Comparison of non-contrast abbreviated MRI and ultrasound as surveillance modalities for HCC.

BACKGROUND & AIMS: Ultrasonography (US) is recommended for HCC surveillance in high-risk patients but has limited performance in detecting early-stage HCC. We aimed to compare the diagnostic performance of biannual US and annual non-contrast abbreviated magnetic resonance imaging (NC-AMRI) as HCC surveillance modalities in high-risk patients. METHODS: This prospective, multicenter cohort study enrolled participants with an estimated annual risk of HCC greater than 5% between October 2015 and April 2017. Participants underwent six rounds of HCC surveillance at 6-month intervals, with both US and NC-AMRI at rounds 1, 3, and 5, and only US at rounds 2, 4, and 6. The sensitivity, diagnostic yield (DY), and false referral rate (FRR) for HCC detection by US and NC-AMRI were compared. RESULTS: In total, 208 participants underwent 980 US and 516 NC-AMRI examinations during 30 months of follow-up. Among them, 34 HCCs were diagnosed in 31 participants, with 20 (64.5%) classified as very early-stage and 11 (35.5%) as early-stage HCC. The sensitivity of annual NC-AMRI (71.0%, 22/31) was marginally higher than that of biannual US (45.2%, 14/31; p = 0.077). NC-AMRI showed a significantly higher DY than US (4.26% vs. 1.43%, p <0.001), with a similar FRR (2.91% vs. 3.06%, p = 0.885). A simulation of alternating US and NC-AMRI at 6-month intervals yielded a sensitivity of 83.9% (26/31), significantly exceeding that of biannual US (p = 0.006). CONCLUSIONS: Annual NC-AMRI showed a marginally higher sensitivity than biannual US for HCC detection in high-risk patients. The DY of annual NC-AMRI was significantly higher than that of biannual US, without increasing the FRR. Thus, alternating US and NC-AMRI at 6-month intervals could be an optimal surveillance strategy for high-risk patients. IMPACT AND IMPLICATIONS: Current guidelines permit the use of magnetic resonance imaging (MRI) as a surveillance tool for hepatocellular carcinoma in patients in whom ultrasonography (US) is inadequate. However, the specific indications, imaging sequences, and intervals for MRI surveillance remain unclear. In our study, we found that annual non-contrast abbreviated MRI exhibited marginally higher sensitivity and significantly better diagnostic yield than biannual US in patients at high risk of hepatocellular carcinoma. Alternating US and non-contrast abbreviated MRI at 6-month intervals led to significantly improved sensitivity compared to biannual US, making it a potentially optimal surveillance strategy for high-risk patients. GOV IDENTIFIER: NCT02551250.

Recombinant expression and tryptophan-assisted analysis of human sweet taste receptor T1R3's extracellular domain in sweetener interaction studies.

The human palate can discern multiple tastes; however, it predominantly perceives five fundamental flavors: sweetness, saltiness, sourness, bitterness, and umami. Sweetness is primarily mediated through the sweet taste receptor, a membrane-bound heterodimeric structure comprising T1R2-T1R3. However, unraveling the structural and mechanistic intricacies of the sweet taste receptor has proven challenging. This study aimed to address this knowledge gap by expressing an extracellular N-terminal domain encompassing the cysteine-rich domain of human hT1R3 (hT1R3-TMD) in Escherichia coli. The expressed protein was obtained as inclusion bodies, purified by metal affinity chromatography, and refolded using the dilution-refolding method. Through rigorous analysis, we confirmed the successful refolding of hT1R3-TMD and elucidated its structural characteristics using circular dichroism spectroscopy. Notably, the refolded protein was found to exist as either a monomer or a dimer, depending on its concentration. A tryptophan fluorescence quenching assay revealed that the dissociation constants for sucrose, sucralose, and brazzein were >9500 µM, 2380 µM and 14.3 µM, respectively. Our findings highlight the utility of this E. coli expression system for producing functional hT1R3-TMD for investigations and demonstrate the efficacy of the tryptophan fluorescence quenching assay in revealing complex interactions between sweet taste receptors and various sweeteners.

Functional significance of serine 13 in the active site of glutathione S-transferase F3 from Oryza sativa.

