Transcription factor RORα enforces stability of the Th17 cell effector program by binding to a Rorc cis-regulatory element.

T helper 17 (Th17) cells regulate mucosal barrier defenses but also promote multiple autoinflammatory diseases. Although many molecular determinants of Th17 cell differentiation have been elucidated, the transcriptional programs that sustain Th17 cells in vivo remain obscure. The transcription factor RORγt is critical for Th17 cell differentiation; however, it is not clear whether the closely related RORα, which is co-expressed in Th17 cells, has a distinct role. Here, we demonstrated that although dispensable for Th17 cell differentiation, RORα was necessary for optimal Th17 responses in peripheral tissues. The absence of RORα in T cells led to reductions in both RORγt expression and effector function among Th17 cells. Cooperative binding of RORα and RORγt to a previously unidentified Rorc cis-regulatory element was essential for Th17 lineage maintenance in vivo. These data point to a non-redundant role of RORα in Th17 lineage maintenance via reinforcement of the RORγt transcriptional program.

Mitochondrial uncoupling proteins protect human airway epithelial ciliated cells from oxidative damage.

Apical cilia on epithelial cells defend the lung by propelling pathogens and particulates out of the respiratory airways. Ciliated cells produce ATP that powers cilia beating by densely grouping mitochondria just beneath the apical membrane. However, this efficient localization comes at a cost because electrons leaked during oxidative phosphorylation react with molecular oxygen to form superoxide, and thus, the cluster of mitochondria creates a hotspot for oxidant production. The relatively high oxygen concentration overlying airway epithelia further intensifies the risk of generating superoxide. Thus, airway ciliated cells face a unique challenge of producing harmful levels of oxidants. However, surprisingly, highly ciliated epithelia produce less reactive oxygen species (ROS) than epithelia with few ciliated cells. Compared to other airway cell types, ciliated cells express high levels of mitochondrial uncoupling proteins, UCP2 and UCP5. These proteins decrease mitochondrial protonmotive force and thereby reduce production of ROS. As a result, lipid peroxidation, a marker of oxidant injury, decreases. However, mitochondrial uncoupling proteins exact a price for decreasing oxidant production; they decrease the fraction of mitochondrial respiration that generates ATP. These findings indicate that ciliated cells sacrifice mitochondrial efficiency in exchange for safety from damaging oxidation. Employing uncoupling proteins to prevent oxidant production, instead of relying solely on antioxidants to decrease postproduction oxidant levels, may offer an advantage for targeting a local area of intense ROS generation.

Small-molecule ion channels increase host defences in cystic fibrosis airway epithelia.

Loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) compromise epithelial HCO3- and Cl- secretion, reduce airway surface liquid pH, and impair respiratory host defences in people with cystic fibrosis1-3. Here we report that apical addition of amphotericin B, a small molecule that forms unselective ion channels, restored HCO3- secretion and increased airway surface liquid pH in cultured airway epithelia from people with cystic fibrosis. These effects required the basolateral Na+, K+-ATPase, indicating that apical amphotericin B channels functionally interfaced with this driver of anion secretion. Amphotericin B also restored airway surface liquid pH, viscosity, and antibacterial activity in primary cultures of airway epithelia from people with cystic fibrosis caused by different mutations, including ones that do not yield CFTR, and increased airway surface liquid pH in CFTR-null pigs in vivo. Thus, unselective small-molecule ion channels can restore host defences in cystic fibrosis airway epithelia via a mechanism that is independent of CFTR and is therefore independent of genotype.

Check-all-that-apply (CATA)- and rate-all-that-apply (RATA)-based sensometric assessment of germinated-wheat beverages.

