A multifaceted approach to explain short- and long-term PM2.5 concentration changes in Northeast Asia in the month of January during 2016-2021.

Changes in PM2.5 concentrations are influenced by interwoven impacts of key drivers (e.g., meteorology, local emissions, and regional emissions). However, it is challenging to quantitatively disentangle their impacts individually at once. Therefore, we introduced a multifaceted approach (i.e., meteorology vs. emissions and self-contribution vs. long-range transport) to analyze the effects of major drivers for long- and short-term PM2.5 concentration changes based on observation and simulation in the month of January during 2016-2021 in Northeast Asia. For the simulations, we conducted modeling with the WRF-CMAQ system. The observed PM2.5 concentrations in China and South Korea in January 2021 decreased by 13.7 and 9.8 µg/m3, respectively, compared to those in January 2016. Emission change was the dominant factor to reduce PM2.5 concentrations in China (-115%) and South Korea (-74%) for the 6 years. However, the short-term changes in PM2.5 concentrations between January of 2020-2021 were mainly driven by meteorological conditions in China (-73%) and South Korea (-68%). At the same time, in South Korea located in downwind area, the impact of long-range transport from upwind area (LTI) decreased by 55% (9.6 µg/m3) over the 6 years whereas the impact of local emissions increased (+2.9 µg/m3/year) during 2016-2019 but decreased (-4.5 µg/m3/year) during 2019-2021. Additionally, PM2.5 concentrations in the upwind area showed a positive relationship with LTIs. However, for the days when westerly winds became weak in the downwind area, high PM2.5 concentrations in upwind area did not lead to high LTIs. These results imply that the decline of PM2.5 concentrations in South Korea was significantly affected by a combination of emission reduction in upwind area and meteorological conditions that hinder long-range transport. The proposed multifaceted approach can identify the main drivers of PM2.5 concentration change in a region by considering the regional characteristics.

Reprogramming of IL-12 secretion in the PDCD1 locus improves the anti-tumor activity of NY-ESO-1 TCR-T cells.

Introduction: Although the engineering of T cells to co-express immunostimulatory cytokines has been shown to enhance the therapeutic efficacy of adoptive T cell therapy, the uncontrolled systemic release of potent cytokines can lead to severe adverse effects. To address this, we site-specifically inserted the interleukin-12 (IL-12) gene into the PDCD1 locus in T cells using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-based genome editing to achieve T-cell activation-dependent expression of IL-12 while ablating the expression of inhibitory PD-1. Methods: New York esophageal squamous cell carcinoma 1(NY-ESO-1)-specific TCR-T cells was investigated as a model system. We generated ΔPD-1-IL-12 -edited NY-ESO-1 TCR-T cells by sequential lentiviral transduction and CRISPR knock-in into activated human primary T cells. Results: We showed that the endogenous PDCD1 regulatory elements can tightly control the secretion of recombinant IL-12 in a target cell-dependent manner, at an expression level that is more moderate than that obtained using a synthetic NFAT-responsive promoter. The inducible expression of IL-12 from the PDCD1 locus was sufficient to enhance the effector function of NY-ESO-1 TCR-T cells, as determined by upregulation of effector molecules, increased cytotoxic activity, and enhanced expansion upon repeated antigen stimulation in vitro. Mouse xenograft studies also revealed that PD-1-edited IL-12-secreting NY-ESO-1 TCR-T cells could eliminate established tumors and showed significantly greater in vivo expansion capacity than control TCR-T cells. Discussion: Our approach may provide a way to safely harness the therapeutic potential of potent immunostimulatory cytokines for the development of effective adoptive T cell therapies against solid tumors.

Reconstruction of Small-Sized Complex Defect on the Foot Dorsum Without Microsurgery: Intrinsic Adipofascial Flap.