Plant glutathione S-transferase (GST, EC 2.5.1.18) is an enzyme that detoxifies various electrophilic compounds including herbicides and organic pollutants by catalyzing the formation of conjugates with reduced glutathione (GSH). Although the structure and function of the GST subunits in rice, an important food in Asia, are not well understood, they are crucial for herbicide development. To investigate the role of active site residues in rice Phi-class GSTF3 (OsGSTF3), evolutionarily conserved serine residues were replaced with alanine using site-directed mutagenesis to obtain the mutants S13A, S38A, S69A, and S169A. These four mutants were expressed in Escherichia coli and purified to electrophoretic homogeneity using immobilized GSH affinity chromatography. Mutation of Ser13 to Ala resulted in substantial reductions in specific activities and kcat/Km values for the GSH-[1-chloro-2,4-dinitrobenzene (CDNB)] conjugation reaction. In contrast, mutations of Ser38, Ser69, and Ser169 to Ala had little effect on the activities and kinetic parameters. Additionally, the mutation of Ser13 to Ala significantly affected the KmGSH and I50 values of S-hexylglutathione and S-(2,4-dinitrophenyl)glutathione, which compete with GSH and the product of GSH-CDNB conjugation, respectively. A pH-log (kcat/KmCDNB) plot was used to estimate the pKa value of GSH in the enzyme-GSH complex of the wild-type enzyme, which was approximately 6.9. However, the pKa value of GSH in the enzyme-GSH complex of the S13A mutant was approximately 8.7, which was about 1.8 pK units higher than that of the wild-type enzyme. OsGSTF3 was also crystallized for crystallographic study, and the structure analyses revealed that Ser13 is located in the active site and that its side chain is in close proximity to the thiol group of glutathione bound in the enzyme. Based on these substitution effects on kinetic parameters, the dependence of kinetic parameters on the pH and 3-dimensional structure, it was suggested that Ser13 in rice OsGSTF3 is the residue responsible for catalytic activity by lowering the pKa of GSH in the enzyme-GSH complex and enhancing the nucleophilicity of the GSH thiol in the active site.

Multiple functions of pyruvate kinase M2 in various cell types.

Glucose metabolism is a mechanism by which energy is produced in form of adenosine triphosphate (ATP) by mitochondria and precursor metabolites are supplied to enable the ultimate enrichment of mature metabolites in the cell. Recently, glycolytic enzymes have been shown to have unconventional but important functions. Among these enzymes, pyruvate kinase M2 (PKM2) plays several roles including having conventional metabolic enzyme activity, and also being a transcriptional regulator and a protein kinase. Compared with the closely related PKM1, PKM2 is highly expressed in cancer cells and embryos, whereas PKM1 is dominant in mature, differentiated cells. Posttranslational modifications such as phosphorylation and acetylation of PKM2 change its cellular functions. In particular, PKM2 can translocate to the nucleus, where it regulates the transcription of many target genes. It is notable that PKM2 also acts as a protein kinase to phosphorylate several substrate proteins. Besides cancer cells and embryonic cells, astrocytes also highly express PKM2, which is crucial for lactate production via expression of lactate dehydrogenase A (LDHA), while mature neurons predominantly express PKM1. The lactate produced in cancer cells promotes tumor progress and that in astrocytes can be supplied to neurons and may act as a major source for neuronal ATP energy production. Thereby, we propose that PKM2 along with its different posttranslational modifications has specific purposes for a variety of cell types, performing unique functions.

Altered muscle recruitment patterns during isometric shoulder abduction in individuals with chronic upper trapezius pain: a cross sectional study.