Sensometrics assesses sensory perspectives in consumer research using statistics and various methodologies. This study evaluated consumer responses to hot and cold germinated-wheat beverages in check-all-that-apply (CATA) and rate-all-that-apply (RATA) assessments using sensometric statistical approaches, including Cochran's Q test, penalty-lift analysis, and multiple factor analysis. Hot beverages (HB) were prepared by infusion using different amounts of germinated wheat (HB_1: 0.8 g/100 mL, HB_2: 2 g/100 mL, and HB_3: 4 g/100 mL), while cold beverages (CB) were made using cooled boiled germinated wheat with varying concentrations (CB_1: 25 g/L, CB_2: 50 g/L, and CB_3: 75 g/L). Results of the CATA study suggested that consumers preferred HB_1 and CB_1 because they expressed the sensory characteristics associated with liking, including "barley tea flavor", "neat taste", and "nutty taste", while "bitterish taste", "stuffy taste", and "astringent taste" were undesirable attributes. "Browning index", "barley tea odor", and "nutty taste" showed significant differences (p < 0.05) in both favorable and unfavorable rating scores. Overall, CB_1 elicited a clear taste and odor with fewer negative emotions. These findings demonstrate the usefulness of the sensometric approach combined with CATA and RATA analyses to obtain more easily interpretable results on the sensory perception of consumers to new food products. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-023-05884-z.

Intra-individual comparison of lumbar spine CT, abdomen-pelvis contrast enhanced CT, and low-dose chest CT for bone density measurement.

BACKGROUND: Dual-energy X-ray absorptiometry (DXA) is the reference standard for the measurement of bone mineral density (BMD) and subsequent diagnosis of osteoporosis. Since various computed tomography (CT) protocols are scanned for various indications, we can incidentally measure BMD using CT. Previous studies have revealed a correlation between BMD and Hounsfield unit (HU) values obtained with different CT protocols. PURPOSE: To compare the diagnostic value of CT protocols (lumbar spine CT [LSCT], abdomen-pelvis contrast-enhanced CT [APCT], and low-dose chest CT [LDCT]) for osteoporosis. MATERIAL AND METHODS: We retrospectively included 17 patients (6 men, 11 women; mean age=68 years) who had undergone all four imaging studies within six months, during 2011-2021. HU values were manually measured at the center of the L1 vertebra by a radiology resident. Pearson correlation test was performed between HU values and BMD of L1 vertebra. The diagnostic performance of each CT protocol was assessed with receiver operating characteristic (ROC) analysis. Intra-individual concordance of the four tests to diagnose osteoporosis was analyzed by tabulating. RESULTS: The mean HU values were 104.4 ± 47.2 HU with LSCT, 149.0 ± 56.9 HU with APCT, and 114.3 ± 60.0 HU with LDCT. HU values from each protocol were positively correlated (r = 0.676-0.735; P < 0.005) with BMD. LDCT had the highest diagnostic performance (area under the ROC curve [AUC] = 0.701) and APCT the lowest (AUC = 0.569). APCT was discordant with the other protocols for diagnosing osteoporosis. CONCLUSION: LDCT had the highest diagnostic performance for osteoporosis with predetermined cutoff value. APCT requires the increase of cutoff value for osteoporosis diagnosis.

Mycobacterium abscessus infection leads to enhanced production of type 1 interferon and NLRP3 inflammasome activation in murine macrophages via mitochondrial oxidative stress.

Mycobacterium abscessus (MAB) is a rapidly growing mycobacterium (RGM), and infections with this pathogen have been increasing worldwide. Recently, we reported that rough type (MAB-R) but not smooth type (MAB-S) strains enhanced type 1 interferon (IFN-I) secretion via bacterial phagosome escape, contributing to increased virulence. Here, we sought to investigate the role of mitochondrial oxidative stress in bacterial survival, IFN-I secretion and NLRP3 inflammasome activation in MAB-infected murine macrophages. We found that live but not heat-killed (HK) MAB-R strains increased mitochondrial ROS (mtROS) and increased release of oxidized mitochondrial DNA (mtDNA) into the cytosol of murine macrophages compared to the effects of live MAB-S strains, resulting in enhanced NLRP3 inflammasome-mediated IL-1ß and cGAS-STING-dependent IFN-I production. Treatment of the infected macrophages with mtROS-modulating agents such as mito-TEMPO or cyclosporin A reduced cytosolic oxidized mtDNA, which inhibited the MAB-R strain-induced production of IL-1ß and IFN-I. The reduced cytosolic oxidized mtDNA also inhibited intracellular growth of MAB-R strains via cytosolic escape following phagosomal rupture and via IFN-I-mediated cell-to-cell spreading. Moreover, our data showed that mtROS-dependent IFN-I production inhibited IL-1ß production, further contributing to MAB-R intracellular survival in murine macrophages. In conclusion, our data indicated that MAB-R strains enhanced IFN-I and IL-1ß production by inducing mtROS as a pathogen-associated molecular pattern (PAMP). These events also enhance bacterial survival in macrophages and dampen inflammation, which contribute to the pathogenesis of MAB-R strains.

