The enamel knot (EK), located at the center of cap stage tooth germs, is a transitory cluster of nondividing epithelial cells. The EK acts as a signaling center that provides positional information ...for tooth morphogenesis and regulates the growth of tooth cusps. To identify species-specific cuspal patterns, this study analyzed the cellular mechanisms in the EK that were related to bone morphogenetic protein (Bmp), which plays a crucial role in cell proliferation and apoptosis. To understand the cellular mechanisms in the EK, the differences between 2 species showing different cuspal patterning, mouse (pointy bunodont cusp) and gerbil (flat lophodont cusp), were analyzed with quantitative reverse transcriptase polymerase chain reaction and immunofluorescent staining. Based on these, we performed protein-soaked bead implantation on tooth germs of the 2 different EK regions and compared the cellular behavior in the EKs of the 2 species. Many genes related with cell cycle, cell apoptosis, and cell proliferation were involved in BMP signaling in the EK during tooth development. A comparison of the cell proliferation and apoptosis associated with Bmp revealed distinctive patterns of the cellular mechanisms. Our findings indicate that the cellular mechanisms, such as cell proliferation and apoptosis, in the EK are related to Bmp4 and play an important role in tooth morphogenesis.
Although endoscopic submucosal dissection (ESD) is increasingly utilized to treat early neoplasms of the gastrointestinal tract, its use for duodenal neoplasms is limited by the thin wall and narrow ...lumen of the duodenum. We have reviewed cases where ESD was used to treat sessile, nonampullary duodenal neoplasms. To do this, we retrospectively reviewed the medical records of patients treated with ESD for adenomas of the duodenum from January 2001 to December 2010, assessing the curative outcomes and complication rates. A total of 14 cases were reviewed. Mean patient age was 56.4 years. The mean size of tumors and mean size of the specimens were 17.1 mm and 26.4 mm, respectively. The en bloc resection rate with ESD was 78.6%, and the complete (R0) resection rate was 85.7%. No patient in the study experienced major bleeding. However, second-look endoscopy revealed minor bleeding requiring endoscopic homeostasis in one case (7.1%). Perforations were observed in five cases (35.7%). Two of the five patients with perforation underwent surgery. The ESD methods yielded acceptable curative resection rates for duodenal adenomas, although ESD was associated with a higher rate of perforation. Therefore, duodenal ESD should be performed with care and only in selected patients to avoid serious complications.
Aging is a biological process characterized by time-dependent functional declines that are influenced by changes in redox status and by oxidative stress-induced inflammatory reactions. An organism’s ...pro-inflammatory status may underlie the aging process and age-related diseases. In this review, we explore the molecular basis of low-grade, unresolved, subclinical inflammation as a major risk factor for exacerbating the aging process and age-related diseases. We focus on the redox-sensitive transcription factors, NF-κB and FOXO, which play essential roles in the expression of pro-inflammatory mediators and anti-oxidant enzymes, respectively. Major players in molecular inflammation are discussed with respect to the age-related up-regulation of pro-inflammatory cytokines and adhesion molecules, cyclo-oxygenase-2, lipoxygenase, and inducible nitric oxide synthase. The molecular inflammation hypothesis proposed by our laboratory is briefly described to give further molecular insights into the intricate interplay among redox balance, pro-inflammatory gene activation, and chronic age-related inflammatory diseases. The final section discusses calorie restriction as an aging-retarding intervention that also exhibits extraordinarily effective anti-inflammatory activity by modulating GSH redox, NF-κB, SIRT1, PPARs, and FOXOs.
For wireless charging of electric vehicle (EV) batteries, high-frequency magnetic fields are generated from magnetically coupled coils. The large air-gap between two coils may cause high leakage of ...magnetic fields and it may also lower the power transfer efficiency (PTE). For the first time, in this paper, we propose a new set of coil design formulas for high-efficiency and low harmonic currents and a new design procedure for low leakage of magnetic fields for high-power wireless power transfer (WPT) system. Based on the proposed design procedure, a pair of magnetically coupled coils with magnetic field shielding for a 1-kW-class golf-cart WPT system is optimized via finite-element simulation and the proposed design formulas. We built a 1-kW-class wireless EV charging system for practical measurements of the PTE, the magnetic field strength around the golf cart, and voltage/current spectrums. The fabricated system has achieved a PTE of 96% at the operating frequency of 20.15 kHz with a 156-mm air gap between the coils. At the same time, the highest magnetic field strength measured around the golf cart is 19.8 mG, which is far below the relevant electromagnetic field safety guidelines (ICNIRP 1998/2010). In addition, the third harmonic component of the measured magnetic field is 39 dB lower than the fundamental component. These practical measurement results prove the effectiveness of the proposed coil design formulas and procedure of a WPT system for high-efficiency and low magnetic field leakage.