BACKGROUND: Upper trapezius (UT) pain with myofascial trigger points (MTrPs) can affect movement at the glenohumeral joint as well as at the scapulothoracic joint. The investigation of muscle recruitment patterns can discern motor control strategies. The purpose of this study was to compare shoulder muscle recruitment patterns and muscle activity according to various loads between individuals with and without chronic UT pain. METHODS: In this cross-sectional study, twenty-four participants that had UT pain with MTrPs and sex, age, body weight matched 24 controls with no UT pain were recruited. Surface EMG electrodes were attached to the UT, the serratus anterior (SA), the lower trapezius (LT) and the middle deltoid (MD). All participants performed isometric shoulder abduction with a load of 25%, 50%, or 75% of the maximum strength at 60° of shoulder abduction. The EMG activity, the activity ratio (SA/UT, LT/UT, MD/UT), and the relative contribution of each muscle activity were calculated. RESULTS: MD activity was significantly decreased in the UT pain group compared to that in the control group (p < 0.05). The EMG activity ratio of SA/UT (p < 0.025) and the relative contribution of SA activity to shoulder abduction (p < 0.05) were significantly greater in the UT pain group than in the control group in the 25% loading condition. CONCLUSION: The results of present study showed that UT pain with MTrPs may increase the relative contribution of SA activity and decrease MD activity at low loads. Altered recruitment patterns of scapular upward rotators can be altered in the proper scapular position, which results in decreased MD activity. Clinicians should consider altered recruitment patterns when managing UT pain. TRIAL REGISTRATION: Clinical Research Information Service: Clinical Research Information Service (KCT0007370; 08/06/2022).

Intermuscular fat density as a novel prognostic factor in breast cancer patients treated with adjuvant chemotherapy.

BACKGROUND: Body composition, including sarcopenia and fat parameters, has received much attention as a prognostic factor in breast cancer. METHODS: A total of 479 breast cancer patients who underwent surgery and received adjuvant chemotherapy were enrolled in this study. Body composition, including the index and density of skeletal muscle, visceral fat, subcutaneous fat, and intermuscular fat calculated by CT scan, was used as a prognostic factor. The endpoints were breast cancer-specific survival (BCSS) and overall survival (OS). RESULTS: The number of patients with stages I, II, and III was 146 (30.5%), 237 (49.5%), and 96 (20%), respectively. Sarcopenia and muscle density were not significant prognostic factors for BCSS and OS. A high visceral fat index (VFI) was an independent prognostic factor for BCSS (HR, 2.55; 95% CI 1.10-5.95, p = 0.03) and OS (HR 2.55, 95% CI 1.26-5.16, p = 0.01). In addition, high intermuscular fat density (IMFD) was also a significant prognostic factor for BCSS (HR, 2.95; 95% CI 1.34-6.46, p = 0.007) and OS (HR 2.28, 95% CI 1.22-4.26, p = 0.01) in multivariate analysis. CONCLUSION: VFI and IMFD were significant prognostic factors for BCSS and OS in breast cancer patients treated with adjuvant chemotherapy.

Characterization of antigenic variant infectious bursal disease virus strains identified in South Korea.

Infectious bursal disease (IBD) is one of the most important immunosuppressive diseases of young chickens, causing considerable economic losses to the poultry industry. More than 30 years ago, an antigenic variant (av) pathotype of the IBD virus (IBDV) was reported to originate in, and subsequently spread among, poultry farms in the USA. Recently, a novel avIBDV lineage was identified in China and was shown to exhibit clear differences in its pathogenicity as well as molecular characteristics compared with the previously isolated variant strains. In this study, we conducted a passive surveillance of chicken carcasses submitted to our research division from June-December 2019, and detected the IBDV strains by reverse transcription PCR. Five avIBDV strains were isolated, and their pathogenicity was determined by necropsy and molecular analysis. Additionally, a coinfection field case involving an avIBDV strain and a very virulent IBDV (vvIBDV) strain was identified. Multiple sequence alignment and phylogenetic analysis of partial viral protein 1 (VP1) and hypervariable region (hv) VP2 genes revealed that those strains originated from two different avIBDV lineages. The co-occurrence of two sub-groups of avIBDVs in South Korea confirms for the first time the evolution of antigenic variant IBDV strains, and highlights the urgency for the development of new strategies for IBDV intervention in South Korea.RESEARCH HIGHLIGHTS Five avIBDV strains were identified in South Korea by passive surveillance test in 2019.A coinfection between two IBDV strains from different genogroups was reported in a field case.By phylogenetic analysis, Korean avIBDVs belonged to two distinct lineages of antigenic variant genogroup.

