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Hyehyun Jeong,1,* Hyeon-Su Im,1,2,* Wanlim Kim,3 Jong-Seok Lee,3 Si Yeol Song,4 Joon Seon Song,5 Kyung-Ja Cho,5 Hye Won Chung,6 Min Hee Lee,6 Jeong Eun Kim,1,* Jin-Hee Ahn1,* 1Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 2Division of Hematology and Oncology, Ulsan University Hospital, Ulsan, Republic of Korea; 3Department of Orthopedic Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 4Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 5Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 6Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea*These authors contributed equally to this workCorrespondence: Jeong Eun Kim; Jin-Hee AhnDepartment of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, Republic of KoreaTel +82-2-3010-3945; +82-2-3010-3222Fax +82-2-3010-6961Email jeongeunkim@amc.seoul.kr; drjiny@amc.seoul.krPurpose: Because of the heterogeneity of sarcomas, establishing a well-collected, sarcoma-specific database is important for sarcoma research. We analyzed the first histology-based, sarcoma-specific institutional registry in Korea, which collected 28 years of patient data according to a predefined data format.Patients and Methods: Adult bone and soft tissue sarcoma patients who were treated from June 1989 to January 2017 were identified and analyzed, based on the ICD-O-3 codes.Results: Among the 3420 patients included, soft tissue and bone sarcomas comprised 77.8% (n = 2661) and 22.2% (n = 759), respectively. Median age at diagnosis was 50 (range, 16– 98) in soft tissue sarcomas and 37 (range, 16– 85) in bone sarcomas. Males and females comprised 45.5% and 54.5% of soft tissue sarcomas and 52.7% and 47.3% of bone sarcomas, respectively. Among the 3407 patients with treatment data available, 90.5% of the patients with soft tissue sarcomas and 80.8% of the patients with bone sarcomas received surgery first, of which 57.8% and 71.7% did not receive any subsequent treatment, respectively. Overall, the proportion of patients who received surgery alone decreased from 85.7% to 60.5% from the pre-2000 period to the 2010– 2017 period. However, the use of adjuvant chemotherapy increased in patients with soft tissue sarcomas (from 8.0% to 17.2% in the same period), and the use of perioperative radiotherapy also increased in both groups (from 1.4% to 22.7% in soft tissue sarcomas, and 0% to 14.5% in bone sarcomas in the same period). In both soft tissue and bone sarcomas, old age (≥ 65 years) and diagnosis in the early study period were associated with poorer survival.Conclusion: We presented a comprehensive summary of our sarcoma registry, including the demographics, changes in treatment patterns, and survival outcomes. This study will provide a framework for future studies.Keywords: bone sarcoma, soft tissue sarcoma, sarcoma-specific registry, real-world evidence

Mei Yuan,1,2,* Xiao-Wen Meng,1,* Jiao Ma,1,* Hong Liu,3 Shao-Yong Song,1 Qing-Cai Chen,1 Hua-Yue Liu,1 Juan Zhang,1 Nan Song,1 Fu-Hai Ji,1 Ke Peng11Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, People’s Republic of China; 2Department of Anesthesiology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215008, People’s Republic of China; 3Department of Anesthesiology and Pain Medicine, University of California Davis Health System, Sacramento, CA 95817, USACorrespondence: Fu-Hai Ji; Ke PengDepartment of Anesthesiology, First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, People’s Republic of ChinaTel +86 5 126 778 0055; +86 5 126 778 0159Email jifuhaisuda@163.com; pengke0422@163.com*These authors contributed equally to this workPurpose: Intracellular calcium ([Ca2+,]i) overload is a major cause of cell injury during myocardial ischemia/reperfusion (I/R). Dexmedetomidine (DEX) has been shown to exert anti-inflammatory and organ protective effects. This study aimed to investigate whether pretreatment with DEX could protect H9c2 cardiomyocytes against oxygen-glucose deprivation/reoxygenation (OGD/R) injury through regulating the Ca2+, signaling.Methods: H9c2 cardiomyocytes were subjected to OGD for 12 h, followed by 3 h of reoxygenation. DEX was administered 1 h prior to OGD/R. Cell viability, lactate dehydrogenase (LDH) release, level of [Ca2+,]i, cell apoptosis, and the expression of 12.6-kd FK506-binding protein/ryanodine receptor 2 (FKBP12.6/RyR2) and caspase-3 were assessed.Results: Cells exposed to OGD/R had decreased cell viability, increased LDH release, elevated [Ca2+,]i level and apoptosis rate, down-regulated expression of FKBP12.6, and up-regulated expression of phosphorylated-Ser2814-RyR2 and cleaved caspase-3. Pretreatment with DEX significantly blocked the above-mentioned changes, alleviating the OGD/R-induced injury in H9c2 cells. Moreover, knockdown of FKBP12.6 by small interfering RNA abolished the protective effects of DEX.Conclusion: This study indicates that DEX pretreatment protects the cardiomyocytes against OGD/R-induced injury by inhibiting [Ca2+,]i overload and cell apoptosis via regulating the FKBP12.6/RyR2 signaling. DEX may be used for preventing cardiac I/R injury in the clinical settings.Keywords: dexmedetomidine, H9c2 cardiomyocytes, oxygen-glucose deprivation/reoxygenation, apoptosis, intracellular calcium overload, FKBP12.6/RyR2