ABO incompatibility is no longer considered a contraindication for adult living donor liver transplantation (ALDLT) due to various strategies to overcome the ABO blood group barrier. We report the ...largest single‐center experience of ABO‐incompatible (ABOi) ALDLT in 235 adult patients. The desensitization protocol included a single dose of rituximab and total plasma exchange. In addition, local graft infusion therapy, cyclophosphamide, or splenectomy was used for a certain time period, but these treatments were eventually discontinued due to adverse events. There were three cases (1.3%) of in‐hospital mortality. The cumulative 3‐year graft and patient survival rates were 89.2% and 92.3%, respectively, and were comparable to those of the ABO‐compatible group (n = 1301). Despite promising survival outcomes, 17 patients (7.2%) experienced antibody‐mediated rejection that manifested as diffuse intrahepatic biliary stricture; six cases required retransplantation, and three patients died. ABOi ALDLT is a feasible method for expanding a living liver donor pool, but the efficacy of the desensitization protocol in targeting B cell immunity should be optimized.
This article presents the clinical results of ABO‐incompatible adult living donor liver transplantation in a single institution.
Immune checkpoint inhibitors (ICIs) have been shown to be beneficial for some patients with advanced non-small-cell lung cancer (NSCLC). However, the underlying mechanisms mediating the limited ...response to ICIs remain unclear.
We carried out whole-exome sequencing on 198 advanced NSCLC tumors that had been sampled before anti-programmed cell death 1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) therapy. Detailed clinical characteristics were collected on these patients. We designed a new method to estimate human leukocyte antigen (HLA)-corrected tumor mutation burden (TMB), a modification which considers the loss of heterozygosity of HLA from conventional TMB. We carried out external validation of our findings utilizing 89 NSCLC samples and 110 melanoma samples from two independent cohorts of immunotherapy-treated patients.
Homology-dependent recombination deficiency was identified in 37 patients (18.7%) and was associated with longer progression-free survival (PFS; P = 0.049). Using the HLA-corrected TMB, non-responders to ICIs were identified, despite having a high TMB (top 25%). Ten patients (21.3% of the high TMB group) were reclassified from the high TMB group into the low TMB group. The objective response rate (ORR), PFS, and overall survival (OS) were all lower in these patients compared with those of the high TMB group (ORR: 20% versus 59%, P = 0.0363; PFS: hazard ratio = 2.91, P = 0.007; OS: hazard ratio = 3.43, P = 0.004). Multivariate analyses showed that high HLA-corrected TMB was associated with a significant survival advantage (hazard ratio = 0.44, P = 0.015), whereas high conventional TMB was not associated with a survival advantage (hazard ratio = 0.63, P = 0.118). Applying this approach to the independent cohorts of 89 NSCLC patients and 110 melanoma patients, TMB-based survival prediction was significantly improved.
HLA-corrected TMB can reconcile the observed disparity in relationships between TMB and ICI responses, and is of predictive and prognostic value for ICI therapies.
•TMB alone is not sufficiently reliable or accurate as a biomarker of response to ICIs in NSCLC.•TMB-based survival prediction is improved by using the HLA-corrected TMB algorithm (TMB in combination with loss of heterozygosity of HLA).•Notably, additional predictive and prognostic value of the HLA-corrected TMB is not limited to certain types of cancer.•The HLA-corrected TMB could be a new strategy for selecting patients who may benefit from immunotherapy.
Abstract Background Adequate nutritional support for patients undergoing major surgery significantly affects postoperative recovery. Data on enteral feeding after liver transplantation (LT) are ...scarce. The aim of this work was to determine the efficacy and complications of feeding tubes inserted with the use of fluoroscopic assistance, endoscopic assistance, or transperitoneal jejunostomy in patients who underwent LT. Methods From January 2008 to August 2013, 2,058 LTs were performed at Asan Medical Center, Seoul, Korea. Enteral feeding tubes were inserted in 155 patients (7.5%) after LT: with the use of fluoroscopic placement in 81 (52%), endoscopic placement in 49 (32%), and transperitoneal jejunostomy in 25 (16%). We retrospectively analyzed the efficacy and complications of enteral feeding tubes. Results The median age was 55 years (interquartile range IQR 49–60). Enteral feeding indications were a high risk of gastric aspiration ( n = 90), gastric stasis ( n = 27), pneumonia ( n = 23), gastrointestinal bleeding ( n = 12), and bowel rest ( n = 3). Median enteral feeding durations were 14.5 days (IQR 8.0–30.7) for fluoroscopic placement, 20.0 days (IQR 8.0–40.0) for endoscopic placement, and 37.5 days (IQR 18.2–86.2) for transperitoneal jejunostomy. Times to establishment of oral feeding were 13.0 days (IQR 6.2–25.7) for fluoroscopic placement, 24.0 days (IQR 10.5–43.5) for endoscopic placement, and 37.0 days (IQR 17.0–64.2) for transperitoneal jejunostomy. After tube insertion, tube dislocation and blockage occurred in 34 patients (22%) and 16 patients (25%), respectively. Conclusions Enteral feeding tube insertion in patients who can not maintain a nasogastric tube or start oral intake for a long time is important for nutritional support after LT. Proper feeding method selection according to patient condition can help patients by improving nutritional support after major operations such as LT.
