A CRISPR activation screen identifies MUC-21 as critical for resistance to NK and T cell-mediated cytotoxicity.

BACKGROUND: Immunotherapy has significantly advanced cancer treatments, but many patients do not respond to it, partly due to immunosuppressive mechanisms used by tumor cells. These cells employ immunosuppressive ligands to evade detection and elimination by the immune system. Therefore, the discovery and characterization of novel immunosuppressive ligands that facilitate immune evasion are crucial for developing more potent anti-cancer therapies. METHODS: We conducted gain-of-function screens using a CRISPRa (CRISPR activation) library that covered the entire human transmembrane sub-genome to identify surface molecules capable of hindering NK-mediated cytotoxicity. The immunosuppressive role and mechanism of MUC21 were validated using NK and T cell mediated cytotoxicity assays. Bioinformatics tools were employed to assess the clinical implications of mucin-21 (MUC21) in cancer cell immunity. RESULTS: Our genetic screens revealed that MUC21 expression on cancer cell surfaces inhibits both the cytotoxic activity of NK cells and antibody-dependent cellular cytotoxicity, but not affecting complement-dependent cytotoxicity. Additionally, MUC21 expression hinders T cell activation by impeding antigen recognition, thereby diminishing the effectiveness of the immune checkpoint inhibitor, anti-PD-L1. Moreover, MUC21 expression suppress the antitumor function of both CAR-T cells and CAR-NK cells. Mechanistically, MUC21 facilitates immune evasion by creating steric hindrance, preventing interactions between cancer and immune cells. Bioinformatics analysis revealed elevated MUC21 expression in lung cancer, which correlated with reduced infiltration and activation of cytotoxic immune cells. Intriguingly, MUC21 expression was higher in non-small cell lung cancer (NSCLC) tumors that were non-responsive to anti-PD-(L)1 treatment compared to responsive tumors. CONCLUSIONS: These findings indicate that surface MUC21 serves as a potent immunosuppressive ligand, shielding cancer cells from NK and CD8+T cell attacks. This suggests that inhibiting MUC21 could be a promising strategy to improve cancer immunotherapy.

The influence of microbial dysbiosis on immunochemotherapy-related efficacy and safety in diffuse large B-cell lymphoma.

The gut microbiome influences cancer development and the efficacy and safety of chemotherapy but little is known about its effects on lymphoma. We obtained stool samples from treatment-naive, newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL) (n = 189). We first performed 16S ribosomal RNA gene sequencing (n = 158) and then conducted whole-genome shotgun sequencing on additional samples (n = 106). We compared the microbiome data from these patients with data from healthy controls and assessed whether microbiome characteristics were associated with treatment outcomes. The alpha diversity was significantly lower in patients with DLBCL than in healthy controls (P < .001), and the microbial composition differed significantly between the groups (P < .001). The abundance of the Enterobacteriaceae family belonging to the Proteobacteria phylum was markedly higher in patients than in healthy controls. Functional analysis of the microbiome revealed an association with opportunistic pathogenesis through type 1 pili, biofilm formation, and antibiotics resistance. Enterobacteriaceae members were significantly enriched in patients who experienced febrile neutropenia and in those who experienced relapse or progression (P < .001). Interestingly, greater abundance of Enterobacteriaceae correlated with shorter progression-free survival (P = .007). The cytokine profiles of patients whose microbiome was enriched with Enterobacteriaceae were significantly associated with interleukin 6 (P = .035) and interferon gamma (P = .045) levels. In summary, patients with DLBCL exhibited gut microbial dysbiosis. The abundance of Enterobacteriaceae correlated with treatment outcomes and febrile neutropenia. Further study is required to elucidate the origin and role of gut dysbiosis in DLBCL.

Enhancing adoptive T-cell therapy with fucoidan-based IL-2 delivery microcapsules.