Jinhyang Choi,1,2 Eunjung Ko,1 Hye-Kyung Chung,3 Jae Hee Lee,1 Eun Jin Ju,1 Hyun Kyung Lim,4 Intae Park,1 Kab-Sig Kim,5 Joo-Hwan Lee,5 Woo-Chan Son,6 Jung Shin Lee,1,7 Joohee Jung,1,4 Seong-Yun Jeong,1,2 Si Yeol Song,1,8 Eun Kyung Choi1,3,8 1Institute for Innovative Cancer Research, 2Asan Institute for Life Sciences, 3Center for Development and Commercialization of Anti-cancer Therapeutics, 4College of Pharmacy, Duksung Women’s University, 5Bio-Synectics, 6Department of Pathology, 7Department of Internal Medicine, 8Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea Abstract: Nanoparticulation of insoluble drugs improves dissolution rate, resulting in increased bioavailability that leads to increased stability, better efficacy, and reduced toxicity of drugs. Docetaxel (DTX), under the trade name Taxotere™, is one of the representative anticancer chemotherapeutic agents of this era. However, this highly lipophilic and insoluble drug has many adverse effects. Our novel and widely applicable nanoparticulation using fat and supercritical fluid (NUFS™) technology enabled successful nanoscale particulation of DTX (Nufs-DTX). Nufs-DTX showed enhanced dissolution rate and increased aqueous stability in water. After confirming the preserved mechanism of action of DTX, which targets microtubules, we showed that Nufs-DTX exhibited similar effects in proliferation and clonogenic assays using A549 cells. Interestingly, we observed that Nufs-DTX had a greater in vivo tumor growth delay effect on an A549 xenograft model than Taxotere™, which was in agreement with the improved drug accumulation in tumors according to the biodistribution result, and was caused by the enhanced permeability and retention (EPR) effect. Although both Nufs-DTX and Taxotere™ showed negative results for our administration dose in the hematologic toxicity test, Nufs-DTX showed much less toxicity than Taxotere™ in edema, paralysis, and paw-withdrawal latency on a hot plate analysis that are regarded as indicators of fluid retention, peripheral neuropathy, and thermal threshold, respectively, for toxicological tests. In summary, compared with Taxotere™, Nufs-DTX, which was generated by our new platform technology using lipid, supercritical fluid, and carbon dioxide (CO2), maintained its biochemical properties as a cytotoxic agent and had better tumor targeting ability, better in vivo therapeutic effect, and less toxicity, thereby overcoming the current hurdles of traditional drugs. Keywords: Nufs-DTX, docetaxel, anticancer efficacy, toxicity

Ha Na Woo1*, Hye Kyung Chung2*, Eun Jin Ju1, Joohee Jung1,3, Hye-Won Kang4, Sa-Won Lee4, Min-Hyo Seo4, Jin Seong Lee5, Jung Shin Lee1,6, Heon Joo Park7, Si Yeol Song1,8, Seong-Yun Jeong1, Eun Kyung Choi1,2,81Institute for Innovative Cancer Research, 2Center for Development and Commercialization of Anti-cancer Therapeutics, Asan Medical Center, Seoul, 3College of Pharmacy, Duksung Women's University, Seoul, 4Department of Parenteral Delivery Program, Samyang Pharmaceuticals R&D, Daejeon, 5Department of Radiology and Research Institute of Radiology, 6Department of Internal Medicine, Asan Medical Center, Seoul, 7Department of Microbiology, College of Medicine, Inha University, Inchon, 8Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea*These authors contributed equally to this studyAbstract: Nanoparticles are useful delivery vehicles for promising drug candidates that face obstacles for clinical applicability. Sirolimus, an inhibitor of mammalian target of rapamycin has gained attention for targeted anticancer therapy, but its clinical application has been limited by its poor solubility. This study was designed to enhance the feasibility of sirolimus for human cancer treatment. Polymeric nanoparticle (PNP)–sirolimus was developed as an injectable formulation and has been characterized by transmission electron microscopy and dynamic light scattering. Pharmacokinetic analysis revealed that PNP–sirolimus has prolonged circulation in the blood. In addition, PNP–sirolimus preserved the in vitro killing effect of free sirolimus against cancer cells, and intravenous administration displayed its potent in vivo anticancer efficacy in xenograft tumor mice. In addition, PNP–sirolimus enhanced the radiotherapeutic efficacy of sirolimus both in vitro and in vivo. Clinical application of PNP–sirolimus is a promising strategy for human cancer treatment.Keywords: sirolimus, polymeric nanoparticle, anticancer, radiotherapy

