Relationship between smoking experience and risk of suicide mortality in South Korean adults: A nationwide population-based retrospective cohort study.

BACKGROUND: Korea has one of the highest suicide rates in the world. Many factors associated with suicidal thoughts or behaviors are known. This study examines the association between 1) smoking status or intensity (pack-years) and 2) risk of suicide mortality in South Korea. METHODS: We analyzed data from 3,966,305 individuals aged ≥20 who underwent health examinations conducted by the South Korean National Health Insurance Service in 2009 and were followed until December 2021. Participants were categorized based on their baseline smoking status and intensity. We performed a Multivariate Cox proportional hazards regression analysis with subgroup analysis by age, sex, body mass index, alcohol consumption, regular exercise, and depression. RESULTS: During an 11.1-year follow-up period, 12,326 individuals died by suicide. Compared with never-smokers, increased hazard ratios of suicide mortality were observed in current smokers (1.64, 95 % CI = 1.56-1.72), but not in ex-smokers. The suicide mortality risk of current smokers increased for all types of smoking intensity without a dose-response relationship. The association between smoking and suicide mortality risk was stronger among women, non-drinkers, adults aged <40 years, non-obese patients, and individuals without depression. LIMITATION: Given that the study used retrospective data, the causal relationship remains unclear. CONCLUSION: Current smoking is associated with a significant increased risk of suicide mortality. Smoking cessation is crucial to prevent suicide, especially among young adults, non-obese individuals, non-drinkers, women, and those without depression. Government policies in South Korea should focus on raising awareness about smoking hazards and providing cessation education to reduce the suicide mortality.

Chemotherapy-related cardiotoxicity and its symptoms in patients with breast cancer: a scoping review.

BACKGROUND: Chemotherapy-related cardiotoxicity is a significant concern because it is a major cause of morbidity. This study aimed to provide in-depth information on the symptoms of chemotherapy-related cardiotoxicity (CRCT) by exploring literature that concurrently reports the types and symptoms of CRCT in patients with breast cancer. METHODS: A scoping review was performed according to an a priori protocol using the Joanna Briggs Institute's guidelines. The participants were patients with breast cancer. The concept was the literature of specifically reported symptoms directly matched with CRCT and the literature, in English, from 2010, and the context was open. The search strategy included four keywords: "breast cancer," "chemotherapy," "cardiotoxicity," and "symptoms." All types of research designs were included; however, studies involving patients with other cancer types, animal subjects, and symptoms not directly related to CRCT were excluded. Data were extracted and presented including tables and figures. RESULTS: A total of 29 articles were included in the study, consisting of 23 case reports, 4 retrospective studies, and 2 prospective studies. There were no restrictions on the participants' sex; however, all of them were women, except for one case report. The most used chemotherapy regimens were trastuzumab, capecitabine, and doxorubicin or epirubicin. The primary CRCT identified were myocardial dysfunction and heart failure, followed by coronary artery disease, pulmonary hypertension, and other conditions. Major tests used to diagnose CRCT include echocardiography, electrocardiography, serum cardiac enzymes, coronary angiography, computed tomography, and magnetic resonance imaging. In all case reports, CRCT was diagnosed through an incidental checkup according to the patient's symptom presentation; however, only 10 of these studies showed a baseline checkup before chemotherapy. The five most common CRCT symptoms were dyspnea, chest pain, peripheral edema, fatigue, and palpitations, which were assessed by patient-reported symptom presentation rather than using a symptom assessment tool. Dyspnea with trastuzumab treatment and chest pain with capecitabine treatment were particularly characteristic. The time for first symptom onset after chemotherapy ranged from 1 hour to 300 days, with anthracycline-based regimens requiring 3-55 days, trastuzumab requiring 60-300 days, and capecitabine requiring 1-7 days. CONCLUSIONS: This scoping review allowed data mapping according to the study design and chemotherapy regimens. Cardiac assessments for CRCT diagnosis were performed according to the patient's symptoms. There were approximately five types of typical CRCT symptoms, and the timing of symptom occurrence varied. Therefore, developing and applying a CRCT-specific and user-friendly symptom assessment tool are expected to help healthcare providers and patients manage CRCT symptoms effectively.