Adoptive cell therapy (ACT) with antigen-specific T cells is a promising treatment approach for solid cancers. Interleukin-2 (IL-2) has been utilized in boosting the efficacy of ACT. However, the clinical applications of IL-2 in combination with ACT is greatly limited by short exposure and high toxicities. Herein, a complex coacervate was designed to intratumorally deliver IL-2 in a sustained manner and protect against proteolysis. The complex coacervate consisted of fucoidan, a specific IL-2 binding glycosaminoglycan, and poly-l-lysine, a cationic counterpart (FPC2). IL-2-laden FPC2 exhibited a preferential bioactivity in ex vivo expansion of CD8+T cells over Treg cells. Additionally, FPC2 was embedded in pH modulating injectable gel (FPC2-IG) to endure the acidic tumor microenvironment. A single intratumoral administration of FPC2-IG-IL-2 increased expansion of tumor-infiltrating cytotoxic lymphocytes and reduced frequencies of myeloid populations. Notably, the activation and persistency of tumor-reactive T cells were observed only in the tumor site, not in the spleen, confirming a localized effect of FPC2-IG-IL-2. The immune-favorable tumor microenvironment induced by FPC2-IG-IL-2 enabled adoptively transferred TCR-engineered T cells to effectively eradicate tumors. FPC2-IG delivery system is a promising strategy for T-cell-based immunotherapies.

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).

Patient-specific instrumentation improves the reproducibility of preoperative planning for the positioning of baseplate components with reverse total shoulder arthroplasty: a comparative clinical study in 39 patients.

BACKGROUND: The application of patient-specific instrumentation (PSI) for reverse total shoulder replacement has been rapidly increasing, which could reduce errors in implant positioning. Although PSI theoretically holds promise, evidence of the accuracy and reliability of PSI in shoulder replacement surgery is limited. METHODS: Thirty-nine shoulders that underwent reverse total shoulder arthroplasty were included in this study and categorized into two groups: the conventional (n = 20) and PSI (n = 19) groups. Screw (length and angle) and baseplate (version, inclination, translation, and rotation) positioning were calculated based on postoperative computed tomography images using a three-dimensional measurement tool. The difference between the values of the preoperative target and postoperative measurement was calculated to evaluate the reproducibility of preoperative planning. Screw involvement in the suprascapular and spinoglenoid notches was assessed. Thus, the correlation between the position of the baseplate and the screws was assessed. RESULTS: The mean differences between the planned length and angle (anteroposterior and superoinferior angles) and postoperative measurement in the PSI group were significantly smaller than those in the conventional group. Similarly, the mean difference in baseplate rotation between the planned and postoperative measurements in the PSI group was significantly lower than that in the conventional group (4.5° vs 10.6°; P < .001). The spinoglenoid notch was involved in 10 cases in the conventional group and 2 cases in the PSI group, and this difference was significant (P = .014). Overall, the mean difference between the preoperative and postoperative version, inferior inclination, and rotation values for the baseplate position was significantly correlated with the values for screw position (length and angle). CONCLUSIONS: PSI improves the reproducibility of preoperative planning for baseplate and screw positioning and reduces the risk of neurovascular injury in reverse total shoulder arthroplasty.

Mucin1 and Mucin16: Therapeutic Targets for Cancer Therapy.

The mucin (MUC) family is a group of highly glycosylated macromolecules that are abundantly expressed in mammalian epithelial cells. MUC proteins contribute to the formation of the mucus barrier and thus have protective functions against infection. Interestingly, some MUC proteins are aberrantly expressed in cancer cells and are involved in cancer development and progression, including cell growth, proliferation, the inhibition of apoptosis, chemoresistance, metabolic reprogramming, and immune evasion. With their unique biological and structural features, MUC proteins have been considered promising therapeutic targets and also biomarkers for human cancer. In this review, we discuss the biological roles of the transmembrane mucins MUC1 and MUC16 in the context of hallmarks of cancer and current efforts to develop MUC1- and MUC16-targeted therapies.

Breast-Conserving Surgery after Neoadjuvant Chemotherapy Using a Three-Dimensional-Printed Surgical Guide Based on Supine Magnetic Resonance Imaging: A Case Report.