Background: Intra-articular distal radial fractures are frequently accompanied by a scapholunate interosseous ligament injury, which may adversely affect the outcomes. Arthroscopy may not be appropriate as a first-line evaluation method to diagnose these injuries because of time, expense, and availability issues. The purpose of this study was to evaluate the effectiveness of the modified carpal stretch test for screening for scapholunate interosseous ligament injuries in patients with an intra-articular distal radial fracture.Methods: The carpal stretch test is a radiographic evaluation in which disruption of the smooth arc of the proximal carpal row joint line indicates a lack of integrity of the scapholunate interosseous ligament. We modified the original carpal stretch test and prospectively performed the modified test on forty-eight patients with a total of forty-nine unstable intra-articular distal radial fractures. With the patient under anesthesia, the injured wrist was evaluated with the modified carpal stretch test with fluoroscopy. The wrist was then examined arthroscopically to classify the scapholunate interosseous ligament injury. Three observers independently determined whether there was disruption of the proximal carpal row joint line (Gilula's arc II), used as an indicator of a grade-III or IV scapholunate interosseous ligament tear, on fluoroscopic images. The fluoroscopic results were compared with the arthroscopic findings.Results: The average sensitivity of the modified carpal stretch test was 78%, the average specificity was 72%, the average positive predictive value was 60%, the average negative predictive value was 87%, and the average accuracy was 74%. The intraclass correlation coefficient (ICC) for interobserver agreement was 0.73, and the ICCs for intraobserver agreement were 0.86, 0.68, and 0.84 for the three observers.Conclusions: The modified carpal stretch test was useful to rule out grade-III or IV scapholunate interosseous ligament tears associated with intra-articular distal radial fractures, but it was not as useful to confirm the presence of a tear. This test may reduce the necessity for arthroscopic assessment to identify scapholunate interosseous ligament injuries following distal radial fractures and may improve the rates of detection of important carpal ligament injuries accompanying intra-articular distal radial fractures. [ABSTRACT FROM AUTHOR]

Background: Capsule endoscopy that could actively move and approach a specific site might be more valuable for the diagnosis or treatment of GI diseases. Objective: We tested the performance of active locomotion of a novel wired capsule endoscope with a paddling-based locomotion mechanism, using 3 models: a silicone tube, an extracted porcine colon, and a living pig. Design: In vitro, ex vivo, and in vivo experiments in a pig model. Setting: Study in an animal laboratory. Interventions: For the in vitro test, the locomotive capsule was controlled to actively move from one side of a silicone tube to the other by a controller-operated automatic traveling program. The velocity was calculated by following a video recording. We performed ex vivo tests by using an extracted porcine colon in the same manner we performed the in vitro test. In in vivo experiments, the capsule was inserted into the rectum of a living pig under anesthesia, and was controlled to move automatically forward. After 8 consecutive trials, the velocity was calculated. Main Outcome Measurements: Elapsed time, velocity, and mucosal damage. Results: The locomotive capsule showed stable and active movement inside the lumen both in vitro and ex vivo. The velocity was 60 cm/min in the silicone tube, and 36.8 and 37.5 cm/min in the extracted porcine colon. In the in vivo experiments, the capsule stably moved forward inside the colon of a living pig without any serious complications. The mean velocity was 17 cm/min over 40 cm length. We noted pinpoint erythematous mucosal injuries in the colon. Limitation: Porcine model experiments, wired capsule endoscope. Conclusions: The novel paddling-based locomotive capsule endoscope performed fast and stable movement in a living pig colon with consistent velocity. Further investigation is necessary for practical use in humans. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: Leptin is a pleiotropic hormone that regulates food intake and metabolic and endocrine functions. Serum leptin levels have been reported to be increased in patients with allergic rhinitis and nasal polyposis; however, the explanation for this is unclear. We aimed to demonstrate the differential expression of leptin receptors in normal human nasal mucosa and nasal polyps, and to elucidate the effects of leptin on mucin gene expression in human nasal polyp epithelial cells.Study Design: Case-control and in vitro study.Methods: Normal ethmoid sinus mucosa was obtained from 10 subjects and used as a control; nasal polyps were obtained from 10 patients. Leptin receptor expression was analyzed using reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis. Leptin-induced expression of major respiratory mucins (MUC5AC and MUC5B) in the human nasal polyp epithelial cells was determined using RT-PCR and enzyme-linked immunosorbent assay.Results: The leptin receptor expression was stronger in the nasal polyps than in the normal nasal mucosa. In human nasal polyp epithelial cells, leptin increased the expression of MUC5AC and MUC5B, in a dose- and time-dependent manner, at the gene and protein levels. Leptin-induced mucin expression was inhibited by the leptin receptor antagonist.Conclusions: The increased expression of leptin receptors in nasal polyps implies leptin has a certain role in nasal polyposis. In addition, leptin appears to induce the expression of MUC5AC and MUC5B through leptin receptors in the human nasal polyp epithelial cells. [ABSTRACT FROM AUTHOR]