Successful Management of Massive Congenital Hepatic Hemangioma and Systemic Hypertension With Sirolimus.

Congenital hepatic hemangioma (CHH) is a common benign vascular tumor of the liver, seen in infancy. The clinical manifestations vary from incidental findings to life-threatening complications. The authors present here a case of an infant with massive CHH who developed systemic hypertension because of compression of the right renal artery by the CHH and did not respond to other lines of treatment. After sirolimus therapy, the CHH size decreased and antihypertensive drugs were no longer necessary. In a critical situation, if the embolization and/or steroids do not seem to control the situation, then adding sirolimus may be considered as secondary therapy with good additive effects.

Effectiveness of epidural steroid injection in patients with lumbar herniated intervertebral disc under a "wait-and-see" policy.

BACKGROUND: There are no consensus and guidelines on the optimal interval of repeat epidural steroid injections (ESI) for patients with lumbar herniated intervertebral disc (HIVD) who respond to initial ESI. PURPOSE: To evaluate the effectiveness of ESI in patients with HIVD under a "wait-and-see" policy, i.e. as-needed injections not on a predetermined schedule. MATERIAL AND METHODS: A total of 592 patients with lumbar HIVD received spine injections between January and December 2017. After excluding patients with excellent (no pain) or poor (>70% residual symptoms) response in the two- or three-week pain assessment, the data of 141 responders were analyzed (60 men, 73 women; age = 50.55±17.25 years). We divided patients into wait-and-see (n=124) and early repeat-ESI (n=17) groups, who received repeat ESIs within three weeks. Evaluations of characteristics and outcomes were performed with the chi-square test or independent Student's t-test. RESULTS: Six patients (4.8%) in the wait-and-see group and 1 (5.9%) in the early repeat-ESI group underwent operation within one year (P=0.85). A mean of 1.52±0.82 ESIs was performed in the wait-and-see and a mean of 2.29±0.47 ESIs in the early repeat-ESI group over one year (P<0.001). The time interval between the first and second ESIs was longer in the wait-and-see group than in the early repeat-ESI group (97.15 vs. 15.47 days, P<0.001). Seventy-eight patients (62.9%) in the wait-and-see group could control their pain with a single ESI. CONCLUSION: A "wait-and-see" policy could be an effective pain management option for patients with lumbar HIVD who respond to initial ESI.

Morphological changes in the superficial medial collateral ligament on knee MR imaging: association with medial meniscal extrusion and posterior root medial meniscus abnormality.

OBJECTIVE: To assess the association between morphological changes in the superficial medial collateral ligament and meniscal extrusion with medial meniscus posterior root tear. MATERIALS AND METHODS: From January 1, 2018, to December 31, 2019, 124 patients who underwent knee MRI within 90 days prior to knee surgery and whose medial meniscus surgically proved intact, with posterior root tear or posterior horn tear, were enrolled. Two radiologists who were blinded to the surgical results assessed the morphological changes in the superficial medial collateral ligament, including thickness, bowing angle, and presence of signal intensity alteration, and medial meniscus extrusion, according to the presence of tears in the posterior root of the medial meniscus or posterior horn of the medial meniscus using the chi-square test, one-way ANOVA, and Cohen's kappa test. RESULTS: Thirty-six posterior root tears, 31 posterior horn tears, and 57 intact medial menisci were observed surgically. The mean values of thickness showed no significant differences among the three groups. The bowing angle was significantly higher in the posterior root tear than in the posterior horn tear (reader 1 = 0.001, reader 2 = 0.002) and normal meniscus groups (readers 1 and 2 < 0.001). The percentage of superficial medial collateral ligament signal intensity alteration and meniscal extrusion was highest in the group with posterior root of the medial meniscus tear (80.6% and 94.4%, respectively) and lowest in the group with normal medial meniscus (17.5% and 10.5%, respectively). CONCLUSION: Morphological changes in the superficial medial collateral ligament and meniscal extrusion were associated with medial meniscus posterior root tears.