Effects of Lipopolysaccharide on Oligodendrocyte Differentiation at Different Developmental Stages: an In Vitro Study.

BACKGROUND: Lipopolysaccharide (LPS) exerts cytotoxic effects on brain cells, especially on those belonging to the oligodendrocyte lineage, in preterm infants. The susceptibility of oligodendrocyte lineage cells to LPS-induced inflammation is dependent on the developmental stage. This study aimed to investigate the effect of LPS on oligodendrocyte lineage cells at different developmental stages in a microglial cell and oligodendrocyte co-culture model. METHODS: The primary cultures of oligodendrocytes and microglia cells were prepared from the forebrains of 2-day-old Sprague-Dawley rats. The oligodendrocyte progenitor cells (OPCs) co-cultured with microglial cells were treated with 0 (control), 0.01, 0.1, and 1 µg/mL LPS at the D3 stage to determine the dose of LPS that impairs oligodendrocyte differentiation. The co-culture was treated with 0.01 µg/mL LPS, which was the lowest dose that did not impair oligodendrocyte differentiation, at the developmental stages D1 (early LPS group), D3 (late LPS group), or D1 and D3 (double LPS group). On day 7 of differentiation, oligodendrocytes were subjected to neural glial antigen 2 (NG2) and myelin basic protein (MBP) immunostaining to examine the number of OPCs and mature oligodendrocytes, respectively. RESULTS: LPS dose-dependently decreased the proportion of mature oligodendrocytes (MBP+ cells) relative to the total number of cells. The number of MBP+ cells in the early LPS group was significantly lower than that in the late LPS group. Compared with those in the control group, the MBP+ cell numbers were significantly lower and the NG2+ cell numbers were significantly higher in the double LPS group, which exhibited impaired oligodendrocyte lineage cell development, on day 7 of differentiation. CONCLUSION: Repetitive LPS stimulation during development significantly inhibited brain cell development by impairing oligodendrocyte differentiation. In contrast, brain cell development was not affected in the late LPS group. These findings suggest that inflammation at the early developmental stage of oligodendrocytes increases the susceptibility of the preterm brain to inflammation-induced injury.

Comparison of the Shoulder External Rotator Strength and Asymmetry Ratio Between Workers With and Without Shoulder Impingement Syndrome.

ABSTRACT: Kim, J-H, Kwon, O-Y, Hwang, U-J, Jung, S-H, Ahn, S-H, and Kim, H-A. Comparison of shoulder external rotator strength and the asymmetry ratio between workers with and without shoulder impingement syndrome. J Strength Cond Res 35(12): 3364-3369, 2021-Shoulder impingement syndrome (SIS) is the most common shoulder problem causing shoulder pain. Several studies have indicated that shoulder external rotator muscles provide dynamic stability to the shoulder joint. However, the relationship of SIS to changes in shoulder external rotator muscle strength remains controversial. The purpose of the study was to compare the shoulder external rotator strength and asymmetry ratio between workers with SIS and the normal group in a side-lying position. Twelve male industrial workers with SIS and the normal group of 12 workers participated in this study. A pulling sensor measured shoulder external rotator muscle strength in a side-lying position with the shoulder at 0° and 90° of flexion. The asymmetry ratio was calculated by a specific formula using the shoulder external rotator muscle strength of the dominant side and the unaffected side. Two-way analysis of variance was used to determine between-group differences in shoulder external rotator muscle strength and the asymmetry ratio among the 2 positions. Subjects with SIS did not exhibit significant differences in shoulder external rotator muscle strength in the side-lying position with the shoulder at 0° and 90° of flexion relative to the normal group. However, subjects with SIS had a significantly increased asymmetry ratio of shoulder external rotation strength in the side-lying position with the shoulder at 90° of flexion compared with the normal group. In conclusion, workers with SIS had an asymmetry of shoulder external rotator strength in side-lying with the shoulder at 90° of flexion.

Two distinct cases with COVID-19 in kidney transplant recipients.