Comparative study on the effects of grain blending on functional compound content and in vitro biological activity.

In this study, changes in bioactive compound contents and the in vitro biological activity of mixed grains, including oats, sorghum, finger millet, adzuki bean, and proso millet, with eight different blending ratios were investigated. The total phenolic compounds and flavonoid contents ranged from 14.43-16.53 mg gallic acid equivalent/g extract and 1.22-5.37 mg catechin equivalent/g extract, respectively, depending on the blending ratio. The DI-8 blend (30% oats, 30% sorghum, 15% finger millet, 15% adzuki bean, and 10% proso millet) exhibited relatively higher antioxidant and anti-diabetic effects than other blending samples. The levels of twelve amino acids and eight organic acids in the grain mixes were measured. Among the twenty metabolites, malonic acid, asparagine, oxalic acid, tartaric acid, and proline were identified as key metabolites across the blending samples. Moreover, the levels of lactic acid, oxalic acid, and malonic acid, which are positively correlated with α-glucosidase inhibition activity, were considerably higher in the DI-blending samples. The results of this study suggest that the DI-8 blend could be used as a functional ingredient as it has several bioactive compounds and biological activities, including anti-diabetic activity.

Anti-4-1BB×PDL1 Bispecific Antibody Reinvigorates Tumor-Specific Exhausted CD8+ T Cells and Enhances the Efficacy of Anti-PD1 Blockade.

PURPOSE: To overcome the limited efficacy of immune checkpoint blockade, there is a need to find novel cancer immunotherapeutic strategies for the optimal treatment of cancer. The novel anti-4-1BB×PDL1 bispecific antibody-ABL503 (also known as TJ-L14B)-was designed to simultaneously target PDL1 and 4-1BB and demonstrated strong antitumor T-cell responses without considerable toxicity. In this study, we investigated the mechanisms by which the combination of ABL503 and anti-PD1 blockade affected the reinvigoration of exhausted tumor-infiltrating CD8+ T cells (CD8+ TIL) and antitumor efficacy. EXPERIMENTAL DESIGN: Single-cell suspensions of hepatocellular carcinoma and ovarian cancer tissues from treatment-naïve patients were used for immunophenotyping of CD8+ TILs and in vitro functional assays. Humanized hPD1/hPDL1/h4-1BB triple-knock-in mice were used to evaluate the effects of ABL503 and anti-PD1 blockade in vivo. RESULTS: We observed that ABL503 successfully restored the functions of 4-1BB+ exhausted CD8+ TILs, which were enriched for tumor-specific T cells but unresponsive to anti-PD1 blockade. Importantly, compared with anti-PD1 blockade alone, the combination of ABL503 and anti-PD1 blockade further enhanced the functional restoration of human CD8+ TILs in vitro. Consistently, the combination of ABL503 with anti-PD1 in vivo significantly alleviated tumor growth and induced enhanced infiltration and activation of CD8+ TILs. CONCLUSIONS: ABL503, a PDL1 and 4-1BB dual-targeting bispecific antibody, elicits pronounced additive tumor growth inhibition, with increased infiltration and functionality of exhausted CD8+ T cells, which in turn enhances the anticancer effects of anti-PD1 blockade. These promising findings suggest that ABL503 (TJ-L14B) in combination with PD1 inhibitors will likely further enhance therapeutic benefit in clinical trials. See related commentary by Molero-Glez et al., p. 3971.

Longitudinal Association between L1 Trabecular Attenuation from Chest Computed Tomography (CT) and Bone Mineral Density from Dualenergy X-ray Absorptiometry (DXA).