Comparative Analysis of Coumarin Profiles in Different Parts of Peucedanum japonicum and Their Aldo-Keto Reductase Inhibitory Activities.

Peucedanum japonicum (Umbelliferae) is widely distributed throughout Southeast Asian countries. The root of this plant is used in traditional medicine to treat colds and pain, whereas the young leaves are considered an edible vegetable. In this study, the differences in coumarin profiles for different parts of P. japonicum including the flowers, roots, leaves, and stems were compared using ultra-performance liquid chromatography time-of-flight mass spectrometry. Twenty-eight compounds were tentatively identified, including three compounds found in the genus Peucedanum for the first time. Principal component analysis using the data set of the measured mass values and intensities of the compounds exhibited distinct clustering of the flower, leaf, stem, and root samples. In addition, their anticancer activities were screened using an Aldo-keto reductase (AKR)1C1 assay on A549 human non-small-cell lung cancer cells and the flower extract inhibited AKR1C1 activity. Based on these results, seven compounds were selected as potential markers to distinguish between the flower part versus the root, stem, and leaf parts using an orthogonal partial least-squares discriminant analysis. This study is the first to provide information on the comparison of coumarin profiles from different parts of P. japonicum as well as their AKR1C1 inhibitory activities. Taken together, the flowers of P. japonicum offer a new use related to the efficacy of overcoming anticancer drug resistance, and may be a promising source for the isolation of active lead compounds.

Evaluating subscapularis tendon tears on axillary lateral radiographs using deep learning.

OBJECTIVE: To develop a deep learning algorithm capable of evaluating subscapularis tendon (SSC) tears based on axillary lateral shoulder radiography. METHODS: A total of 2,779 axillary lateral shoulder radiographs (performed between February 2010 and December 2018) and the patients' corresponding clinical information (age, sex, dominant side, history of trauma, and degree of pain) were used to develop the deep learning algorithm. The radiographs were labeled based on arthroscopic findings, with the output being the probability of an SSC tear exceeding 50% of the tendon's thickness. The algorithm's performance was evaluated by determining the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, negative predictive value (NPV), and negative likelihood ratio (LR-) at a predefined high-sensitivity cutoff point. Two different test sets were used, with radiographs obtained between January and December 2019; Test Set 1 used arthroscopic findings as the reference standard (n = 340), whereas Test Set 2 used MRI findings as the reference standard (n = 627). RESULTS: The AUCs were 0.83 (95% confidence interval, 0.79-0.88) and 0.82 (95% confidence interval, 0.79-0.86) for Test Sets 1 and 2, respectively. At the high-sensitivity cutoff point, the sensitivity, NPV, and LR- were 91.4%, 90.4%, and 0.21 in Test Set 1, and 90.2%, 89.5%, and 0.21 in Test Set 2, respectively. Gradient-weighted Class Activation Mapping identified the subscapularis insertion site at the lesser tuberosity as the most sensitive region. CONCLUSION: Our deep learning algorithm is capable of assessing SSC tears based on changes at the lesser tuberosity on axillary lateral radiographs with moderate accuracy. KEY POINTS: • We have developed a deep learning algorithm capable of assessing SSC tears based on changes at the lesser tuberosity on axillary lateral radiographs and previous clinical data with moderate accuracy. • Our deep learning algorithm could be used as an objective method to initially assess SSC integrity and to identify those who would and would not benefit from further investigation or treatment.

MEF2D-BCL9 B-Lymphoblastic Leukemia Blast Morphology Does Not Always Mimic Mature B-Cell Leukemia.

MEF2D (myocyte enhancer factor 2D)-rearranged acute lymphoblastic leukemia (ALL) has recently been documented by transcriptome sequencing in B-cell precursor ALL. It is associated with older age of onset (median: 14 y), and characterized by very early relapse and poorer outcomes than other B-cell precursor ALL groups. According to report by Suzuki and colleagues, all 4 cases of MEF2D-BCL9-fusion ALL among 59 children with relapsed or primary refractory ALL had leukemic blasts morphologically mimicking mature B-cell leukemia cells. However, we display morphologically different blast populations in 2 patients with MEF2D-BCL9-rearranged ALL. Mature B-cell leukemia-like morphology would aid the detection of MEF2D-BCL9 fusion, but not all cases might have typical morphology.