Tumor localization in patients receiving neoadjuvant chemotherapy (NACT) is challenging because substantial therapeutic remission of the original tumor after NACT is often noted. Currently, there is no guidance device that allows for an accurate estimation of the resection range in breast-conserving surgery after NACT. To increase the accuracy of tumor resection, we used a 3-dimensional-printed breast surgical guide based on magnetic resonance imaging (MRI) in the supine position for a breast cancer patient who underwent breast-conserving surgery after NACT. Using this device, the breast tumor with apparent therapeutic changes after NACT on imaging was successfully removed with clear resection margins by identifying the original tumor site in the affected breast. Irrespective of whether the residual tumor area after NACT is well defined, it is possible to confirm and target the tumor area on pre-NACT MRI using this device.

Unilateral Biportal Endoscopy for Decompression of Extraforaminal Stenosis at the Lumbosacral Junction: Surgical Techniques and Clinical Outcomes.

OBJECTIVE: The aims of this study were to describe the unilateral biportal endoscopic (UBE) technique for decompression of extraforaminal stenosis at L5-S1 and evaluate 1-year clinical outcomes. Especially, we evaluated compression factors of extraforaminal stenosis at L5-S1 and described the surgical technique for decompression in detail. METHODS: Thirty-five patients who underwent UBE decompression for extraforaminal stenosis at L5-S1 between March 2018 and February 2019 were enrolled. Clinical results were analyzed using the MacNab criteria, the visual analogue scale (VAS) for back and leg pain, and the Oswestry Disability Index (ODI). Compression factors evaluated pseudoarthrosis within the transverse process of L5 and ala of sacrum, disc bulging with or without osteophytes, and the thickened lumbosacral and extraforaminal ligament. RESULTS: The mean back VAS was 3.7 ± 1.8 before surgery, which dropped to 2.3 ± 0.8 at 1-year postoperative follow-up (p < 0.001). There was a significant drop in postoperative mean VAS for leg pain from 7.2 ± 1.1 to 2.3 ± 1.2 at 1 year (p < 0.001). The ODI was 61.5 before surgery and 28.6 (p < 0.001). Pseudoarthrosis between the transverse process and the ala was noted in all cases (35 of 35, 100%). Pure disc bulging was seen in 12 patients (34.3%), and disc bulging with osteophytes was demonstrated in 23 patients. The thickened lumbosacral and extraforaminal ligament were identified in 19 cases (51.4%). No complications occurred in any of the patients. CONCLUSION: In the current study, good surgical outcomes without complications were achieved after UBE decompression for extraforaminal stenosis at L5-S1.

Allogeneic transplant can abrogate the risk of relapse in the patients of first remission acute myeloid leukemia with detectable measurable residual disease by next-generation sequencing.

In patients with acute myeloid leukemia (AML) consolidation treatment options are between allogeneic hematopoietic stem cell transplantation (HCT) and chemotherapy, based on disease risk at the time of initial presentation and age. Measurable residual disease (MRD) following induction chemotherapy could be incorporated as a useful parameter for treatment decisions. The present study evaluated treatment outcomes according to the next-generation sequencing (NGS)-based MRD status and the type of consolidation therapy in patients with normal karyotype (NK)-AML. By sequencing 278 paired samples collected at diagnosis and first remission (CR1), we identified 361 mutations in 124 patients at diagnosis and tracked these at CR1. After excluding mutations associated with age-related clonal hematopoiesis, 82 mutations in 50 of the 124 patients (40.3%) were detected at CR1. Survival benefit was observed in favor of allogeneic HCT over chemotherapy consolidation in the MRDpos subgroup with respect to overall survival (HR 0.294, p = 0.003), relapse-free survival (HR 0.376, p = 0.015) and cumulative incidence of relapse (HR 0.279, p = 0.004) in multivariate analysis, but not in the MRDneg subgroup. In summary, these data support allogeneic HCT in NK-AML patients with detectable MRD by NGS in CR1. Randomized clinical trials will be required to confirm this observation.