BACKGROUND: Many studies have shown that vertebral trabecular attenuation measured on CT scan corresponds well to DXA results for bone mineral density. These studies were based on crosssectional data. Hence, there were limitations in explaining the constantly changing vertebral trabecular attenuation from CT and T-score from DXA over time. OBJECTIVE: This study aimed to determine the longitudinal association between the vertebral trabecular attenuation measured on computed tomography (CT) and the T-score measured by dual-energy X-ray absorptiometry (DXA). METHODS: We performed a database search for 333 patients who underwent surgery for breast cancer, preoperative treatment, and at least one follow-up chest CT and DXA from January, 2013 through May, 2021. One musculoskeletal radiologist measured the mean vertebral trabecular attenuation of lumbar vertebra 1(L1) on axial unenhanced images at the pedicle level by manually placing the region of interest (ROI). DXA of the lumbar spine was performed, and the lowest T-score of the lumbar spine was used for the analysis. We evaluated the association between L1 trabecular attenuation from chest CT and T-score from DXA over time using the generalized estimating equations (GEE) model to analyze longitudinal corrected data. RESULTS: A total of 150 women (mean age, 52.4 ± 11.0 years) were included. There was a statistically significant association between L1 trabecular attenuation from chest CT and T-score from DXA in the unadjusted model (p < 0.001) and adjusted model (p < 0.001). T-score value increased by 0.172 (95% confidence interval (CI): 0.145-0.200, p < 0.001) per 10 unit (HU) of L1 trabecular attenuation at time = 0 in unadjusted model and by 0.173 (95% CI: 0.143-0.203, p < 0.001) in all adjusted model. CONCLUSION: We demonstrated that L1 attenuation from chest CT images was longitudinally associated with T-score from DXA, and the degree of association appeared to be decreased over time in breast cancer patients regardless of their medical condition.

Effects of a simplified drilling protocol at 50 rpm on heat generation under water-free conditions: an in vitro study.

PURPOSE: In recent years, guided implant surgery has been widely used for the convenience of patients and surgeons. Further streamlining the surgical procedure would make implant surgery more convenient. Low-speed water-free conditions are often used in guided implant surgery. Therefore, in this study, we attempted to confirm once again whether drilling was safe at a low speed without water. The main purpose of this study was to evaluate whether a simplified drilling protocol that omits some intermediate steps in the drilling process was safe from the viewpoint of heat generation. METHODS: D1 density artificial bone blocks were drilled under 50 rpm, 10 N·cm water-free conditions, and the surface temperature was measured using a digital infrared camera. First, drilling was performed with the sequential drilling method, which is the most widely used technique. Second, for each drill diameter, the temperature change was measured while performing simplified drilling with omission of the previous 1, 2, or 3 steps. RESULTS: In sequential drilling, the heat generated during drilling at all diameters was less than the critical temperature of osteonecrosis (47°C) except for the ⌀2 drill. Statistical significance was observed in all groups when comparing sequential and simplified drilling in the ⌀3.2, ⌀3.8, and ⌀4.3 drills (P<0.001). However, in the simplified drilling procedures, the temperature was below the osteonecrosis threshold temperature (47°C) except for the ⌀4.3 drill with the omission of the previous 3 steps (⌀3.0, ⌀3.2, and ⌀3.8). CONCLUSIONS: In general, drilling under low-speed, water-free conditions has shown stable results in terms of heat generation. Simplified drilling showed statistically significantly greater heat generation than sequential drilling. However, most of the diameters and omitted steps seem to be clinically acceptable, so it will be useful if an appropriate selection is made according to the patient's clinical condition.

Primary Colonic Epithelioid Angiosarcoma with Hepatic Metastasis: A Case Report.

Colonic angiosarcoma is an extremely rare and aggressive malignant tumor with poor prognosis. We report a case of colonic epithelioid angiosarcoma with colonic obstruction and rapidly progressive hepatic metastasis in a 44-year-old female. Abdominal CT revealed a heterogeneously enhancing irregular mass in the ascending colon, causing proximal bowel distension. The patient underwent surgery, and histopathological examination revealed a poorly differentiated carcinoma. A follow-up liver dynamic MRI after 4 months revealed newly developed diffusely scattered numerous small nodules in both hepatic lobes with peripheral and nodular marked arterial hyperenhancement, raising the suspicion of hepatic angiosarcoma. A pathologic second opinion was obtained, and additional immunohistochemistry revealed colonic epithelioid angiosarcoma. The patient showed progressive hepatic metastasis on follow-up abdominal CT after 6 months and died 8 months after initial diagnosis. We describe an educational case of colonic angiosarcoma, a rare malignant tumor, with rapidly progressive hepatic metastasis that showed radiologic findings suggestive of angiosarcoma and enabled a re-diagnosis for proper treatment and prognosis prediction.