The fatality of novel coronavirus disease 2019 (COVID-19) is precipitously increased in patients with underlying comorbidities or elderly people. Kidney transplant (KT) recipients are one of the vulnerable populations for infection. COVID-19 infection in KT recipients might be a complicated and awkward situation, but there has been a lack of reports concerning this group. Herein, we demonstrated two distinct cases with different clinical progress. The first case was a 36-year-old man who underwent KT 3 years ago. He was diagnosed with COVID-19 expressing relevant symptoms. Following administration of lopinavir/ritonavir and hydroxychloroquine with reduced immunosuppressant, he recovered from COVID-19. However, the unexpected fluctuations in tacrolimus trough levels needed to be managed because of drug-to-drug interaction. The second case was developed in a 56-year-old man without any symptoms. He received a second KT from an ABO-incompatible donor 8 years ago. He was diagnosed with COVID-19 by screening due to exposure history. During the hospitalization period, the chest infiltrative lesion showed a wax and wane, but he successfully recovered by administration of hydroxychloroquine with azithromycin. These apparently different cases suggest that assertive screening and management could improve the clinical course. In addition, antiviral agents should be used cautiously, especially in patients on calcineurin inhibitors.

Application of laser-induced breakdown spectroscopy for detection of elements in flowback water samples from shale gas wells.

Laser-induced breakdown spectroscopy (LIBS) was applied to rapidly detect elements in flowback water samples from shale gas wells in Oklahoma. Two types of LIBS systems (aerosolization and collection on a substrate) were used. The LIBS with an aerosolization system provided rapid determination of elements in flowback water, but moisture present in the chamber and variation in the water droplet size could make quantification difficult. In the substrate collection system, a comparison among substrate types showed that a hydrophilic cellulose filter gave the most homogeneous sample distribution after drying and provided the best performance. The elements in flowback water samples were also determined by inductively coupled plasma-optical emission spectroscopy (ICP-OES). ICP-OES data showed spatial variations for the elements among the different wells. Among the elements, K showed the highest variation (relative standard ${\rm deviation} = {62.8}\% $deviation=62.8%) and Mg the lowest (relative standard ${\rm deviation} = {39.1}\% $deviation=39.1%). Good correlations (${ r} = {0.98 - 0.99}$r=0.98-0.99) were observed between Ca, K, Mg, and Na LIBS peak areas determined using the cellulose filter and their mass concentrations (ppm) measured by ICP-OES for aqueous solutions. The limits of detection for Ca, K, Mg, and Na by LIBS were 122 ppm, 68 ppm, 36 ppm, and 142 ppm, respectively. Both the LIBS and ICP-OES data showed that element concentrations in the flowback water samples were in the order of Na, Ca, Mg, and K from highest to lowest. Our data suggest that the LIBS technique could rapidly detect elements in flowback water samples on site. However, accurate quantification of elements present in low concentrations in water samples is limited.

Hemosuccus pancreaticus with a variant of separate orifices in the duodenal papilla treated with a covered self-expandable metal stent.

This is the peculiar report of endoscopic treatment with metal stent in a patient with hemosuccus pancreaticus by pancreatic cancer, who refused surgical treatment due to old age and patient's intention. Reports of endoscopic hemostasis in hemosuccus pancreaticus are very rare. Moreover our case showed variant location of separate orifices in major duodenal papilla. This rare variant should be handled with importance because late recognition could result in unnecessary manipulation and treatment failure.

Effect of Abdominal Electrical Muscle Stimulation Training With and Without Superimposed Voluntary Muscular Contraction on Lumbopelvic Control.

CONTEXT: Electrical muscle stimulation (EMS) was designed for artificial muscle activation or superimposed training. OBJECTIVES: To compare the effects of 8 weeks of superimposed technique (ST; application of electrical stimulation during a voluntary muscle action) and EMS on the cross-sectional area of the rectus abdominis, lateral abdominal wall, and on lumbopelvic control. SETTING: University research laboratory. DESIGN: Randomized controlled trial. PARTICIPANTS: Fifty healthy subjects were recruited and randomly assigned to either the ST or EMS group. INTERVENTION: The participants engaged with the electrical stimulation techniques (ST or EMS) for 8 weeks. MAIN OUTCOME MEASURES: In all participants, the cross-sectional area of the rectus abdominis and lateral abdominal wall was measured by magnetic resonance imaging and lumbopelvic control, quantified using the single-leg and double-leg lowering tests. RESULTS: There were no significant differences in the cross-sectional area of the rectus abdominis (right: P = .70, left: P = .99) or lateral abdominal wall (right: P = .07, left: P = .69) between groups. There was a significant difference between groups in the double-leg lowering test (P = .03), but not in the single-leg lowering test (P = .88). There were significant differences between the preintervention and postintervention in the single-leg (P < .001) and double-leg lowering tests (P < .001). CONCLUSIONS: ST could improve lumbopelvic control in the context of athletic training and fitness.

