ETV5 promotes lupus pathogenesis and follicular helper T cell differentiation by inducing osteopontin expression.

Follicular helper T (TFH) cells mediate germinal center reactions to generate high affinity antibodies against specific pathogens, and their excessive production is associated with the pathogenesis of systemic autoimmune diseases such as systemic lupus erythematosus (SLE). ETV5, a member of the ETS transcription factor family, promotes TFH cell differentiation in mice. In this study, we examined the role of ETV5 in the pathogenesis of lupus in mice and humans. T cell-specific deletion of Etv5 alleles ameliorated TFH cell differentiation and autoimmune phenotypes in lupus mouse models. Further, we identified SPP1 as an ETV5 target that promotes TFH cell differentiation in both mice and humans. Notably, extracellular osteopontin (OPN) encoded by SPP1 enhances TFH cell differentiation by activating the CD44-AKT signaling pathway. Furthermore, ETV5 and SPP1 levels were increased in CD4+ T cells from patients with SLE and were positively correlated with disease activity. Taken together, our findings demonstrate that ETV5 is a lupus-promoting transcription factor, and secreted OPN promotes TFH cell differentiation.

Medial Epicanthal Fold Correction Using a Y-W Epicanthoplasty in Asian Eyelids.

Many surgical techniques for managing epicanthal folds have been reported, but their main drawbacks include a noticeable scar in Asians, acute medial canthal angle, and applicability only in mild or moderate epicanthal folds. This study described a novel surgical technique, Y-W epicanthoplasty, and assessed the medial canthal shape and scarring in patients who underwent Y-W epicanthoplasty. Patients with moderate or severe epicanthal folds between January 2004 and February 2017 were included in this study. Pre- and postoperative intercanthal distance (ICD), inner canthal angle (ICA), and interpupillary distance (IPD) were measured. The ICD ratios (ICD/IPD) and extent of postoperative scarring were evaluated. A Y-W epicanthoplasty was performed on 18 patients. The ICD ratio of the total study cohort showed a significant reduction following surgery (preoperative ICD ratio=0.62±0.04, postoperative ICD ratio=0.58±0.03, P<0.001). The ICA was 51.8±7.7° and 49.8±5.6° in the pre- and postoperative periods, respectively (P=0.086) Eleven patients showed no apparent scar, and 6 patients were found to have minimal scarring that was visible only under close inspection. One patient had a hypertrophic scar that was successfully managed with triamcinolone acetonide injections. Y-W epicanthoplasty can provide good aesthetic results without a visible scar in patients with moderate-to-severe epicanthal folds. The Y-W epicanthoplasty avoids a medially extended skin incision and excessive tension on the skin flaps. Moreover, an acutely shaped or webbed medial canthus after epicanthoplasty can be prevented by adding a small triangular flap. The Y-W epicanthoplasty procedure is simple and straightforward, and it is appropriate for moderate-to-severe epicanthal fold correction.

AXL receptor tyrosine kinase inhibition improves the anti-tumor effects of CD8+ T cells by inducing CD103+ dendritic cell-mediated T cell priming.

AXL is a member of TAM receptor family and has been highlighted as a potential target for cancer treatment. Accumulating evidence has uncovered the critical role of the AXL signaling pathway in tumor growth, metastasis, and resistance against anti-cancer drugs, as well as its association with cancer immune escape. However, the function of AXL as a manipulator of the immune system in the tumor microenvironment (TME) remains unclear. Therefore, in this study, we investigated the impact of AXL on immune cells in the TME of a syngeneic tumor model using AXL knockout (AXL-/-) mice. Compared to AXL wild-type (AXL+/+) mice, tumor growth was significantly suppressed in AXL-/- mice, and an induced population of tumor-infiltrated CD8+ T cells and CD103+ dendritic cells (DCs) was observed. The change of CD8+ T cells and CD103+ DCs was also confirmed in tumor-draining lymph nodes (TdLN). In addition, the clonal expansion of OVA-specific CD8+ T cells was dominant in AXL-/- mice. Finally, anti-PD-1 treatment evidenced synergistic anti-cancer effects in AXL-/- mice. Overall, our data indicate that AXL signaling may inhibit the clonal expansion of tumor-specific CD8+ T cells through the regulation of the migration of CD8+ T cells and DCs in TME. Thus, AXL may be a powerful molecular target to improve anti-cancer effects through single or combined therapy with immune checkpoint inhibitors (ICI).

Regulation of uterus and placenta remodeling under high estradiol levels in gestational diabetes mellitus models†.