Role of Additional Inferomedial Supporting Screws in Osteoporotic 3-Part Proximal Humerus Fracture: Finite Element Analysis.

INTRODUCTION: Importance of inferomedial supporting screws in preventing varus collapse has been investigated for the proximal humerus fracture. However, few studies reported the results of osteoporotic complex fracture. This study aimed to demonstrate the stress distribution pattern, particularly in osteoporotic 3-part proximal humerus fractures involving greater tuberosity (GT) with different screw configurations. MATERIALS AND METHODS: Using the computed tomography (CT) images of 2 patients, who had osteoporosis and the other had normal bone density, 3-part fractures involving the GT, without medial support were reconstructed. To reflect the osteoporosis or real bone density, Hounsfield unit of CT scans were utilized. A force of 200 N was applied in 30° varus direction. The proximal screws were set in 2 ways: 6 screws without inferomedial supporting screws and 9 screws with inferomedial supporting screws. Qualitative and quantitative analysis of internal stress distribution were performed. RESULTS: The most proximal part area near humeral head vertex and near the 1st screw's passage and tip had more stress concentrated in osteoporotic 3-part fractures. The stress distribution around the proximal screws was found near the GT fracture line and its lateral side, where the local max values located. Inferomedial supporting screws decreased these effects by changing the points to medial side from the GT. The ratio in osteoporotic bone model decreased to that in normal bone model when inferomedial supporting screws were applied (normal bone, 2.97%-1.30%; osteoporosis bone, 4.76%-1.71%). CONCLUSIONS: In osteoporotic 3-part proximal humerus fracture, the stress distribution was concentrated on the area near the humeral vertex, 1st row screw tips, and lateral side region from the GT fracture line. Moreover, inferomedial supporting screws ensured that the stress distribution is similar to that in normal bone setting, particularly in osteoporotic condition.

Impact of air pollution on breast cancer incidence and mortality: a nationwide analysis in South Korea.

Breast cancer is one of the major female health problems worldwide. Although there is growing evidence indicating that air pollution increases the risk of breast cancer, there is still inconsistency among previous studies. Unlike the previous studies those had case-control or cohort study designs, we performed a nationwide, whole-population census study. In all 252 administrative districts in South Korea, the associations between ambient NO2 and particulate matter 10 (PM10) concentration, and age-adjusted breast cancer mortality rate in females (from 2005 to 2016, Nmortality = 23,565), and incidence rate (from 2004 to 2013, Nincidence = 133,373) were investigated via multivariable beta regression. Population density, altitude, rate of higher education, smoking rate, obesity rate, parity, unemployment rate, breastfeeding rate, oral contraceptive usage rate, and Gross Regional Domestic Product per capita were considered as potential confounders. Ambient air pollutant concentrations were positively and significantly associated with the breast cancer incidence rate: per 100 ppb CO increase, Odds Ratio OR = 1.08 (95% Confidence Interval CI = 1.06-1.10), per 10 ppb NO2, OR = 1.14 (95% CI = 1.12-1.16), per 1 ppb SO2, OR = 1.04 (95% CI = 1.02-1.05), per 10 µg/m3 PM10, OR = 1.13 (95% CI = 1.09-1.17). However, no significant association between the air pollutants and the breast cancer mortality rate was observed except for PM10: per 10 µg/m3 PM10, OR = 1.05 (95% CI = 1.01-1.09).

Antioxidant and anti-inflammatory effects of Lilium lancifolium bulbs extract.