Comparison of MRI cross-sectional area and functions of core muscles among asymptomatic individuals with and without lumbar intervertebral disc degeneration.

BACKGROUND: Previous studies suggested that patients with symptomatic intervertebral disc degeneration (IDD) of lumbar spine have reduced cross-sectional area (CSA) and functions of core muscles. However, reduced CSA and functions of core muscles have been observed not only in patients with symptomatic IDD but also in patients with other subgroups of low back pain (LBP). Thus, it is uncertain whether reduced CSA and functions of core muscles lead to IDD and LBP, or pain leads to reduced CSA and functions of core muscles in patients with symptomatic IDD. Therefore, this study aimed to compare the CSA and functions of core muscles between asymptomatic participants with and without IDD in magnetic resonance imaging (MRI). METHODS: Twenty asymptomatic participants (12 men and 8 women) participated in this study. Ten participants had asymptomatic IDD at L4-5. The others were healthy controls (without IDD at all levels of lumbar spine). The CSA of core muscles was measured using MRI. Maximal isometric trunk flexor strength and side bridge strength were measured by a Smart KEMA strength sensor. Trunk flexor endurance test, side bridge endurance test and plank endurance test were used to measure core endurance. Double legs loading test was used to measure core stability. Mann-Whitney U test was used to compare the differences between two groups. RESULTS: There were no significant differences in core muscle functions between the two groups (p > 0.05). Moreover, there was no significant difference in CSA between the two groups (p > 0.05). CONCLUSIONS: There was no significant difference in CSA and core muscle functions between asymptomatic participants with and without IDD. These findings indicate that a degenerative or bulging disc in asymptomatic individuals has little effect on CSA and functions of core muscles, especially in young age. Therefore, the general core endurance test or strength test could not differentiate asymptomatic people with and without IDD of lumbar spine. TRIAL REGISTRATION NUMBER: Clinical Research information Service. KCT0004061. Registered 13 June 2019. retrospectively registered.

Comparative toxicity of silver nanoparticles and silver ions to Escherichia coli.

With the increase in silver (Ag)-based products in our lives, it is essential to test the potential toxicity of silver nanoparticles (AgNPs) and silver ions (Ag ions) on living organisms under various conditions. Here, we investigated the toxicity of AgNPs with Ag ions to Escherichia coli K-12 strain under various conditions. We observed that both AgNPs and Ag ions display antibacterial activities, and that Ag ions had higher toxicity to E. coli K-12 strain than AgNPs under the same concentrations. To understand the toxicity of AgNPs at a cellular level, reactive oxygen species (ROS) enzymes were detected for use as antioxidant enzymatic biomarkers. We have also studied the toxicity of AgNPs and Ag ions under various coexistence conditions including: fixed total concentration, with a varied the ratio of AgNPs to Ag ions; fixed the AgNPs concentration and then increased the Ag ions concentration; fixed Ag ions concentration and then increasing the AgNPs concentration. Exposure to AgNPs and Ag ions clearly had synergistic toxicity; however, decreased toxicity (for a fixed AgNPs concentration of 5mg/L, after increasing the Ag ions concentration) to E. coli K-12 strain. AgNPs and Ag ions in the presence of L-cysteine accelerated the bacterial cell growth rate, thereby reducing the bioavailability of Ag ions released from AgNPs under the single and coexistence conditions. Further works are needed to consider this potential for AgNPs and Ag ions toxicity across a range of environmental conditions. ENVIRONMENTAL SIGNIFICANCE STATEMENT: As silver nanoparticles (AgNPs)-based products are being broadly used in commercial industries, an ecotoxicological understanding of the AgNPs being released into the environment should be further considered. Here, we investigate the comparative toxicity of AgNPs and silver ions (Ag ions) to Escherichia coli K-12 strain, a representative ecotoxicological bioreporter. This study showed that toxicities of AgNPs and Ag ions to E. coli K-12 strain display different relationships when existing individually or when coexisting, and in the presence of L-cysteine materials. These findings suggest that the toxicology research of nanomaterials should consider conditions when NPs coexist with and without their bioavailable ions.