Dorsal foot defects are difficult to cover and often require major flap surgery by microsurgeons, even for defects of limited sizes. Intrinsic adipofascial flaps for small-sized complex defects are simple and do not require microsurgery; thus, a flap specialist is unnecessary. This study aimed to assess our institutional experience with this technique and define its role in dorsal foot reconstruction. Nine patients aged 48 to 86 years with soft tissue defects of the dorsal foot were treated with the intrinsic adipofascial flap by rotating the adjacent adipofascial tissues from May 2019 and January 2021 in our institution. Demographic, clinical, and followup data were evaluated. Primary outcomes include flap viability, flap bulkiness, ability to wear shoes, and donor site morbidity. The mean followup period was 24.5 months (range, 10-30 months) and the mean defect size was 6.4 cm2 (range, 3.0-9.0 cm2). Eight flaps survived providing an adequate contour and durable coverage with a thin flap. Among 8 cases of healed flaps, 6 required secondary skin grafts while the other 2 healed spontaneously without additional operation. One patient (defect size: 3.0 cm × 3.0 cm) with underlying diabetes mellitus and peripheral arterial occlusive disease encountered flap total necrosis. Revisional flap surgery was performed to cover the flap total necrosis. In conclusion, the intrinsic adipofascial flap is a relatively simple and suitable method for complex dorsal foot defect reconstruction because it provides minimal donor site morbidity. However, relatively large defect size and comorbidities, such as underlying diabetes mellitus and vascular occlusive disease could accompany a risk of flap necrosis.

Incidence and pattern of concurrent capitellum fracture associated with radial head and neck fractures.

BACKGROUND: Radial head and neck fracture is a common fracture around the elbow. It is mostly caused by axial or valgus loading after a fall in elbow extension and forearm pronation. When a radial head and neck fracture occurs, the capitellum collides with the radial head and experiences a shear force, leading to capitellum fracture. The primary aim of this study was to evaluate the incidence of concurrent capitellum fracture and analyze its patterns among patients treated for radial head and neck fractures based on computed tomography. Secondary aim is to determine factors associated with concurrent capitellum fractures. HYPOTHESIS: Capitellum fractures are more common than expected in radial head and neck fractures and show a consistent pattern. With the higher the Mason type fracture, the higher the incidence of concurrent capitellum fracture will be shown. METHODS: A total of 101 patients treated surgically (27 patients) or non-surgically (74 patients) for radial head and neck fractures from January 2017 to December 2020 were retrospectively analyzed. Initial computed tomography was reviewed to identify concurrent capitellum fractures. A fracture was diagnosed when the bone continuity was lost in two consecutive images in any one of the three directions of computed tomography scan images. Seventeen patients with capitellum fractures were classified as group 1 and 84 patients without capitellum fractures as group 2. Each group of patients was assessed using Mason classification, whether fracture extended to the radial neck or not, fracture location, and treatment method. To determine the fracture location, radial head was trisected using three anatomical landmarks: safe zone, posteromedial zone, and anteromedial zone. And it was determined as the location where the fracture was most comminuted. RESULTS: The average age of the 101 patients was 44.6 years old. There were 54 (53.5%) males and 47 (46.5%) females. Capitellum fracture was accompanied in 17 cases. Its incidence was 16.8%. The rate of accompanying capitellum fracture was 9.5% (6/63) for Mason type 1, 25.0% (6/24) for Mason type 2, and 41.7% (5/12) for Mason type 3. The ratio of radial neck extension of fracture was significantly higher in group 2. There was no isolated radial neck fracture in group 1. However, there were 33 in group 2. After eliminating isolated radial neck fracture patients, significantly more fractures were located in the safety zone in group 1. Group 1 had a significantly higher rate of surgical treatment than group 2 (52.9% (9/17) vs. 21.4% (18/84) p=0.007). CONCLUSION: For radial head and neck fractures, the higher the Mason type fracture, the higher the incidence of concurrent capitellum fracture. When the fracture extended to the radial neck, the comorbidity of the capitellum fracture was decreased. Among radial head fractures, when the fracture was located in the safe zone, the comorbidity of capitellum fracture was increased. The rate of surgical treatment was higher in radial head and neck fracture patients with concurrent capitellum fractures. LEVEL OF EVIDENCE: IV; diagnostic study.

Engineering second-generation TCR-T cells by site-specific integration of TRAF-binding motifs into the CD247 locus.

