evaluate the effectiveness of quantitative CVR by examining the difference in the presence or absence of CVR in patients with acute stroke.

Genome-wide association studies of stress score in a Korean Cohort.

Despite ongoing research on factors affecting stress, there is a shortage of research on genetic variation using single nucleotide polymorphisms (SNPs). Thus, this study aims to identify genes that may affect the risk of stress in a large-scale Korean cohort. The stress survey used in this study consisted of 40 questions, organized into the following four categories: 10 questions on General Stress (GenST); 10 questions on Mental Stress (MenST); 10 questions on Physical Stress (PhyST); and 10 questions on Activity Stress (ActST). An overall stress score was calculated as the sum of the survey scores from each category, with a high stress score defined as a stress score in which the proportion of insomnia was large. Genome-wide association studies of approximately 320,000 SNPs acquired from the Korea Centers for Disease Control and Prevention (KCDC) were conducted to explore the risk of stress in the four categories. As a result, three loci were identified for GenST, no significant loci were observed for MenST, four loci were identified for PhyST, and two loci were identified for ActST. The most significant SNP of GenST (rs9353437) was located in an epidermal growth factor gene (eyes shut homolog, EYS) and expressed in the photoreceptor layer of the retina. The genome-wide association studies' (GWAS) results of PhyST showed a significant SNP (rs4924370) in a spliceosomal factor (Aquarius intron-binding spliceosomal factor, AQR). Notably, the second most significant SNP (rs1991002) was located in an oxidoreductase gene (NADH:Ubiquinone Oxidoreductase Subunit S4, NDUFS4) and was also marginally associated with GenST, MenST, and ActST (p-value < 0.05). A bioinformatics analysis of the genes linked to the identified SNPs demonstrated the presence of many genes that could be associated with neurotransmission or stress. Although the stress survey or classification criteria for stress scores used in this study were ambiguous, such results may be the first to expand upon the understanding of the genetic variations and the molecular mechanisms that may cause vulnerabilities to stress.

Multi-Probiotic Lactobacillus Supplementation Improves Liver Function and Reduces Cholesterol Levels in Jeju Native Pigs.

We evaluated the dietary effects of multiple probiotics in Jeju native pigs, using basal diet and multi-probiotic Lactobacillus (basal diet with 1% multi-probiotics) treatments (n = 9 each) for 3 months. We analyzed growth performance, feed efficiency, backfat thickness, blood parameters, hematological profiles, adipokines, and immune-related cytokines in pig tissues. Average daily gain, feed intake, feed efficiency, backfat thickness, and body weight were not significantly different between both groups. In Lactobacillus group, total protein (p < 0.08) and bilirubin (p < 0.03) concentrations increased; blood urea nitrogen (p < 0.08), alkaline phosphatase (p < 0.08), and gamma-glutamyltransferase (p < 0.08) activities decreased. Lactobacillus group showed decreased adiponectin (p < 0.05), chemerin (p < 0.05), and visfatin expression in adipose tissues, and increased TLR4 (p < 0.05), MYD88 (p < 0.05), TNF-α (p < 0.001), and IFN-γ (p < 0.001) expression in the liver. Additionally, NOD1 (p < 0.05), NOD2 (p < 0.01), and MYD88 (p < 0.05) mRNA levels in proximal colon tissue upregulated significantly. Colon, longissimus dorsi muscle, fat tissue, and liver histological analyses revealed no significant differences between the groups. Conclusively, Lactobacillus supplementation improved liver function and reduced cholesterol levels. Its application may treat metabolic liver disorders, especially cholesterol-related disorders.