BACKGROUND: We developed a capsule endoscope (CE), 'MiRo,' with the novel transmission technology of electric-field propagation. The technology uses the human body as a conductive medium for data transmission. Specifications of the prototype include the ability to receive real-time images; size, 10.8 x 24 mm; weight, 3.3 g; field of view, 150 degrees; resolution of power, 320 x 320 pixels; and transmittal speed, 2 frames per second. OBJECTIVE: To evaluate the clinical safety and diagnostic feasibility of the prototype MiRo, we conducted a multicenter clinical trial. DESIGN AND PATIENTS: All volunteers underwent baseline examinations, including EGD and electrocardiography for the screening of GI obstructive and cardiovascular diseases, before the trial. In the first 10 cases, 24-hour Holter monitoring was also performed. To evaluate the diagnostic feasibility, transmission rate of the captured images, inspection rate of the entire small bowel, and quality of transmitted images (graded as outstanding, excellent, good/average, below average, and poor) were analyzed. RESULTS: Of the 49 healthy volunteers, 45 were included in the trial, and 4 were excluded because of baseline abnormalities. No adverse effects were noted. All CEs were expelled within 2 days, and the entire small bowel could be explored in all cases. The transmission rates of the captured image in the stomach, small bowel, and colon were 99.5%, 99.6%, and 97.2%, respectively. The mean total duration of image transmission was 9 hours, 51 minutes, and the mean transit time of the entire small bowel was 4 hours, 33 minutes. Image quality was graded as good or better in 41 cases (91.1%). Details of the villi and vascular structures of the entire small bowel were clearly visualized in 31 cases (68.9%). CONCLUSIONS: MiRo is safe and effective for exploring the entire small bowel, with good image quality and real-time feasibility. This novel transmission technology may have applications beyond the field of capsule endoscopy. [ABSTRACT FROM AUTHOR]

The purpose of this article is to advance the field of children exposed to violence by proposing an agenda for evidence-based school bullying prevention and intervention research and practice. It is argued that school bullying is a complex ecological problem that requires an innovative model to address it effectively. By critically reviewing the research literature, the real bullying problem is explained, a protective peer ecology framework of bullying prevention and intervention is presented. and an evidence-based practice model of bullying intervention is detailed. [ABSTRACT FROM AUTHOR]

This study was designed to determine the accuracy and agreement of a self-collection method using pad for human papillomavirus (HPV) DNA. One hundred and thirty-four patients at university hospitals voluntarily participated in the accuracy study, and 314 volunteers participated in the agreement study at local clinics. DNA was extracted and amplified using HPV L1 consensus primers designed for the direct sequencing. In the accuracy study, all samples were probed via histological examinations. With regard to the detection of squamous intraepithelial lesion (SIL), self-collection pad sampling displays sensitivity, of 76.9%, and specificity, of 93.3%. Three hundred and fourteen self-collection pad samples and the concurrent physicians' samples showed a 97.8% agreement, with a Kappa value of 0.9200. A new self-collection pad for the detection of HPV DNA appears to constitute an easy, rapid, and convenient alternative method for the cervical cancer screening of many women with the virtue of being incredibly readily accessible. [ABSTRACT FROM AUTHOR]

Vertically well-aligned ZnO nanorods were synthesized without employing any metal catalysts onvarious substrates including glass, Si(111), 6H-SiC(0001) and sapphire (0001), which were pre-coatedwith c-oriented ZnO buffer layers, by simple physical vapour deposition. The alignments ofthe ZnO nanorods on the different substrates depend on the crystallographicalignments of the pre-coated ZnO buffer layers. The ZnO nanorods grown on glass andSi(111) are vertically aligned but randomly oriented in the in-plane direction. Incontrast, the vertically aligned ZnO nanorods on 6H-SiC(0001) and sapphire(0001) show an in-plane alignment with azimuthally sixfold symmetry, whichindicates the epitaxial relationship between ZnO and the substrate. Similarly,photoluminescence measurements show the distinct appearance of ZnO nanorods ondifferent substrates. Besides the UV band, which was attributed to the recombination offree excitons near the band edge, defect-related visible emissions were also observedfor the samples grown on both glass and Si(111) substrates. However, the ZnOnanorods exhibit only strong band edge emission peaks with no noticeable deep levelemissions when grown on the 6H-SiC(0001) and sapphire (0001) substrates, whichconfirms the good crystalline and optical quality of the epitaxial ZnO nanorods. [ABSTRACT FROM AUTHOR]