Enhancement of the solubility of recombinant proteins by fusion with a short-disordered peptide.

In protein biotechnology, large soluble fusion partners are widely utilized for increased yield and solubility of recombinant proteins. However, the production of additional large fusion partners poses an additional burden to the host, leading to a decreased protein yield. In this study, we identified two highly disordered short peptides that were able to increase the solubility of an artificially engineered aggregation-prone protein, GFP-GFIL4, from 0.6% to 61% (D3-DP00592) and 46% (D4-DP01038) selected from DisProt database. For further confirmation, the peptides were applied to two insoluble E. coli proteins (YagA and YdiU). The peptides also enhanced solubility from 52% to 90% (YagA) and from 27% to 93% (YdiU). Their ability to solubilize recombinant proteins was comparable with strong solubilizing tags, maltose-binding protein (40 kDa) and TrxA (12 kDa), but much smaller (< 7 kDa) in size. For practical application, the two peptides were fused with a restriction enzyme, I-SceI, and they increased I-SceI solubility from 24% up to 75%. The highly disordered peptides did not affect the activity of I-SceI while I-SceI fused with MBP or TrxA displayed no restriction activity. Despite the small size, the highly disordered peptides were able to solubilize recombinant proteins as efficiently as conventional fusion tags and did not interfere with the function of recombinant proteins. Consequently, the identified two highly disordered peptides would have practical utility in protein biotechnology and industry.

LAG-3xPD-L1 bispecific antibody potentiates antitumor responses of T cells through dendritic cell activation.

Several preclinical studies demonstrate that antitumor efficacy of programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade can be improved by combination with other checkpoint inhibitors. Lymphocyte-activation gene 3 (LAG-3) is an inhibitory checkpoint receptor involved in T cell exhaustion and tumor immune escape. Here, we describe ABL501, a bispecific antibody targeting LAG-3 and PD-L1 in modulating immune cell responses against tumors. ABL501 that efficiently inhibits both LAG-3 and PD-L1 pathways enhances the activation of effector CD4+ and CD8+ T cells with a higher degree than a combination of single anti-LAG-3 and anti-PD-L1. The augmented effector T cell responses by ABL501 resulted in mitigating regulatory-T-cell-mediated immunosuppression. Mechanistically, the simultaneous binding of ABL501 to LAG-3 and PD-L1 promotes dendritic cell (DC) activation and tumor cell conjugation with T cells that subsequently mounts effective CD8+ T cell responses. ABL501 demonstrates its potent in vivo antitumor efficacy in a humanized xenograft model and with knockin mice expressing human orthologs. The immune profiling analysis of peripheral blood reveals an increased abundance of LAG-3hiPD-1hi memory CD4+ T cell subset in relapsed cholangiocarcinoma patients after gemcitabine plus cisplatin therapy, which are more responsive to ABL501. This study supports the clinical evaluation of ABL501 as a novel cancer immunotherapeutic, and a first-in-human trial has started (NCT05101109).

AK2 is an AMP-sensing negative regulator of BRAF in tumorigenesis.

The RAS-BRAF signaling is a major pathway of cell proliferation and their mutations are frequently found in human cancers. Adenylate kinase 2 (AK2), which modulates balance of adenine nucleotide pool, has been implicated in cell death and cell proliferation independently of its enzyme activity. Recently, the role of AK2 in tumorigenesis was in part elucidated in some cancer types including lung adenocarcinoma and breast cancer, but the underlying mechanism is not clear. Here, we show that AK2 is a BRAF-suppressor. In in vitro assays and cell model, AK2 interacted with BRAF and inhibited BRAF activity and downstream ERK phosphorylation. Energy-deprived conditions in cell model and the addition of AMP to cell lysates strengthened the AK2-BRAF interaction, suggesting that AK2 is involved in the regulation of BRAF activity in response to cell metabolic state. AMP facilitated the AK2-BRAF complex formation through binding to AK2. In a panel of HCC cell lines, AK2 expression was inversely correlated with ERK/MAPK activation, and AK2-knockdown or -knockout increased BRAF activity and promoted cell proliferation. Tumors from HCC patients showed low-AK2 protein expression and increased ERK activation compared to non-tumor tissues and the downregulation of AK2 was also verified by two microarray datasets (TCGA-LIHC and GSE14520). Moreover, AK2/BRAF interaction was abrogated by RAS activation in in vitro assay and cell model and in a mouse model of HRASG12V-driven HCC, and AK2 ablation promoted tumor growth and BRAF activity. AK2 also bound to BRAF inhibitor-insensitive BRAF mutants and attenuated their activities. These findings indicate that AK2 monitoring cellular AMP levels is indeed a negative regulator of BRAF, linking the metabolic status to tumor growth.