BACKGROUND: The incorporation of co-stimulatory signaling domains into second-generation chimeric antigen receptors (CARs) significantly enhances the proliferation and persistence of CAR-T cells in vivo, leading to successful clinical outcomes. METHODS: To achieve such functional enhancement in transgenic T-cell receptor-engineered T-cell (TCR-T) therapy, we designed a second-generation TCR-T cell in which CD3ζ genes modified to contain the intracellular domain (ICD) of the 4-1BB receptor were selectively inserted into the CD247 locus. RESULTS: This modification enabled the simultaneous recruitment of key adaptor molecules for signals 1 and 2 on TCR engagement. However, the addition of full-length 4-1BB ICD unexpectedly impaired the expression and signaling of TCRs, leading to suboptimal antitumor activity of the resulting TCR-T cells in vivo. We found that the basic-rich motif (BRM) in the 4-1BB ICD was responsible for the undesirable outcomes, and that fusion of minimal tumor necrosis factor receptor-associated factor (TRAF)-binding motifs at the C-terminus of CD3ζ (zBBΔBRM) was sufficient to recruit TRAF2, the key adaptor molecule in 4-1BB signaling, while retaining the expression and proximal signaling of the transgenic TCR. Consequently, TCR-T cells expressing zBBΔBRM exhibited improved persistence and expansion in vitro and in vivo, resulting in superior antitumor activity in a mouse xenograft model. CONCLUSIONS: Our findings offer a promising strategy for improving the intracellular signaling of TCR-T cells and their application in treating solid tumors.

Lipoma with osteocartilaginous metaplasia in infrapatellar fat pad: A case report and review of literature.

RATIONALE: Lipomas are tumors composed of mature adipocytes, originating from the mesoderm, and are the most common soft tissue tumor. According to the World Health Organization classification of human soft tissue and bone tumors, there are 14 types of benign tumors, including mature adipose tissue. Osteolipoma is known as the rarest subtype of lipoma. PATIENT CONCERNS: A 63-year-old female presented to our hospital for the evaluation and treatment of a palpable mass with pain in the right knee. DIAGNOSIS: The diagnosis was confirmed as lipoma with osteocartilaginous metaplasia. INTERVENTIONS: Surgical removal of the tumor was performed. OUTCOMES: The main symptoms improved immediately after the surgery and recovered without any complications or recurrence until 2 years after surgery. LESSONS: Lipoma with osteochondral degeneration is a rare variant of lipoma and it is important to differentiate it from other malignant tumors. Pathological confirmation should be performed after marginal resection of the mass.

Prognostic Factors Leading to Good or Poor Outcomes Based on Functional and Radiological Findings After a Rotator Cuff Retear.

BACKGROUND: A retear after rotator cuff repair is a common problem; however, there is little information related to the prognosis after a retear. In addition, some patients with retears have satisfactory outcomes, which raises the question of whether a retear leads to a poor prognosis. PURPOSE: To identify radiological factors that influence the prognosis after a retear. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A total of 51 patients with retears confirmed by magnetic resonance imaging at 1 year after arthroscopic rotator cuff repair with a minimum follow-up of 24 months were enrolled in this study. Patients were divided into 2 groups according to whether they achieved the minimal clinically important difference for clinical outcome measures. Range of motion and radiological variables, including preoperative and postoperative anteroposterior (AP) and mediolateral (ML) tear sizes, sagittal extent of the retear, acromiohumeral distance (AHD), and degree of fatty degeneration, were analyzed using magnetic resonance imaging. RESULTS: Overall, 36 patients were allocated to the good prognosis (GP) group and 15 to the poor prognosis (PP) group. The 2 groups had no significant differences in baseline demographics and preoperative radiological parameters. Postoperative range of motion was decreased in the PP group at the last follow-up. The AP and ML retear sizes decreased in both groups after arthroscopic rotator cuff repair, but the retear size was significantly larger in the PP group (both P < .05). The AHD increased in the GP group (P < .001) but decreased in the PP group (P = .230) postoperatively. Logistic regression analysis revealed that postoperative AHD (P = .003), fatty degeneration of the infraspinatus tendon (P = .001), posterior (P = .007) and anterior (P = .025) sagittal extent of the retear, and change in the AP tear size (P = .017) were related to poor outcomes after a retear. However, change in the ML tear size (P = .105) and middle sagittal extent of the retear (P = .878) were not related to a poor prognosis. Also, further analysis showed that posterior (P = .006) and anterior (P = .003) sagittal extent of the retear were related to rotator cable involvement. CONCLUSION: An increased AP retear size and decreased AHD were radiological parameters that were associated with poor clinical outcomes after a retear. In particular, patients who had posterior and anterior sagittal extent of the retear, possibly with rotator cable involvement and more severe fatty degeneration of the infraspinatus tendon, showed worse outcomes.