Comparison of biannual ultrasonography and annual non-contrast liver magnetic resonance imaging as surveillance tools for hepatocellular carcinoma in patients with liver cirrhosis (MAGNUS-HCC): a study protocol.

BACKGROUND: Ultrasonography (US) is recommended as a standard surveillance tool for patients with a high risk of developing hepatocellular carcinoma (HCC). However, the low sensitivity of US for small HCC can lead to surveillance failure, resulting in advanced stage tumor presentations. For the early detection of HCC in high-risk patients and to improve survival and prognosis, a new efficient imaging tool with a high sensitivity for HCC detection is needed. The purpose of this study is to evaluate and compare the feasibility and efficacy of non-contrast magnetic resonance imaging (MRI) with US as a surveillance tool for HCC in patients with liver cirrhosis. METHODS: MAGNUS-HCC is a prospective, multicenter clinical trial with a crossover design for a single arm of patients. This study was approved by six Institutional Review Boards, and informed consent was obtained from all participants. All patients will undergo liver US every 6 months and non-contrast liver MRI every 12 months during a follow-up period of 3 years. If a focal liver lesion suspected of harboring HCC is detected, dynamic liver computed tomography (CT) will be performed to confirm the diagnosis. After the last surveillance round, patients without suspicion of HCC or who are not diagnosed with HCC will be evaluated with a dynamic liver CT to exclude false-negative findings. The primary endpoint is to compare the rate of detection of HCC by US examinations performed at 6-month intervals with that of yearly non-contrast liver MRI studies during a 3-year follow-up. The secondary endpoint is the survival of the patients who developed HCC within the 3-year follow-up period. DISCUSSION: MAGNUS-HCC is the first study to compare the feasibility of non-contrast MRI with US as a surveillance tool for the detection of HCC in high-risk patients. We anticipate that the evidence presented in this study will establish the efficacy of non-contrast MRI as a surveillance tool for HCC in high-risk patients. TRIAL REGISTRATION: The date of trial registration ( NCT02551250 ) in this study was September 15, 2015, and follow-up is still ongoing.

Leucine-rich glioma inactivated 3 and tumor necrosis factor-α regulate mutually through NF-κB.

Leucine-rich glioma inactivated 3 (LGI3) is a secreted protein member of LGI family. We previously reported that LGI3 increased in obese adipose tissues and suppressed adipogenesis through its receptor, ADAM23. We proposed that LGI3 may be a pro-inflammatory adipokine secreted predominantly by preadipocytes and macrophages. In this study, we showed that LGI3 and tumor necrosis factor-α (TNF-α) upregulated each other in 3T3-L1 cells. Treatment of 3T3-L1 preadipocytes with LGI3 protein increased TNF-α mRNA and protein. LGI3 treatment led to NF-κB activation and binding to an NF-κB binding site (-523 to -514) in TNF-α promoter. TNF-α treatment increased mRNA and protein expression of LGI3 and ADAM23. TNF-α increased NF-κB binding to a predicted binding site (-40 to -31) in LGI3 promoter. High fat diet-fed mice showed that LGI3 and TNF-α were increased and colocalized in adipose tissue inflammation. Taken together, these results suggested that mutual upregulation of LGI3 and TNF-α may play a role in adipose tissue inflammation in obesity.

Disturbance of DKK1 level is partly involved in survival of lung cancer cells via regulation of ROMO1 and γ-radiation sensitivity.