Gene expression profiles of pro-inflammatory mediators in the conjunctiva of patients with epiblepharon.

PURPOSE: To investigate the gene expression of pro-inflammatory mediators in the conjunctiva of pediatric patients with epiblepharon in a case-control study. METHODS: Twenty healthy controls and 15 pediatric patients with epiblepharon were enrolled from April 23, 2020 to June 15, 2020. Epiblepharon severity was divided into class I-III (least to moderate severity) and class IV (most severe). We obtained impression cytologic specimens from the medial palpebral conjunctiva of the participants to measure the gene expression of interleukin (IL)-1ß, IL-6, matrix metalloproteinase 9 (MMP9), and mucin 5AC (MUC5AC) using quantitative reverse transcription polymerase chain reaction. RESULTS: The mean age in the epiblepharon group was 9 years (range 7.5-11 years), and that in the healthy control group was 9.5 years (range 8-11.3 years). IL-1ß, IL-6, and MMP9 expression levels were 2.08 (p < 0.05), 2.11 (p < 0.05), and 2.48 (p < 0.05) fold higher, respectively, in the epiblepharon group than in the healthy control group. However, MUC5AC gene expression was not different between healthy subjects and patients with epiblepharon. IL-1ß, IL-6, and MMP9 expression levels in class IV patients were 1.32 (p < 0.05), 1.77 (p < 0.05), and 1.98 (p < 0.05) fold higher, respectively, than in class I-III patients. CONCLUSION: Epiblepharon may induce chronic inflammatory changes in the conjunctiva in addition to corneal epithelial damage. Therefore, early corrective surgery should be considered to prevent conjunctival inflammation.

The application of bacteriophage to control Cronobacter sakazakii planktonic and biofilm growth in infant formula milk.

The goal was to identify the biofilm-forming ability of Cronobacter sakazakii on surfaces of stainless steel (SS) and silicone rubber (SR) in contact with infant formula milk. Two representative bacteriophages (PBES04 and PBES19) were used to control the growth of C. sakazakii as well as its biofilm forming ability on either SS or SR surfaces. Bacterial growth was confirmed at 20 °C when PBES04 and PBES19 were used, whereas C. sakazakii was not normally detected in infant formula milk treated with both bacteriophages for 6 h. In an additional biofilm reduction experiment, the biofilm on SS or SR surfaces were reduced by 3.07 and 1.92 log CFU cm-2, respectively after PBES04 treatment, and 3.06 and 2.14 log CFU cm-2, respectively, after PBES19 treatment. These results demonstrate that bacteriophages can be effective in inactivating C. sakazakii in biofilms which could potentially increase food safety in commercial facilities.

Fat-suppressed T2 mapping of human knee femoral articular cartilage: comparison with conventional T2 mapping.

BACKGROUND: There is paucity of studies applying fat suppressed (FS) technique to T2 mapping to overcome chemical shift artifacts. The purpose of the study is to difference between FS T2 and conventional T2 mapping and reproducibility of FS T2 mapping in the femoral articular cartilage. METHODS: Eighteen patients who had normal-looking femoral cartilage and underwent knee MRI with conventional T2 and FS T2 mapping were included. T2 values of each mapping were measured by two readers independently from nine regions in the medial femoral condyle (MFC) and lateral femoral condyle (LFC). Each anatomical region was divided by lines at ± 10°, 30°, 50°, 70°, 90°, and 110°. Comparisons of T2 values between conventional and FS T2 mapping were statistically analyzed. The T2 values between FS and conventional T2 mapping in the anterior, central and posterior femoral condyles were compared. RESULTS: The overall femoral condyle T2 values from the FS T2 map were significantly lower than those from the conventional T2 map (48.5ms vs. 51.0ms, p < 0.001). The differences in the T2 values between the two maps were significantly different among the three divisions of the LFC (p = 0.009) and MFC (p = 0.031). The intra-class correlation coefficients indicated higher agreement in the FS T2 map than in the conventional T2 map (0.943 vs. 0.872). CONCLUSIONS: The T2 values of knee femoral cartilage are significantly lower on FS T2 mapping than on conventional T2 mapping. FS T2 mapping is a more reproducible method for evaluating knee femoral cartilage.