Complications associated with open reduction and internal fixation for adult distal humerus fractures: a multicenter retrospective study.

BACKGROUND: Open reduction and plate fixation are the preferred treatment options for most distal humerus fractures in adults. However, it is often challenging for orthopedic surgeons because of the complex anatomy and the difficulty in achieving stable fixation. This multicenter study aimed to analyze the complication types and rates of patients with distal humerus fractures treated with open reduction and plate fixation, and compare the results with those found in the literature. In addition, we describe the clinical outcomes. METHODS: This retrospective multicenter study was conducted between September 2001 and March 2021 and included data from four hospitals. In total, 349 elbows underwent surgical treatment at these hospitals during the study period. Patients > 17 years of age who were treated by plate fixation were included, and patients who were treated by other fixation methods were excluded. A total of 170 patients were included in the study. The following types of complications were investigated: (1) nerve related; (2) fixation and instrument related; (3) osteosynthesis related; (4) infection; and (5) others. RESULTS: The following complications were found: (1) 26 (15.3%) cases of postoperative ulnar nerve symptoms; 4 (2.4%) of postoperative radial nerve symptoms; (2) one (0.6%) case of screw joint penetration and screw loosening; and eight (4.7%) cases of hardware removal due to instrument skin irritation; (3) seven (4.1%) cases of nonunion; (4) two (1.2%) and four (2.2%) cases of superficial and deep infection, respectively, and seven (3.9%) cases of wound complication; and (5) 37 (21.8%) cases of heterotrophic ossification, 79 (46.5%) cases of elbow stiffness (did not achieve functional range of motion [ROM]), and 41 (24.1%) cases of osteoarthritis over Broberg and Morrey Grade I. Paradoxically, the postoperative ulnar nerve symptoms were more frequent in the prophylactic ulnar nerve anterior transposition group. However, this difference was not statistically significant (p = 0.086). The mean ROM was 123.5° flexion to 9.5° extension. The average Disabilities of the Arm, Shoulder and Hand (DASH) score was 14.5 ± 15.6. CONCLUSIONS: Open reduction and plate fixation for distal humeral fractures is a reasonable treatment option with acceptable complication rates and favorable clinical outcomes. Surgeons must be vigilant about ulnar nerve complications. Level of Evidence Therapeutic Level III.

Colchicine as a novel drug for the treatment of osteosarcoma through drug repositioning based on an FDA drug library.

Background: Colchicine is a traditional medication that is currently approved to treat gout and familial Mediterranean fever (FMF). However, colchicine has a wide range of anti-inflammatory activities, and several studies have indicated that it may be useful in a variety of other conditions, such as rheumatic disease, cardiac disease, and cancer. Osteosarcoma, the most common type of bone sarcoma, is derived from primitive bone-forming mesenchymal cells. In this study, we investigated whether colchicine could be used to treat osteosarcoma through the regulation of cell cycle signaling. Methods: Two human osteosarcoma cell lines, U2OS and Saos-2, were used. A clonogenic assay was used to determine the antiproliferative effects of colchicine on osteosarcoma cells. Reactive oxygen species (ROS) production and apoptosis were measured by flow cytometry. Migration and invasion assays were performed to investigate the inhibitory effects of colchicine. The signaling pathways related to colchicine treatment were verified by GO biological process (GOBP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Results: Colchicine was selected as the lead compound based on the results of initial screening and cell viability assays conducted in Saos-2 and U2Os cells. Colchicine reduced the viability of Saos-2 and U2OS cells in a concentration-dependent manner. It also significantly inhibited colony-forming ability and induced ROS production and apoptosis. It also inhibited the migration and invasion of both Saos-2 and U2OS cells. GOBP and KEGG enrichment analyses indicated the involvement of microtubule-based processes and cancer-related pathways. Conclusions: These findings suggest that colchicine has therapeutic potential in osteosarcoma.