Dickkopf1 (DKK1), a secreted protein involved in embryonic development, is a potent inhibitor of the Wnt signaling pathway and has been postulated to be a tumor suppressor or tumor promoter depending on the tumor type. In this study, we showed that DKK1 was expressed differently among non-small-cell lung cancer cell lines. The DKK1 expression level was much higher in A549 cells than in H460 cells. We revealed that blockage of DKK1 expression by silencing RNA in A549 cells caused up-regulation of intracellular reactive oxygen species (ROS) modulator (ROMO1) protein, followed by partial cell death, cell growth inhibition, and loss of epithelial-mesenchymal transition property caused by ROS, and it also increased γ-radiation sensitivity. DKK1 overexpression in H460 significantly inhibited cell survival with the decrease of ROMO1 level, which induced the decrease of cellular ROS. Thereafter, exogenous N-acetylcysteine, an antioxidant, or hydrogen peroxide, a pro-oxidant, partially rescued cells from death and growth inhibition. In each cell line, both overexpression and blockage of DKK1 not only elevated p-RB activation, which led to cell growth arrest, but also inactivated AKT/NF-kB, which increased radiation sensitivity and inhibited cell growth. This study is the first to demonstrate that strict modulation of DKK1 expression in different cell types partially maintains cell survival via tight regulation of the ROS-producing ROMO1 and radiation resistance.

Accuracy of preoperative T2 gallbladder tumor localization and the adequate surgical resection.

INTRODUCTION: The agreement between the radiologic and histopathologic tumor locations in T2 gallbladder cancer is critical. There is no consensus regarding the extent of curative resection by tumor locations. METHODS: Between January 2010 and December 2019, a consecutive series of 118 patients with pathological T2 gallbladder cancer who underwent surgery were retrospectively analyzed in terms of the accordance between radiologic and histopathologic tumor locations, the extents of hepatic resection and the numbers of harvested lymph nodes. Radical resection was defined as liver resection with harvesting of at least four lymph nodes. RESULTS: The accuracy of preoperative tumor localization was only 68%. After radical resection, the 5-year overall survival (OS) was 59.4%; after nonradical resection, the figure was 46.1% (p = 0.092). In subanalyses, the 5-year OS was marginally better for patients who underwent liver resection or from whom at least four lymph nodes were harvested than those who did not undergo liver resection or from whom three or fewer lymph nodes were harvested (58.2% vs. 39.4%, p = 0.072; 59.9% vs. 50.0%, p = 0.072, respectively). In patients with peritoneal side tumor, the 5-year OSs of those who did and did not undergo liver resection were 67% and 41.2%, respectively (p = 0.028). In multivariate analysis, perineural invasion and radical resection were independently prognostic of OS. CONCLUSION: The accuracy of preoperative tumor localization was 68%. Hepatic resection, lymph node dissection harvesting of at least four lymph nodes are required for curative resection for gallbladder cancer, regardless of tumor location.

Leucine-rich glioma inactivated 3 regulates adipogenesis through ADAM23.

Leucine-rich glioma inactivated 3 (LGI3) is a secreted protein and a member of LGI/epitempin family. We previously showed that LGI3 was highly expressed in brain and played regulatory roles in neuronal exocytosis and differentiation. Besides the nervous system, LGI3 was shown to be expressed in diverse tissues. In this study, we found that LGI3 and its receptor candidate ADAM23 were expressed in adipose tissues and 3T3-L1 cells. 3T3-L1 preadipocytes secreted a 60-kDa protein, a major secreted form of LGI3, which declined with adipocyte differentiation. LGI3 was also expressed in adipose tissue macrophages in the ob/ob mice and in macrophage cell line. The 60-kDa LGI3 protein was selectively increased in the ob/ob adipose tissues comparing with the lean mice. Pull-down experiments, coimmunoprecipitation and immunocytochemistry indicated that LGI3 associated with ADAM23 in adipose tissues and 3T3-L1 cells. Knockdown of LGI3 or ADAM23 by siRNA increased adipogenesis in 3T3-L1 cells. Treatment with LGI3 protein did not affect preadipocyte proliferation but attenuated adipogenesis and this effect was reversed by siRNA-mediated knockdown of ADAM23. Taken together, we propose that LGI3 may be a candidate adipokine that is perturbed in obesity and suppresses adipogenesis through its receptor, ADAM23.