BACKGROUND: Polymorphisms in the gene for interleukin 1beta (IL-1B) have been found to increase the risks of gastric cancer and its precursors in response to Helicobacter pylori infection in white populations. however, there has been no independent confirmation of the role of IL-1B markers in gastric cancer patients from Asian populations. Moreover, there have been conflicting data regarding the effect of IL-1B-511/-31 on the risk of gastric cancer or its precursors in Asian populations. Therefore, we assessed an additional polymorphism in the promoter region of IL-1B at position-1473 with the IL-1B-511/-31 polymorphisms in a Korean population. METHODS: In a case-control study, including 331 gastric cancer cases and 433 controls, we assessed the association between the three polymorphisms and the risk of gastric cancer. All genotyping was performed in duplicate. To assess the DNA-binding activity of IL-1B-1473 in vitro, we performed an electrophoretic mobility shift assay (EMSA). RESULTS: When cases were divided according to the histologic type of the tumor, a significant difference in genotype frequencies for IL-1B-1473 was observed only between intestinal-type cases and controls (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.0-3.5 and OR 2.1 and 95% CI, 1.1-4.2 in the CG and GG genotypes, respectively). In the cases, there was a deviation from Hardy-Weinberg equilibrium in the IL-1B-511/-31 loci confined to the intestinal type, due to the excess of heterozygotes. The IL-1B-1473G allele showed decreased binding to nuclear extract, indicating a wearker promoter activity on EMSA. CONCLUSIONS: We identified a novel single-nucleotide polymorphism, 1473C-->G, in the IL-1B promoter that was significantly associated with gastric cancer among Koreans. Our results also suggest that the association between IL-1B polymorphism and an increased risk of gastric cancer may depend on the histologic type of gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Among treatment modalities for unresectable hepatocellular carcinoma (HCC), radiofrequency ablation (RFA) is getting popular due to low morbidity and its effectiveness. However, when the tumor is located just under the diaphragm, a percutaneous approach for RFA is often impossible because of the difficulty in visualizing the tumor with conventional ultrasonographic examination.Method: Simultaneous thoraco-laparoscopic transthoracic transdiaphragmatic intraoperative RFA was performed on a 55 year-old male with HCC just beneath the diaphragm as well as laparoscopic RFA for dysplastic nodule near the gallbladder. Most of all, the patient wanted to undergo liver transplantation for the HCC and underlying liver cirrhosis. Therefore we chose to provide this procedure as a bridge to the liver transplantation. A total of four trocars (12 mm, 10 mm, 5 mm trocars for laparoscopy, and one 5 mm trocar for thoracoscopy), a 10 mm flexible laparoscope, a 5 mm thoracoscpe, and a laparoscopic ultrasound were used for this surgical procedure. After finishing laparoscopic RFA for dysplastic nodule near the gallbladder, the patient was placed into the left lateral decubitus for dual-scope guided transthoracic transdiaphragmatic intraoperative RFA. Complete separation of the diaphragm from the hepatic dome and good visualization of the subdiaphragmatic vessels provided a safe procedure without any injury to the diaphragm and other vessels.Results: The operative time was 240 minutes and the blood loss was zero. The postoperative course was uneventful. The diet was started on the operative day. A chest tube and an abdominal drain was removed on first day after surgery. The patient discharged on the second day after surgery. The patient has been followed up for three months after the dual-scope guided intraoperative RFA without any evidence of tumor recurrence. He is now actively being evaluated for liver transplantation.Conclusion: Dual-scope guided (simultaneous thoraco-laparoscopic) transthoracic transdiaphragmatic intraoperative RFA is an easy, safe, and effective minimal invasive modality for treatment of the selective patient with HCC, with liver cirrhosis, which is located immediately under the diaphragm. Further experiences and a long term follow up is mandatory. [ABSTRACT FROM AUTHOR]

The prediction of response to treatment would be valuable for managing cervical carcinoma with neoadjuvant chemotherapy.~Background~Background~To this end, the expression of VEGF was analyzed by immunohistochemistry using paraffin-embedded pre-treatment cervical biopsy tissues. This study included 29 patients with bulky IB to IIA cervical squamous cell carcinoma treated with neoadjuvant chemotherapy.~Methods~Methods~Fifteen (51.7%) of 29 patients were scored as VEGF-positive. Response to chemotherapy (complete response or residual tumor with less than 3 mm stromal invasion) was observed in eight patients (27.6%), and it was negatively associated with VEGF expression (P = 0.009). With logistic regression analysis, VEGF positivity continued to be an independent predictor for poor response (P = 0.032). In addition, the progression-free survival rate was significantly lower in patients with VEGF-positive tumors (P = 0.033).~Results~Results~Pretreatment assessment of VEGF expression may provide additional information for identification of patients with cervical cancer who had a low likelihood of response to neoadjuvant chemotherapy and an unfavorable prognosis.~Conclusion~Conclusions [ABSTRACT FROM AUTHOR]