Lilium lancifolium is native to Northeast Asia and its bulbs have been used for medicinal treatment. Moreover, Japan has been using L. lancifolium bulbs more actively as food ingredients than Korea. Therefore, this study was to investigate the characteristics of Korean L. lancifolium bulbs, with respect to food component and functionality. As a result of proximate composition analysis, L. lancifolium bulbs have an abundant carbohydrate content. HPLC analysis indicated p-coumaric acid and ferulic acid contents of Korean L. lancifolium extract were 1.14 ± 0.01, 1.46 ± 0.00 mg/g, but only p-coumaric acid was less detected in Japanese extract. Also, Korean L. lancifolium bulbs extract exhibited significant antioxidant effects, as evaluated with antioxidant activity and compound, than Japanese extract. Furthermore, Korean L. lancifolium bulbs extract significantly inhibited pro-inflammatory protein expressions through MyD88 dependent pathway. Therefore, these results suggested Korean L. lancifolium bulbs have the potential to being functional food ingredients. PRACTICAL APPLICATIONS: Lilium lancifolium is a perennial plant belonging to the Liliaceae family. The storage organ of L. lancifolium is surrounded by several fleshy nodes at the base of the stem, called the bulb, which has been used as food or medicine to treat pneumonia and bronchitis. L. lancifolium is widely found in countries of Northeast Asia, such as Korea, Japan, and China, and its bulbs have been studied for presence of bioactive compounds that have important functional activities. The bioactive compounds in the L. lancifolium bulbs may vary from region to region. In this study, the difference observed in the contents of different bioactive compounds and the efficacy of anti-inflammatory effects of L. lancifolium bulbs from different regions were consistent in this regard. As a comparative study of food materials by region, these L. lancifolium bulbs have the potential to be used as a food material for preventing inflammatory diseases.

Anti­photoaging effect of fermented agricultural by­products on ultraviolet B­irradiated hairless mouse skin.

Processed products from agricultural produce generate a large number of agricultural by­products that contain a number of functional substances. These are often discarded owing to the lack of suitable processing methods. The present study investigated the anti­photoaging properties of fermented rice bran (FRB), soybean cake (FSB) and sesame seed cake (FSC) on ultraviolet B (UVB)­irradiated hairless mouse skin. Results indicated that the oral administration of FRB, FSB and FSC effectively inhibited the UVB irradiation­induced expression of matrix metalloproteinase (MMP)­2, MMP­9, MMP­3 and MMP­13. Reverse transcription­quantitative polymerase chain reaction results also demonstrated that FRB, FSB and FSC significantly inhibited the UVB­induced expression of the genes encoding tumor necrosis factor­α, inducible nitric oxide synthase, interleukin (IL)­6 and IL­1ß when compared with the UVB­vehicle group (P<0.05). Additionally, collagen degradation and mast cell infiltration were reduced in hairless mouse skin. Furthermore, UVB­induced wrinkle formation was also significantly reduced in mouse skin compared with the UVB­vehicle group (P<0.05). These results reveal that fermented agricultural by­products may serve as potential functional materials with anti­photoaging activities.

Remission clone in acute myeloid leukemia shows growth advantage after chemotherapy but is distinct from leukemic clone.

In a previously published case study of acute myeloid leukemia, we tracked the dynamics of somatic mutations over 9 years. Interestingly, we observed a group of mutations that expanded during remission, which we named the "remission clone." To determine the nature of the remission clones, we performed flow cytometry-based cell sorting followed by ultradeep sequencing. The remission clone repeatedly expanded after chemotherapeutic cycles and was suppressed during relapse in the myeloid lineage (multipotent hematopoietic stem, progenitor, and myeloid cells). On the other hand, the remission clone was consistently observed in lymphoid lineages (B and T cells) regardless of the disease state. When transfected into the HEK-293 cell line, the NR2C2(A93V) mutant exhibited a growth advantage (all p values < 0.05). The results indicate that the remission clone seems to be another form of clonal hematopoiesis, but without a clear association with leukemia. As the remission clone is present in both myeloid and lymphoid lineages, it likely originates from ancestral hematopoietic cell lineages. More importantly, the remission clone is distinct from the leukemic clone; therefore, mutations expanded during remission require special interpretation when performing next-generation sequencing-based measurable residual disease assessment.

Clinical and radiological outcomes of unilateral biportal endoscopic lumbar interbody fusion (ULIF) compared with conventional posterior lumbar interbody fusion (PLIF): 1-year follow-up.