Development of a Customized Endoscopic Dual-Diffusing Optical Fiber Probe for Pancreatic Cancer Therapy: Toward Clinical Use.

Objective: We developed a dual-diffusing optical fiber probe (DDOFP), capable of uniformly illuminating the anatomical structure of pancreatic duct for photodynamic therapy (PDT) of pancreatic cancer in clinical settings. Background: Optical fiber presents a unique route for pancreatic PDT by enabling access to the pancreatic duct. For effective pancreatic PDT, the optical fiber should produce a uniform illumination covering of the pancreatic duct, while maintaining its transmission property under thermomechanical stresses in surgical environments. Methods: The transmission profiles of DDOFP were measured using a charge-coupled device (CCD) camera at two directions: front-spherical and side-cylindrical areas of the optical fiber. We simulated the change in transmission property by curved tube structures using optically transparent phantom. DDOFP was integrated with 19-gauge needle catheter that is commercially used as an optical guide to treat pancreatic cancer. The temperature of DDOFP was measured at the end face using a thermistor probe in the bovine tissue, while delivering laser energy of over 200 and 500 J. Results: DDOFP was customized to secure the inner diameter of the 19-gauge needle catheter of 686 µm to be integrated as a clinical device. The round ball lens fiber tip minimized the back-burn effect caused by blood carbonization during surgery and induced front-spherical diffusion. DDOFP produced uniform light illumination with intensity difference of <10%. When DDOFP was bent with a small curvature <15 mm, the transmission intensity was consistent. Under high-power laser transmission, DDOFP was found to be robust to cracking or deformation. Conclusions: DDOFP was customized for pancreatic PDT with superior thermomechanical property and uniform light illumination at both the front-spherical and side-cylindrical areas. This is the smallest clinically available optical fiber per our knowledge and officially approved by the Korea Food and Drug Administration (item approval number: 17-516). DDOFP can contribute immensely toward the efficient delivery of pancreatic PDT and photothermal therapy.

Clinical Feasibility of Shear Wave Dispersion Slope for Noninvasive Diagnosis of Nonalcoholic Steatohepatitis in Patients With Morbid Obesity: Preliminary Results Using US Shear Wave Elastography.

ABSTRACT: We aimed to investigate the clinical feasibility of shear wave dispersion slope for assessing nonalcoholic steatohepatitis (NASH) in patients with morbid obesity before bariatric surgery.This prospective study collected data from 25 participants who received liver biopsy during bariatric surgery between February 2019 and December 2020. All participants underwent ultrasonography shear wave elastography before surgery and shear wave speed and shear wave dispersion slope were measured. Liver specimens were evaluated by 1 pathologist scored histologically for nonalcoholic fatty liver disease (NAFLD). Ultrasonography measurements were compared according to histopathologic findings. Diagnostic performance in differentiating NASH from NAFLD was evaluated using the area under the receiver operating characteristic curve (AUC). Median shear wave speed (1.48 vs 1.62 m/s, P = 0.014) and dispersion slope (8.40 vs 11.80 [m/s]/kHz, P = 0.004) were higher in NASH group than in NAFLD group. Shear wave dispersion slope tended to increase step by step as the severity of activity grade (P = 0.032) and hepatic fibrosis (P = 0.015) increased. The AUC of shear wave dispersion slope for differentiating NASH from NAFLD (AUC, 0.83; 95% confidence intervals, 0.66-1.00) was higher than that of shear wave speed (AUC, 0.78; 95% CI, 0.60-0.97), although it did not reach statistical significance (P = 0.729). Shear wave dispersion slope could be a feasible tool for assessing NASH in patients with morbid obesity.