Follicular helper T (Tfh) cells promote B cell differentiation and antibody production in the B cell follicles of secondary lymphoid organs. Tfh cells express their signature transcription factor BCL6, interleukin (IL)-21, and surface molecules including inducible T cell costimulator (ICOS), programmed cell death-1 (PD-1), and C-X-C motif chemokine receptor 5 (CXCR5). Migration of Tfh cells to B cell follicles largely depends on the CXCR5 expression induced by interactions with antigen-presenting dendritic cells in the T cell area. How Tfh cells acquire sufficient levels of CXCR5 expression, however, has remained unclear. Using our in vitro culture system to generate CXCR5low Tfh-like cells from naive CD4+ T cells with IL-6 in the absence of other cell types, we found that the active form of vitamin D, calcitriol, markedly enhanced CXCR5 expression after the release from persistent T cell receptor (TCR) stimulation. CH-223191, an aryl hydrocarbon receptor antagonist, further enhanced CXCR5 expression. IL-12 but not IL-4, in place of IL-6, also supported calcitriol to enhance CXCR5 expression even before the release from TCR stimulation, whereas the cell viability sharply decreased after the release. The Tfh-like cells generated with IL-6 and calcitriol exhibited chemotaxis toward C-X-C motif chemokine ligand 13 (CXCL13), expressed IL-21, and helped B cells to produce IgG antibodies in vitro more efficiently than Tfh-like cells generated without added calcitriol. Calcitriol injections into antigen-primed mice increased the proportion of CXCR5+PD-1+CD4+ cells in their lymphoid organs, and enhanced T cell entry into B cell follicles. These results suggest that calcitriol promotes CXCR5 expression in developing Tfh cells and regulates their functional differentiation., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Society for Immunology.)

Phosphorescence in carbon dots (CDs) from triplet exciton radiative recombination at room temperature has achieved significant advancement. Confinement and nanoconfinement, serving as valuable techniques, are commonly utilized to brighten triplet exciton in CDs, thereby enhancing their phosphorescence. However, a comprehensive and universally applicable physical description of confinement-enhanced phosphorescence is still lacking, despite efforts to understand its underlying nature. In this study, the dominance of entropy is revealed in triplet exciton emission from CDs through the establishment of a microscopic vibration state model. CDs with varying entropy levels are studied, indicating that in a low entropy system, the multi-energy triplet exciton emission in CDs exhibits enhanced brightness, accompanied by a corresponding increase in their lifetimes. The product of lifetime and intensity in CDs serves as a descriptor for their phosphorescence properties. Moreover, an entropy-dependent information variation system based on the CDs is demonstrated. Specifically, in a low-entropy system, information is retained, whereas the corresponding information is erased in a high-entropy system. This work elucidates the underlying physical nature of confinement-enhanced triplet exciton emission, offering a deeper understanding of achieving ultralong phosphorescence in the future., (© 2024 Wiley‐VCH GmbH.)

Purpose: This study aimed to evaluate the efficacy of local ablative therapy (LAT) combined with pembrolizumab in patients with synchronous oligometastatic non-small cell lung cancer (NSCLC) and to identify patients who would most benefit from LAT., Methods and Materials: We retrospectively identified patients who received diagnosis of synchronous oligometastatic NSCLC (≤5 metastatic lesions and ≤3 organs involved) and were treated with first-line pembrolizumab between January 2017 and December 2022. Patients who underwent LAT, including surgery or radiation therapy at all disease sites, were compared with those who did not undergo LAT. A recursive partitioning analysis (RPA) model was developed using prognostic factors for progression-free survival (PFS)., Results: Among the 258 patients included, 78 received LAT with pembrolizumab, and 180 received pembrolizumab alone. The median follow-up duration was 15.5 months (range, 3.0-71.2 months). In the entire cohort, LAT was independently associated with significantly improved PFS (hazard ratio [HR], 0.64; P = .015) and overall survival (OS) (HR, 0.61; P = .020). In the propensity score-matched cohort (N = 74 in each group), the median PFS was 19.9 months and 9.6 months, respectively (P = .003), and the median OS was 42.2 months and 20.5 months, respectively (P = .045), for the LAT and non-LAT groups. Based on the RPA model, incorporating the number of metastatic lesions, performance status, and programmed cell death-ligand 1 expression level, patients were stratified into 3 risk groups with distinct PFS. LAT significantly improved PFS and OS in the low- and intermediate-risk groups; however, no difference was observed in the high-risk group. LAT was more effective as a consolidative treatment after pembrolizumab initiation than as an upfront therapy., Conclusions: LAT combined with pembrolizumab was associated with higher PFS and OS compared with pembrolizumab alone in selected patients with synchronous oligometastatic NSCLC. The RPA model could serve as a valuable clinical tool for identifying appropriate patients for LAT., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: There are few studies that have examined clinical and radiological outcomes at 5 years after isolated medial patellofemoral ligament (MPFL) reconstruction. To date, midterm outcomes after isolated double-bundle (DB) MPFL reconstruction are not well known., Hypothesis: Isolated DB MPFL reconstruction using a patellar suture anchor technique would lead to improved functional scores and radiological findings, and these improvements would remain stable over the 5-year postoperative period., Study Design: Case series; Level of evidence, 4., Methods: Isolated MPFL reconstruction was performed in patients with recurrent patellar instability between March 2013 and February 2017. Clinical and functional evaluations were performed via an interview using the Kujala, Lysholm, and Tegner scores preoperatively and at 6, 12, 24, and 60 months postoperatively. Radiographs were taken preoperatively, immediately postoperatively, and at 24 and 60 months after surgery. Radiographic assessments included measuring the modified Insall-Salvati ratio, congruence angle, and lateral patellofemoral angle., Results: A total of 31 patients (31 knees) underwent isolated MPFL reconstruction; 4 patients did not complete 5-year follow-up, and thus, 27 patients (27 knees) were enrolled in the study. The mean age at the time of surgery was 22.0 ± 6.4 years (range, 14-32 years). All clinical and functional scores significantly improved in the first 2 years ( P < .001), with the mean Kujala, Lysholm, and Tegner scores improving from 52.7 to 90.7, 49.6 to 92.7, and 2.9 to 5.1, respectively. There was no significant difference in scores between 2- and 5-year follow-up. All radiographic parameters significantly improved between preoperatively and immediately postoperatively ( P < .001), with mean values for the modified Insall-Salvati ratio, congruence angle, and lateral patellofemoral angle improving from 1.7° to 1.6°, 5.7° to -6.6°, and 3.0° to 5.9°, respectively. No significant differences were observed in radiographic measurements between the postoperative time points. No patients experienced a patellar redislocation or fracture., Conclusion: The prospective analysis of isolated DB MPFL reconstruction at 5-year follow-up showed that clinical and radiological outcomes significantly improved postoperatively and were maintained to 5 years. These midterm results suggest that isolated DB MPFL reconstruction is an effective treatment option for patients with patellar instability., Competing Interests: The authors have declared that there are no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2024.)