Aims
In the preliminary study, kimchi, a traditional food fermented with Chinese cabbage, protected scopolamine‐induced mouse memory deficit in passive avoidance test. Therefore, we screened ...protective ingredients, particularly lactic acid bacteria, from Chinese cabbage kimchi against scopolamine‐induced memory deficit in mice.
Methods and Results
Lactic acid bacteria, isolated from Chinese cabbage kimchi, were identified by 16S rDNA sequence analysis, G+C content and cellular fatty acid composition and sugar fermentation test. Memory deficit was induced in mice by intraperitoneally injecting with scopolamine.
Kimchi, particularly its supernatant, protected scopolamine‐induced memory deficit in mice in passive avoidance test. Of kimchi ingredients, a lactic acid bacterium, strain C29, potently protected scopolamine‐induced memory deficit in mice. C29 was a gram‐positive, catalase‐negative, anaerobic and non‐motile rod. Its pylogenetic property was near to Lactobacillus pentosus (99%) and Lact. plantarum (99%). However, C29 fermented inulin and L‐rhamnose and grew in pH 3 and at 45°C in contrast with Lact. pentosus and Lact. plantarum. Therefore, it named to be Lact pentosus var. plantarum C29. The strain C29 protected scopolamine‐induced memory deficit in Y‐maze and Morris water maze tests. Furthermore, C29 increased hippocampal BDNF and p‐CREB expressions, which were reduced by scopolamine.
Conclusion
Lactobacillus pentosus var. plantarum C29 may protect memory deficit by inducing BDNF and p‐CREB expressions.
Significance and Impact of the Study
Lactic acid bacteria, such as Lact pentosus var. plantarum C29, may prevent memory deficit and its contained fermented foods may be beneficial for dementia.
The large volume of adult living donor liver transplantations (ALDLTs) at our center affords a unique opportunity to examine the impact of acute‐on‐chronic liver failure (ACLF) among high–Model for ...End‐Stage Liver Disease MELD score patients. From February 1998 to March 2010, 1958 cirrhotic recipients were analyzed to study the relationship between MELD scores and ALDLT outcomes. A total of 327 high‐MELD score recipients were categorized into ACLF and non‐ACLF groups, and their outcomes were compared. The 5‐year graft and patient survival in the high‐MELD group were 75.2% and 76.4%, respectively, which were significantly worse than the low and intermediate MELD groups. The presence of ACLF associated with higher MELD scores appeared to be the dominant factor responsible for the inferior results of patients with MELD score of 30–34 points. The 5‐year graft survivals in the ACLF group was 70.5% and in the non‐ACLF group it was 81.0% (p = 0.035). Therefore, ALDLT should be performed as soon as possible in high‐MELD score patients prior to ACLF development. Moreover, ACLF patients should be separately categorized when analyzing the outcomes of ALDLT. ALDLT for ACLF patients should not be discouraged because favorable outcomes can be expected through timely ALDLT and comprehensive management.
While adult living donor liver transplantation should be performed as soon as possible before acute‐on‐chronic liver failure develops, it should not be discouraged for patients with acute‐on‐chronic liver failure since timely transplantation and comprehensive management can bring a favorable outcome.
The genetics behind the progression of myelodysplasia to secondary acute myeloid leukemia (sAML) is poorly understood. In this study, we profiled somatic mutations and their dynamics using next ...generation sequencing on serial samples from a total of 124 patients, consisting of a 31 patient discovery cohort and 93 patients from two validation cohorts. Whole-exome analysis on the discovery cohort revealed that 29 of 31 patients carry mutations related to at least one of eight commonly mutated pathways in AML. Mutations in genes related to DNA methylation and splicing machinery were found in T-cell samples, which expand at the initial diagnosis of the myelodysplasia, suggesting their importance as early disease events. On the other hand, somatic variants associated with signaling pathways arise or their allelic burdens expand significantly during progression. Our results indicate a strong association between mutations in activated signaling pathways and sAML progression. Overall, we demonstrate that distinct categories of genetic lesions play roles at different stages of sAML in a generally fixed order.
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