Differentiation between spinal subchondral bone metastasis with focal pathologic endplate fracture and oedematous Schmorl's node.

INTRODUCTION: We aimed to identify imaging-based findings that can differentiate between spinal subchondral bone metastasis with focal pathologic endplate fracture and oedematous Schmorl's nodes that have been histopathologically confirmed. METHODS: Between March 2010 and April 2016, 11 patients who had undergone spinal magnetic resonance (MR) imaging or computed tomography (CT) with final radiologic reports that included 'subchondral bone metastasis with focal pathologic endplate fracture' or 'edematous Schmorl's node' and had also undergone percutaneous imaging-guided spinal biopsies were included. Two radiologists retrospectively evaluated the following imaging features in consensus: size, location, presence of sclerotic margin, presence of intralesional or perilesional enhancement and opposite endplate enhancement of the involved disc, presence of disc height loss and presence of metabolic uptake at a corresponding lesion on nuclear medicine imaging. RESULTS: A total of 11 patients, including six patients with spinal subchondral bone metastasis with focal pathologic endplate fracture and five patients with oedematous Schmorl's nodes, were included in this study (median age, 58 years; range, 50-63 years; six men). Sclerotic margin (P = 0.002) and enhancement on the opposite endplate of the involved disc (P = 0.047) were significantly different between oedematous Schmorl's node and subchondral bone metastasis with focal pathologic endplate fracture. CONCLUSION: Sclerotic margin and enhancement on the opposite endplate of the involved disc suggest oedematous Schmorl's node rather than subchondral bone metastasis with focal pathologic endplate fracture. Decreased disc height is likely to be an oedematous Schmorl's node rather than subchondral bone metastasis with focal pathologic endplate fracture.

Finger Millet Ethanol Extracts Prevent Hypertension by Inhibiting the Angiotensin-Converting Enzyme Level and Enhancing the Antioxidant Capacity in Spontaneously Hypertensive Rats.

Finger millet (Eleusine coracana) contains high levels of calcium and polyphenols, which have a variety of beneficial functions. We tested the hypothesis that finger millet ethanol extracts (FEs) have an antihypertensive effect in spontaneously hypertensive rats (SHRs). The study groups were assigned as follows: (1) Wistar Kyoto rats (normal); (2) SHRs treated with saline (negative control); (3) SHRs treated with captopril 50 mg/kg bw (positive control); (4) SHRs treated with FE 250 mg/kg bw (FE250); and (5) SHRs treated with FE 500 mg/kg bw (FE500). FE supplementation improved the lipid profiles, including the triglyceride, total cholesterol, and low-density lipoprotein cholesterol levels, without deterioration in liver function. The thiobarbituric acid reactive substance concentration and superoxide dismutase activity significantly improved after the application of FE250 and FE500. Interestingly, FE250 and FE500 application dramatically reduced the systolic blood pressure. FE supplementation exhibited powerful control over the renin-angiotensin system by reducing the angiotensin-converting enzyme levels and renin mRNA expression in the kidney. Additionally, FE500 application ameliorated vascular remodeling, reversed the thickening media, and decreased the media thickness/lumen diameter ratio of the aorta. These results imply that FEs are a potent antihypertensive nutraceutical for regulating the renin-angiotensin system and simultaneously inhibiting oxidative stress.

Oat Extract Avenanthramide-C Reverses Hippocampal Long-Term Potentiation Decline in Tg2576 Mice.