Objective: We aimed to evaluate whether subcutaneous tunneling in peripherally inserted central catheters (PICC) placement could reduce the occurrence of central-line associated blood stream infection (CLABSI)., Methods: We conducted an open-label, multicentre, randomized, controlled trial in five tertiary hospitals. Adult hospitalized patients requiring a PICC were randomized in a one-to-one ratio to conventional (cPICC) or tunneled PICC (tPICC) arms using a centralized web-based computer-generated stratified randomization. CLABSI rates between groups were compared in a modified intention-to-treat population. Safety including the incidence of exit-site infection or hemorrhage-associated catheter removal were also compared. This trial was registered with Clinical Research Information Service of Republic of Korea (KCT0005521)., Results: From November 2020 to March 2023, 1,324 participants were enrolled and randomly assigned to tPICC (n=662) and cPICC (n=662). This study was terminated early due to the cohort CLABSI rate being lower than estimated, therefore, the original sample size of 1,694 would render the study underpowered to detect a difference in CLABSI rates. In the tPICC, CLABSI occurred in 13 of 651 participants over 11,071 catheter-days (1.2/1,000 catheter-days), compared with 20 among 650 patients with cPICC over 11,141 catheter-days (1.8/1,000 catheter-days, rate ratio 0.65, 95% CI 0.30-1.38, p=0.30). The incidence of exit-site infection (29 tPICC, 36 cPICC, p=0.5) and hemorrhage-associated catheter removal (11 tPICC, 11 cPICC, p=0.99) was not different between both groups., Conclusion: Due to insufficient sample size, this study could not demonstrate a statistically significant CLABSI risk reduction in the tPICC group compared to the cPICC group. Both groups had similar rates of exit site infection and bleeding., Competing Interests: Conflict of interest statement The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

The Al alloy melting behavior and interfacial reactions during the steelmaking process of high-Al automotive steel were investigated in this study. The total dissolution time of Al bars (20 × 20 × 80 mm) in molten steel was quite short, decreasing from 21.4 s to 10.0 s with an increase in bath temperature from 1580 to 1620 °C. The Al alloy melting process at the molten steel temperature of 1600 °C included the formation of a solidified steel layer, the latter's rapid melting, and Al alloy normal melting, while at 1600 °C, the process included a second increase in the thickness of the solidified layer. Because steel elements such as [Fe], [C], [O], and [N] could diffuse during the whole Al alloy melting process, an Fe (Al)-FeAl-FeAl 2 -Fe 2 Al 5 -Al diffusion layer along the direction of the Al-rich matrix could be found at the Fe-Al interface. Moreover, Fe x O, Al 2 O 3 , and unstable AlN inclusions could be observed in the FeAl layer. This study also investigated how to reduce the number of these easily formed inclusions. Decreasing the pre-heating process time and dissolved oxygen content could be useful in decreasing Fe x O and Al 2 O 3 inclusion formation. Some small-sized AlN inclusions formed in the center of the Al bars where they could not come into contact with the molten steel directly during the melting process; even for the immersion time of only 1 second, these inclusions were not stable in molten steel at the refining temperature and disappeared during the melting process.