Characteristics of surgically treated Guyon canal syndrome: A multicenter retrospective study.

Guyon canal (GC) syndrome is a rare peripheral neuropathy involving the distal part of the ulnar nerve. Several causes are associated with GC syndrome, including anatomic variations, space-occupying tumors, and trauma. Because of disease rarity, the only reported studies of GC syndrome are case series with small sample size. We conducted a multicenter study to identify the basic characteristics of patients with surgically treated GC syndrome and the risk factors for the disease. This retrospective multicenter study was conducted between January 2001 and December 2020. We screened 70 patients who underwent GC release surgery by seven hand surgeons at six institutes. A total of 56 patients were included in this study, including 38 patients (67.9%) who underwent isolated GC decompression and 18 (32.1%) who underwent combined peripheral nerve decompression. The mean patient age was 48.4 years (range: 20-89 years), and 40 patients (71.4%) were male. The average preoperative symptom duration was 18.5 months, and most patients were office workers. Ultrasound was positive for GC syndrome in 7/10 patients evaluated, CT in 2/5, MRI in 17/23, and electrodiagnostic studies in 35/44. The most common cause of GC syndrome was tumor (n = 23), followed by idiopathic (n = 17), trauma (n = 12), anatomic variants (n = 3), and inflammation (n = 3). In conclusion, most patients with GC syndrome in this study were male and had symptoms in one wrist. The most common cause of GC syndrome in this study was a tumor, including a ganglion cyst. Level of Evidence: Level IV case series.

Incidence and Survival Rates of Cutaneous Melanoma in South Korea Using Nationwide Health Insurance Claims Data.

PURPOSE: Melanoma incidence is rising worldwide along with the associated personal and socioeconomic health expenditures. We investigated the incidence and survival-rate patterns of melanoma in South Korea using nationwide data. MATERIALS AND METHODS: This retrospective cohort study included patients with melanoma between 2004 and 2017, based on National Health Insurance (NHI) claims data in South Korea. The incidence, prevalence, and survival rate were analyzed along with baseline demographic characteristics. We collected solar irradiation dose (SID) and healthcare ranking score (HRS) according to the administrative district from the Korea Meteorological Administration and Korea Health Promotion Institute. The incidence and survival rates were assessed using Pearson's correlation, the Kaplan-Meier estimation, multiple linear regression, and multiple logistic regression methods. RESULTS: Twenty-five thousand, five hundred ninety-one patients with melanoma were diagnosed during the study period. The age-standardized incidence of melanoma steadily increased from 2004 to 2017 from 2.6 to 3.0/100,000/yr. The incidence of melanoma increased with significantly higher income (p < 0.05). The prevalence followed a similar pattern as the incidence. According to multivariate analysis, HRS significantly influenced the incidence of melanoma in high sun-exposed sites (p < 0.001). There was no significant change in annual mortality. Women had a higher 5-year survival rate than men (78.4% vs. 72.8%). Mortality by the administrative district was highly correlated with HRS. CONCLUSION: The incidence of melanoma is increasing in South Korea. A low HRS is associated with both higher incidence and mortality. The findings of this study could be utilized as a guideline for treating melanoma patients.

Anti-inflammatory clearance of amyloid-ß by a chimeric Gas6 fusion protein.