Memory deterioration in Alzheimer's disease (AD) is thought to be underpinned by aberrant amyloid ß (Aß) accumulation, which contributes to synaptic plasticity impairment. Avenanthramide-C (Avn-C), a polyphenol compound found predominantly in oats, has a range of biological properties. Herein, we performed methanolic extraction of the Avns-rich fraction (Fr. 2) from germinated oats using column chromatography, and examined the effects of Avn-C on synaptic correlates of memory in a mouse model of AD. Avn-C was identified in Fr. 2 based on 1H-NMR analysis. Electrophysiological recordings were performed to examine the effects of Avn-C on the hippocampal long-term potentiation (LTP) in a Tg2576 mouse model of AD. Avn-C from germinated oats restored impaired LTP in Tg2576 mouse hippocampal slices. Furthermore, Avn-C-facilitated LTP was associated with changes in the protein levels of phospho-glycogen synthase kinase-3ß (p-GSK3ß-S9) and cleaved caspase 3, which are involved in Aß-induced synaptic impairment. Our findings suggest that the Avn-C extract from germinated oats may be beneficial for AD-related synaptic plasticity impairment and memory decline.

Clinical Feasibility of High-Resolution Contrast-Enhanced Dynamic T1-Weighted Magnetic Resonance Imaging of the Upper Abdomen Using Compressed Sensing.

OBJECTIVE: The objective of this study was to evaluate the clinical feasibility of high-resolution contrast-enhanced dynamic T1-weighted imaging (T1WI) using compressed sensing (CS) in magnetic resonance imaging. METHODS: This study retrospectively included 35 patients who underwent dynamic T1WI using volumetric interpolated breath-hold examination (VIBE) with CS reconstruction (CS-VIBE) and 35 patients with conventional VIBE for comparison. Two observers assessed the liver and pancreas edges, hepatic artery, motion artifacts, and overall image quality. Quantitative analysis was performed by measuring signal intensity and image noise. RESULTS: The results showed that CS-VIBE achieved significantly better anatomic delineation of the liver and pancreas edges and hepatic artery clarity than VIBE (P < 0.001). There were no significant differences in motion artifacts in dynamic phases and overall image quality. The signal intensities and INs of CS-VIBE were higher than VIBE. CONCLUSIONS: High-resolution dynamic T1WI using CS provides better anatomic delineation with comparable or better overall image quality than conventional VIBE.

Novel anti-4-1BB×PD-L1 bispecific antibody augments anti-tumor immunity through tumor-directed T-cell activation and checkpoint blockade.

BACKGROUND: Stimulation of 4-1BB with agonistic antibodies is a promising strategy for improving the therapeutic efficacy of immune checkpoint inhibitors (ICIs) or for overcoming resistance to ICIs. However, dose-dependent hepatotoxicity was observed in clinical trials with monoclonal anti-4-1BB agonistic antibodies due to the activation of 4-1BB signaling in liver resident Kupffer cells. METHODS: To avoid this on-target liver toxicity, we developed a novel bispecific antibody (4-1BB×PD-L1 bispecific antibody, termed "ABL503") uniquely designed to activate 4-1BB signaling only in the context of PD-L1, while also blocking PD-1/PD-L1 signaling. RESULTS: Functional evaluation using effector cells expressing both 4-1BB and PD-1 revealed superior biological activity of ABL503 compared with the combination of each monoclonal antibody. ABL503 also augmented T-cell activation in in vitro assays and further enhanced the anti-PD-L1-mediated reinvigoration of tumor-infiltrating CD8+ T cells from patients with cancer. Furthermore, in humanized PD-L1/4-1BB transgenic mice challenged with huPD-L1-expressing tumor cells, ABL503 induced superior anti-tumor activity and maintained an anti-tumor response against tumor rechallenge. ABL503 was well tolerated, with normal liver function in monkeys. CONCLUSION: The novel anti-4-1BB×PD-L1 bispecific antibody may exert a strong anti-tumor therapeutic efficacy with a low risk of liver toxicity through the restriction of 4-1BB stimulation in tumors.

Preoperative Routine Laboratory Markers for Predicting Postoperative Recurrence and Death in Patients with Breast Cancer.