This study retrospectively compared clinical and radiological outcomes of unilateral biportal endoscopic lumbar interbody fusion (ULIF) to those of conventional posterior lumbar interbody fusion (PLIF). Seventy-one ULIF (age, 68 ± 8 years) and 70 PLIF (66 ± 9 years) patients for one lumbosacral segment followed more than 1 year were selected. Parameters for surgical techniques (operation time, whether transfused), clinical results [visual analogue scale (VAS) for back and leg pain, Oswestry disability index (ODI)], surgical complications (dural tear, nerve root injury, infection), and radiological results (cage subsidence, screw loosening, fusion) between the two groups were compared. The PLIF group demonstrated a significantly shorter operation time and more transfusions done than the ULIF group. The VAS for leg pain in both groups and for back pain in the ULIF group significantly improved at 1 week, while the VAS for back pain in the PLIF group significantly improved at 1 year. ODI scores improved at 1 year in both groups. Complication rates were not significantly different between groups. Fusion rates with definite and probable grades were not significantly different between groups. However, the ULIF group had significantly (P = 0.013) fewer cases of definite fusion and more cases of probable fusion [43 (74.1%) and 15 (25.9%) cases, respectively] than the PLIF group [58 (92.1%) and 5 (7.9%) cases, respectively]. ULIF is less invasive while just as effective as conventional PLIF in improving clinical outcomes and obtaining fusion. However, ULIF has a longer operation time than PLIF and requires further development to improve the fusion grade.

Development and Validation of an Analytical Method for Carnosol, Carnosic Acid and Rosmarinic Acid in Food Matrices and Evaluation of the Antioxidant Activity of Rosemary Extract as a Food Additive.

Antioxidants are used to prevent the oxidation of foods. When used for food additive purposes, the dosage should be regulated and the functionality evaluated to ensure stability. In this study, we performed a method validation for the quantitative analysis of rosemary extract residues and evaluated the antioxidant activity of rosemary extract in food matrices. The validated method was able to determine rosemary extract under the optimized high-performance liquid chromatography-photodiode array (HPLC-PDA) conditions. Furthermore, the antioxidant activity was evaluated by peroxide value, acid value, and in terms of the residual antioxidant levels in lard oil. For HPLC-PDA analysis, the limit of detection and quantification of rosemary extracts was ranged from 0.22 to 1.73 µg/mL, 0.66 to 5.23 µg/mL and the recoveries of the rosemary extracts ranged from 70.6 to 114.0%, with relative standard deviations of between 0.2% and 3.8%. In terms of antioxidant activity, carnosic acid performed better than carnosol. Furthermore, by evaluation of the residual antioxidant level using HPLC, we found that carnosic acid is more stable in lard oil than carnosol. These results indicate that rosemary extract can be used as an antioxidant and that the analytical method is suitable for the determination of rosemary extract in various food samples.

Low morphometric complexity of emphysematous lesions predicts survival in chronic obstructive pulmonary disease patients.

OBJECTIVES: To investigate whether morphometric complexity in the lung can predict survival and act as a new prognostic marker in patients with chronic obstructive pulmonary disease (COPD). METHODS: COPD (n = 302) patients were retrospectively reviewed. All patients underwent volumetric computed tomography and pulmonary function tests at enrollment (2005-2015). For complexity analysis, we applied power law exponent of the emphysema size distribution (Dsize) as well as box-counting fractal dimension (Dbox3D) analysis. Patients' survival at February 2017 was ascertained. Univariate and multivariate Cox proportional hazards analyses were performed, and prediction performances of various combinatorial models were compared. RESULTS: Patients were 66 ± 6 years old, had 41 ± 28 pack-years' smoking history and variable GOLD stages (n = 20, 153, 108 and 21 in stages I-IV). The median follow-up time was 6.1 years (range: 0.2-11.6 years). Sixty-three patients (20.9%) died, of whom 35 died of lung-related causes. In univariate Cox analysis, lower Dsize and Dbox3D were significantly associated with both all-cause and lung-related mortality (both p < 0.001). In multivariate analysis, the backward elimination method demonstrated that Dbox3D, along with age and the BODE index, was an independent predictor of survival (p = 0.014; HR, 2.08; 95% CI, 1.16-3.71). The contributions of Dsize and Dbox3D to the combinatorial survival model were comparable with those of the emphysema index and lung-diffusing capacity. CONCLUSIONS: Low morphometric complexity in the lung is a predictor of survival in patients with COPD. KEY POINTS: • A newly suggested method for quantifying lung morphometric complexity is feasible. • Morphometric complexity measured on chest CT images predicts COPD patients' survival. • Complexity, diffusing capacity and emphysema index contribute similarly to the survival model.