18:0 Lyso PC Derived by Bioactivity-Based Molecular Networking from Lentil Mutant Lines and Its Effects on High-Fat Diet-Induced Obese Mice.

Lentil (Lens culinaris; Fabaceae), one of the major pulse crops in the world, is an important source of proteins, prebiotics, lipids, and essential minerals as well as functional components such as flavonoids, polyphenols, and phenolic acids. To improve crop nutritional and medicinal traits, hybridization and mutation are widely used in plant breeding research. In this study, mutant lentil populations were generated by γ-irradiation for the development of new cultivars by inducing genetic diversity. Molecular networking via Global Natural Product Social Molecular Networking web platform and dipeptidyl peptide-IV inhibitor screening assay were utilized as tools for structure-based discovery of active components in active mutant lines selected among the lentil population. The bioactivity-based molecular networking analysis resulted in the annotation of the molecular class of phosphatidylcholine (PC) from the most active mutant line. Among PCs, 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine (18:0 Lyso PC) was selected for further in vivo study of anti-obesity effect in a high-fat diet (HFD)-induced obese mouse model. The administration of 18:0 Lyso PC not only prevented body weight gain and decreased relative gonadal adipose tissue weight, but also attenuated the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, and leptin in the sera of HFD-induced obese mice. Additionally, 18:0 Lyso PC treatment inhibited the increase of adipocyte area and crown-like structures in adipose tissue. Therefore, these results suggest that 18:0 Lyso PC is a potential compound to have protective effects against obesity, improving obese phenotype induced by HFD.

Intra-articular facet joint steroid injection-related adverse events encountered during 11,980 procedures.

OBJECTIVES: To analyze the incidence and characteristics of intra-articular facet joint injection (FJI)-related adverse events requiring hospitalization and emergency room visits. METHODS: From January 2007 to December 2017, a total of 11,980 FJI procedures in 6066 patients (mean age 66.8 years, range 15-97 years, M:F = 2004:4062) were performed in our department. Of these, we retrospectively reviewed 489 cases in 432 patients who were hospitalized or visited the emergency room within a month of FJI. FJI-related adverse events were classified as procedure-related complications, drug-related systemic events, or uncertain etiology events, on the basis of consensus of two spine radiologists. This is a descriptive study without statistical analysis. RESULTS: There were 101 FJI-related adverse event cases in 99 patients (mean age 71.8 years, range 39-97 years, M:F = 39:60). The overall incidence of FJI-related adverse events was 0.84% (101/11,980) per case and 1.63% (99/6066) per patient. The incidence of procedure-related complications and drug-related systemic adverse events was 0.07% (8/11,980) and 0.15% (18/11,980), respectively; the rate of uncertain etiology events was 0.63% (75/11,980). All eight procedure-related complication cases involved major complications. There are seven cases of infectious spondylitis and one was progression of systemic aspergillosis to the spine. One patient died of an uncontrolled infection with infective endocarditis, and two patients experienced partial recovery with neurological sequelae. CONCLUSIONS: The overall incidence of FJI-related adverse events is low, and procedure-related major complications are rare without dural puncture or epidural hematoma. Nevertheless, infection can occur, resulting in serious outcomes. KEY POINTS: • The incidence of FJI-related adverse events requiring hospitalization or ER visit was 0.84%. • The incidence of major procedure-related complications was 0.07%. • All major complications were associated with infection and there were no cases of epidural hematoma.

Better Failure-Free Survival and Graft-versus-Host Disease-Free/Failure Free Survival with Fludarabine-Based Conditioning in Stem Cell Transplantation for Aplastic Anemia in Children.