A unique nucleus, the cerebrospinal fluid-contacting nucleus (CsfR), has been identified in the brain parenchyma. This nucleus features neurons with somas located within the parenchyma and processes extending into the cerebrospinal fluid (CSF). This anatomical configuration suggests that the CsfR may serve as a crucial interface between the nervous and body fluid regulatory systems, potentially playing a significant role in overall physiological modulation. Despite its importance, the precise biological significance of the CsfR remains to be fully elucidated. Previous research has characterized the CsfR, providing detailed information on its position, neighboring structures, neuron distribution, and 3D reconstruction in both rats and non-human primates, with stereotaxic coordinates specifically provided for the rat model. Given the relevance of mice as a model organism, especially the C57BL/6J strain, this study aims to explore the existence and morphology of the CsfR in mice. Our findings confirm the presence of the CsfR, consistently located in the ventral gray area of the lower part of the aqueduct and the upper part of the fourth ventricle floor. It is bilaterally symmetrical and heart-shaped in the coronal plane, which differs slightly from the Y-shape observed in coronal sections of rats. This study provides significant references for researchers investigating this specialized nucleus., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

CD2-Associated protein (CD2AP) is a candidate susceptibility gene for Alzheimer's disease, but its role in the mammalian central nervous system remains largely unknown. We show that CD2AP protein is broadly expressed in the adult mouse brain, including within cortical and hippocampal neurons, where it is detected at pre-synaptic terminals. Deletion of Cd2ap altered dendritic branching and spine density, and impaired ubiquitin-proteasome system activity. Moreover, in mice harboring either one or two copies of a germline Cd2ap null allele, we noted increased paired-pulse facilitation at hippocampal Schaffer-collateral synapses, consistent with a haploinsufficient requirement for pre-synaptic release. Whereas conditional Cd2ap knockout in the brain revealed no gross behavioral deficits in either 3.5- or 12-month-old mice, Cd2ap heterozygous mice demonstrated subtle impairments in discrimination learning using a touchscreen task. Based on unbiased proteomics, partial or complete loss of Cd2ap triggered perturbation of proteins with roles in protein folding, lipid metabolism, proteostasis, and synaptic function. Overall, our results reveal conserved, dose-sensitive requirements for CD2AP in the maintenance of neuronal structure and function, including synaptic homeostasis and plasticity, and inform our understanding of possible cell-type specific mechanisms in Alzheimer's Disease., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Radiofrequency (RF) and intense pulsed light (IPL) have been reported as efficient adjuvant treatment modalities for acne vulgaris., Objective: We sought to evaluate the clinical efficacy and safety of a combined needle RF and vacuum IPL device for acne treatment without the use of other conventional topical or oral agents., Methods: This randomized, split-faced study was designed to include patients with moderate to severe acne vulgaris. Comedone extraction was performed on both parts of the face prior to laser treatment. One side of the face was treated with RF and IPL in 2-week intervals, while the other side was left untreated as a control. Two independent blinded investigators evaluated the patients for improvement using clinical photographs. We also assessed for possible adverse effects., Results: The study included 44 patients with acne vulgaris (27 men and 17 women). Their ages ranged from 19-39 years (average, 23 years). At the final 12-week follow-up visit, the acne reduction rate was 34.80% (±33.45%; range, 30.92%-19.03%) on the treated side and 13.76% (±37.58%; range, 28.26%-23.27%) in the control group compared to baseline, constituting a significant difference. The difference in reduction rate between the treated and control sides was 21.03% (±25.09%), with the treated side experiencing more significant improvement ( p <0.05). In the assessment of adverse events, one patient experienced mild surrounding erythema that spontaneously improved., Conclusion: Combined treatment of needle RF and IPL could improve acne lesions., Competing Interests: The authors have nothing to disclose., (© 2024 The Korean Dermatological Association and The Korean Society for Investigative Dermatology.)

Plexiform schwannomas representing a rare subset, comprise 5% of all schwannomas. However, their occurrence in the thyroid gland is exceptionally rare. A 32-year-old male presented with an incidentally discovered, asymptomatic thyroid mass. Imaging revealed an approximately 5 cm heterogeneous solid mass on the right thyroid lobe extending to the upper mediastinum and directly invading the upper trachea. Under the suspicion of thyroid malignancy, the patient underwent right thyroidectomy. Histological examination confirmed a plexiform schwannoma with S100-positive spindle cells. Currently, the patient is undergoing outpatient follow-up, with no reported complications. To our knowledge, this is the first documented case of plexiform schwannoma of the thyroid gland within the English literature. This case highlights the diverse and unpredictable clinical manifestations of thyroid masses, emphasizing the importance of a multidisciplinary approach for diagnosing and managing rare entities, such as thyroid gland schwannomas.