Positive association between moderate altitude and chronic lower respiratory disease mortality in United States counties.

For patients with chronic lower respiratory disease, hypobaric hypoxia at a high altitude is considered a risk factor for mortality. However, the effects of residing at moderately high altitudes remain unclear. We investigated the association between moderate altitude and chronic lower respiratory disease mortality. In particular, we examined the lower 48 United States counties for age-adjusted chronic lower respiratory disease mortality rates, altitude, and socioeconomic factors, including tobacco use, per capita income, population density, sex ratio, unemployment, poverty, and education between 1979 and 1998. The socioeconomic factors were incorporated into the correlation analysis as potential covariates. Considerable positive (R = 0.235; P <0.001) and partial (R = 0.260; P <0.001) correlations were observed between altitude and chronic lower respiratory disease mortality rate. In the subgroup with high COPD prevalence subgroup, even stronger positive (R = 0.346; P <0.001) and partial (R = 0.423, P <0.001) correlations were observed. Multivariate regression analysis of all available socioeconomic factors revealed that additional knowledge on altitude improved the adjusted R2 values from 0.128 to 0.186 for all counties and from 0.301 to 0.421 for counties with high COPD prevalence. We concluded that in the lower 48 United States counties, even a moderate altitude may pose considerable risks in patients with chronic lower respiratory disease.

Changes in the Anti-Allergic Activities of Sesame by Bioconversion.

Sesame is an important oilseed crop, which has been used as a traditional health food to ameliorate the prevention of various diseases. We evaluated the changes in the anti-allergic activities of sesame by bioconversion. SDS-PAGE of non-fermented sesame proteins showed major allergen bands, while that of fermented sesame showed only a few protein bands. Additionally, we investigated the effectiveness of fermented sesame by bioconversion in tumor necrosis factor-α (TNF-α)- and interferon-γ (IFN-γ)-induced HaCaT cells. In HaCaT cells, fermented sesame inhibited the mRNA expression of interleukin-6 (IL-6) and interleukin-1ß (IL-1ß), thymus and macrophage-derived chemokine (MDC/CCL22), activation-regulated chemokine (TARC/CCL17), and intercellular adhesion molecule-1 (ICAM-1). Moreover, fermented sesame inhibited the activation of nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 1 (STAT1). Fermented sesame exerts anti-allergic effects by suppressing the expression of chemokines and cytokines via blockade of NF-κB and STAT1 activation.

Identifying method validation and measurement uncertainty of brominated vegetable oil in soft drinks and carbonated waters commonly consumed in South Korea.

This study investigated a method for validating and determining the measurement uncertainty for the composition of brominated vegetable oil (BVO) in soft drinks and carbonated waters commonly consumed in South Korea. First, we studied a simple and precise qualitative colorimetric method at the maximum residues level 15 ppm. And an analytical method using ion chromatography (IC) was validated and identified with brominated fatty acids by gas chromatography electron ionization mass spectrometry (GC/EI-MS). The measurement uncertainty was evaluated based on the precisional study and confirmed by the preliminary inter-laboratory study. For IC analysis, the recovery range of BVO was from 97.8% to 107.2% with relative standard deviations between 0.18% and 0.69%. In addition, the expanded uncertainty of the BVO was 1.59. These results indicate that the validated method is appropriate for identifying of BVO and can be used to verify the safety of soft drinks or carbonated waters containing BVO residues.