Simple, convenient, and reliable preoperative prognostic indicators are needed to estimate the future risk of recurrences and guide the treatment decisions associated with breast cancer. We evaluated preoperative hematological markers related to recurrence and mortality and investigated independent risk factors for recurrence and mortality in patients after breast cancer surgery. We reviewed electronic medical records of patients with invasive breast cancer diagnosed at our tertiary institution between November 2005 and December 2010 and followed them until 2015. We compared two groups of patients classified according to recurrence or death and identified risk factors for postoperative outcomes. Data from 1783 patients were analyzed ultimately. Cancer antigen (CA) 15-3 and red cell distribution width (RDW) had the highest area under the curve values among several preoperative hematological markers for disease-free survival and overall survival (0.590 and 0.637, respectively). Patients with both preoperative CA 15-3 levels over 11.4 and RDW over 13.5 had a 1.7-fold higher risk of recurrence (hazard ratio (HR): 1.655; 95% confidence interval (CI): 1.154-2.374; p = 0.007) and mortality (HR: 1.723; 95% CI: 1.098-2.704; p = 0.019). In conclusion, relatively high preoperative RDW (>13.5) and CA 15-3 levels (>11.4) had the highest predictive power for mortality and recurrence, respectively. When RDW and CA 15-3 exceeded the cut-off value, the risk of recurrence and death also increased approximately 1.7 times.

Antioxidant and anti-inflammatory effects of Peanut (Arachishypogaea L.) skin extracts of various cultivars in oxidative-damaged HepG2 cells and LPS-induced raw 264.7 macrophages.

This study was performed to investigate the distribution of phenolic compounds in the peanut skins of various cultivars, as well as their antioxidant and anti-inflammatory effect (Arachishypogaea L. cv. K-Ol, cv. Sinpalkwang, cv. Daan, cv. Heuksaeng) and extraction solvent. The major components of red peanut cultivars (K-Ol, Sinpalkwang, and Daan) were identified as proanthocyanidin, catechin, gallic acid, coumaric acid, and hesperidine, whereas the major components of black peanut cultivar (Heuksaeng) were identified as anthocyanin, ferulic acid, and quercetin. The DPPH and ABTS radical scavenging activities, and FRAP values were the highest in Daan followed by Sinpalkwng, K-Ol, and Heuksang. Furthermore, the skin extracts of red peanuts effectively improved cell viability, reactive oxygen species generation, MDA concentration, and antioxidant enzyme activity (GR, GPx, CAT, and superoxide dismutase) in oxidative stress-induced HepG2 cells, and reduced the expression of pro-inflammatory factors (NO, TNF-α, IL-6, and IL-1ß) in LPS-stimulated RAW 264.7 macrophages. These results suggest that red peanut skin extracts could effectively mediate physiological activity and provide valuable information for the use of peanut byproducts as functional food materials.

Reproducibility and diagnostic performance of the vascular index of superb microvascular imaging in real-time breast ultrasonography for evaluating breast masses.

PURPOSE: This study aimed to evaluate the reproducibility and diagnostic performance of a quantitative parameter of superb microvascular imaging (SMI) in real-time breast ultrasonography (US) for differentiating benign from malignant breast masses. METHODS: Eighty-seven breast masses in 75 patients who underwent both B-mode US and SMI before US-guided core needle biopsy were included in this study. Two radiologists performed B-mode US and measured the vascular index (VI) of SMI respectively for each lesion in real time. Intraobserver and interobserver agreements were analyzed for the VI of SMI. The diagnostic performance of B-mode US using the Breast Imaging Reporting and Database System lexicon and combined use with the VI of SMI was evaluated compared to pathology. RESULTS: The median VI of malignant masses (n=32) was significantly higher than that of benign masses (n=55) (7.6% and 2.6%, respectively; P<0.001). The intraobserver agreement for VI was excellent regardless of the pathology, size, or depth of the lesion. The interobserver agreement for VI was excellent regardless of the presence of a measurement interval. The interobserver agreement for the final diagnostic decision was improved by combining B-mode US and VI (κ=0.883) in comparison with B-mode US only (κ=0.617). Adding VI led to significant improvements in the specificity (87.2% vs. 52.7%, 83.6% vs. 49.0%), accuracy (89.7% vs. 69.3%, 84.0% vs. 65.9%) and positive predictive value (81.5% vs. 55.1%, 75.6% vs. 52.6%) of B-mode US for both observers compared with B-mode US alone (all, P=0.001). CONCLUSION: The VI of SMI for real-time breast US is highly reproducible and leads to improved diagnostic performance for differentiating between benign and malignant breast lesions in combination with B-mode US.