Clearing amyloid-ß (Aß) through immunotherapy is one of the most promising therapeutic approaches to Alzheimer's disease (AD). Although several monoclonal antibodies against Aß have been shown to substantially reduce Aß burden in patients with AD, their effects on improving cognitive function remain marginal. In addition, a significant portion of patients treated with Aß-targeting antibodies experience brain edema and microhemorrhage associated with antibody-mediated Fc receptor activation in the brain. Here, we develop a phagocytosis inducer for Aß consisting of a single-chain variable fragment of an Aß-targeting monoclonal antibody fused with a truncated receptor binding domain of growth arrest-specific 6 (Gas6), a bridging molecule for the clearance of dead cells via TAM (TYRO3, AXL, and MERTK) receptors. This chimeric fusion protein (αAß-Gas6) selectively eliminates Aß plaques through TAM receptor-dependent phagocytosis without inducing NF-kB-mediated inflammatory responses or reactive gliosis. Furthermore, αAß-Gas6 can induce synergistic clearance of Aß by activating both microglial and astrocytic phagocytosis, resulting in better behavioral outcomes with substantially reduced synapse elimination and microhemorrhage in AD and cerebral amyloid angiopathy model mice compared with Aß antibody treatment. Our results suggest that αAß-Gas6 could be a novel immunotherapeutic agent for AD that overcomes the side effects of conventional antibody therapy.

Genome editing of immune cells using CRISPR/Cas9.

The ability to read, write, and edit genomic information in living organisms can have a profound impact on research, health, economic, and environmental issues. The CRISPR/Cas system, recently discovered as an adaptive immune system in prokaryotes, has revolutionized the ease and throughput of genome editing in mammalian cells and has proved itself indispensable to the engineering of immune cells and identification of novel immune mechanisms. In this review, we summarize the CRISPR/ Cas9 system and the history of its discovery and optimization. We then focus on engineering T cells and other types of immune cells, with emphasis on therapeutic applications. Last, we describe the different modifications of Cas9 and their recent applications in the genome-wide screening of immune cells. [BMB Reports 2021; 54(1): 59-69].

Microfluidic on-chip immunohistochemistry directly from a paraffin-embedded section.

We present here a novel microfluidic platform that can perform microfluidic on-chip immunohistochemistry (IHC) processes on a formalin-fixed paraffin-embedded section slide. Unlike previous microfluidic IHC studies, our microfluidic chip made of organic solvent-resistant polyurethane acrylate (PUA) is capable of conducting on-chip IHC processes consecutively. A narrow channel wall structure of the PUA chip shows effective sealing by pressure-based reversible assembly with a section slide. We performed both on-chip IHC and conventional IHC processes and compared the IHC results based on the immunostaining intensity. The result showed that the effects of the on-chip deparaffinization, antigen retrieval, and immunoreaction processes on the IHC result were equivalent to conventional methods while reducing the total process time to less than 1/2. The experiment with breast cancer tissue shows that human epidermal growth factor receptor 2 (HER2) classification can be performed by obtaining a clearly distinguishable immunostaining intensity according to the HER2 expression level. We expect our on-chip microfluidic platform to provide a facile technique suitable for miniaturized, automated, and precise diagnostic devices, including a point-of-care device.

Pipetting-driven microfluidic immunohistochemistry to facilitate enhanced immunoreaction and effective use of antibodies.

Immunohistochemistry (IHC), which has been used to detect antigens in cells of a tissue section using an immunoreaction between an antibody and an antigen, is a practical tool for identifying the type and stage of diseases in cancer diagnosis and scientific research. However, conventional IHC requires long, laborious process times and high costs. Although microfluidic IHC platforms have been developed to overcome these limitations, the application of microfluidic IHC in real-world environments is still limited due to the additional equipment needed to operate the microfluidic systems. In addition, continuous flow in a microfluidic channel leads to a waste of unbound antibodies. In this study, we demonstrate a novel and easy-to-use microfluidic IHC platform operated only using a manual pipette that is commonly available in research laboratories or hospitals. No other device such as a pump or a controller is required to operate our system. Bidirectional flows of the antibody solution in a microfluidic device are induced by repetitive manual pipetting which facilitates the enhanced antigen-antibody reaction and enables the effective use of a limited amount of antibody. When breast cancer cell and tissue sections are reacted with antibodies using our platform, pipetting for less than 2 min is sufficient to obtain immunostaining results without damaging the sample. The staining intensity by our method is similar to that of the sample stained for 1 h by a conventional batch process. We believe that this pipetting-based approach to the operation of a microfluidic system allows end users to use microfluidic IHC more conveniently and easily in real-world environments.