BACKGROUND: This study aimed to assess the outcome of stem cell transplantation (SCT), including overall survival (OS), failure-free survival (FFS) and graft-versus-host disease (GvHD)-free/failure-free survival (GFFS), and to analyze prognostic factors in children with aplastic anemia (AA). METHODS: From 1991 to 2018, 43 allogeneic SCT recipients were enrolled in the study to investigate the demographic characteristics, survival outcomes and prognostic factors. RESULTS: With the median follow-up of 7.1 years, the estimated 10-year OS, FFS, GFFS were 86.0%, 60.5%, and 51.2%, respectively. Matched related donors (MRD, n = 28) showed better 10-year OS than unrelated donors (n = 15) (96.4% vs. 66.7%; P = 0.006). Engraftment failure was seen in 13 patients (30.2%). Donor-type aplasia was seen in 13.8% (4/29) after fludarabine (Flu)-based conditioning (Flu-group), while in 42.6% (6/14) after cyclophosphamide (Cy)-based regimen (Cy-group) (P = 0.035). Six patients died. The 10-year OS in Cy-group was 92.9% (n = 14, all MRD), while that of Flu-group was 82.1% (n = 29; P = 0.367). But Flu-group tended to have better FFS and GFFS than Cy-group, although Flu-group had less MRDs (41.4% vs. 100%; P = 0.019), and higher proportion of previous immunosuppressive treatment (IST; 62% vs. 21.4%, P = 0.012). In MRD transplants, OS was similar between Flu-group (100%, n = 14) and Cy-group (92.9%, n = 14), while FFS (100.0% vs. 42.9%; P = 0.001) and GFFS (85.7% vs. 35.7%; P = 0.006) were significantly better in Flu-group. Stem cell sources, irradiation in the conditioning, and method of GvHD prophylaxis did not significantly influence the outcome. CONCLUSION: This study reviewed SCT outcomes for pediatric AA with changes of transplant strategies over the last 25 years. The FFS and GFFS were higher in Flu-group than in Cy-group, especially in matched related transplantation. Graft failure including donor-type aplasia remains troublesome even with Flu-based conditioning. Further refinement of transplant strategies to ensure better quality-of-life should be pursued.

Constituents of Coreopsis lanceolata Flower and Their Dipeptidyl Peptidase IV Inhibitory Effects.

A new polyacetylene glycoside, (5R)-6E-tetradecene-8,10,12-triyne-1-ol-5-O-ß-glucoside (1), was isolated from the flower of Coreopsis lanceolata (Compositae), together with two known compounds, bidenoside C (10) and (3S,4S)-5E-trideca-1,5-dien-7,9,11-triyne-3,4-diol-4-O-ß-glucopyranoside (11), which were found in Coreopsis species for the first time. The other known compounds, lanceoletin (2), 3,2'-dihydroxy-4-3'-dimethoxychalcone-4'-glucoside (3), 4-methoxylanceoletin (4), lanceolin (5), leptosidin (6), (2R)-8-methoxybutin (7), luteolin (8) and quercetin (9), were isolated in this study and reported previously from this plant. The structure of 1 was elucidated by analyzing one-dimensional and two-dimensional nuclear magnetic resonance and high resolution-electrospray ionization-mass spectrometry data. All compounds were tested for their dipeptidyl peptidase IV (DPP-IV) inhibitory activity and compounds 2-4, 6 and 7 inhibited DPP-IV activity in a concentration-dependent manner, with IC50 values from 9.6 to 64.9 µM. These results suggest that C. lanceolata flower and its active constituents show potential as therapeutic agents for diseases associated with type 2 diabetes mellitus.

Codium fragile F2 sensitize colorectal cancer cells to TRAIL-induced apoptosis via c-FLIP ubiquitination.

This study demonstrates that combined treatment with subtoxic doses of Codium extracts (CE), a flavonoid found in many fruits and vegetables, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), induces apoptosis in TRAIL-resistant colorectal cancer (CRC) cells. Effective induction of apoptosis by combined treatment with CE and TRAIL was not blocked by Bcl-xL overexpression, which is known to confer resistance to various chemotherapeutic agents. While TRAIL-mediated proteolytic processing of procaspase-3 was partially blocked in various CRC cells treated with TRAIL alone, co-treatment with CE efficiently recovered TRAIL-induced caspase activation. We observed that CE treatment of CRC cells did not change the expression of anti-apoptotic proteins and pro-apoptotic proteins, including death receptors (DR4 and DR5). However, CE treatment markedly reduced the protein level of the short form of the cellular FLICE-inhibitory protein (c-FLIPS), an inhibitor of caspase-8, via proteasome-mediated degradation. Collectively, these observations show that CE recovers TRAIL sensitivity in various CRC cells via down-regulation of c-FLIPS.