The present study aimed to investigate the regulation of placentas and uterus remodeling and involvement of estradiol in gestational diabetes mellitus. To achieve this, we established in vitro and in vivo models for gestational diabetes mellitus placentas by culturing human placental choriocarcinoma cells (BeWo) under hyperglycemic concentration and treating pregnant rats with streptozotocin. We evaluated the expression of angiogenesis-related proteins. The expression of the anti-angiogenic factor, excess placental soluble fms-like tyrosine kinase 1 was increased in our in vitro gestational diabetes mellitus model compared with the control. Moreover, the expressions of placental soluble fms-like tyrosine kinase 1 and the von Willebrand factor were also significantly elevated in the placenta of streptozotocin-treated rats. These data indicate the disruption of angiogenesis in the gestational diabetes mellitus placentas. The expression levels of connexin 43, a component of the gap junction and collagen type I alpha 2 chain, a component of the extracellular matrix, were decreased in the gestational diabetes mellitus uterus. These results suggest that uterus decidualization and placental angiogenesis are inhibited in gestational diabetes mellitus rats. Our results also showed upregulation of the expression of genes regulating estradiol synthesis as well as estrogen receptors in vivo models. Accordingly, the concentration of estradiol measured in the culture medium under hyperglycemic conditions, as well as in the serum and placenta of the streptozotocin-treated rats, was significantly elevated compared with the control groups. These results suggest that the dysregulated remodeling of the placenta and uterus may result in the elevation of estradiol and its signaling pathway in the gestational diabetes mellitus animal model to maintain pregnancy.

75% radiation dose reduction using deep learning reconstruction on low-dose chest CT.

OBJECTIVE: Few studies have explored the clinical feasibility of using deep-learning reconstruction to reduce the radiation dose of CT. We aimed to compare the image quality and lung nodule detectability between chest CT using a quarter of the low dose (QLD) reconstructed with vendor-agnostic deep-learning image reconstruction (DLIR) and conventional low-dose (LD) CT reconstructed with iterative reconstruction (IR). MATERIALS AND METHODS: We retrospectively collected 100 patients (median age, 61 years [IQR, 53-70 years]) who received LDCT using a dual-source scanner, where total radiation was split into a 1:3 ratio. QLD CT was generated using a quarter dose and reconstructed with DLIR (QLD-DLIR), while LDCT images were generated using a full dose and reconstructed with IR (LD-IR). Three thoracic radiologists reviewed subjective noise, spatial resolution, and overall image quality, and image noise was measured in five areas. The radiologists were also asked to detect all Lung-RADS category 3 or 4 nodules, and their performance was evaluated using area under the jackknife free-response receiver operating characteristic curve (AUFROC). RESULTS: The median effective dose was 0.16 (IQR, 0.14-0.18) mSv for QLD CT and 0.65 (IQR, 0.57-0.71) mSv for LDCT. The radiologists' evaluations showed no significant differences in subjective noise (QLD-DLIR vs. LD-IR, lung-window setting; 3.23 ± 0.19 vs. 3.27 ± 0.22; P = .11), spatial resolution (3.14 ± 0.28 vs. 3.16 ± 0.27; P = .12), and overall image quality (3.14 ± 0.21 vs. 3.17 ± 0.17; P = .15). QLD-DLIR demonstrated lower measured noise than LD-IR in most areas (P < .001 for all). No significant difference was found between QLD-DLIR and LD-IR for the sensitivity (76.4% vs. 72.2%; P = .35) or the AUFROCs (0.77 vs. 0.78; P = .68) in detecting Lung-RADS category 3 or 4 nodules. Under a noninferiority limit of -0.1, QLD-DLIR showed noninferior detection performance (95% CI for AUFROC difference, -0.04 to 0.06). CONCLUSION: QLD-DLIR images showed comparable image quality and noninferior nodule detectability relative to LD-IR images.

Vitreous hemorrhage during GLP-1 receptor agonist treatment.

BACKGROUND: The purpose of this case report is to describe a case of vitreous hemorrhage in a patient with a history of diabetic retinopathy and receiving dulaglutide for the management of type 2 diabetes mellitus (T2DM). CASE SUMMARY: A 64-year-old African American male with a past medical history of T2DM and severe diabetic retinopathy for 4 years was restarted on dulaglutide 1.5 mg weekly after being off therapy for 3 months. Baseline laboratory test results included hemoglobin A1c (HbA1c) of 8.8% and random blood glucose (BG) of 280 mg/dL. In addition, the patient had an average fasting BG of 150 mg/dL. In absence of intolerance, the dulaglutide dose was gradually maximized to 4.5 mg weekly and HbA1c decreased to 7.3% and random BG to 121 mg/dL at week 12 since reinitiation. At week 17 of therapy, the patient presented to the emergency department with a 1-day history of vision loss in the left eye and was diagnosed as having vitreous hemorrhage. The etiology for vitreous hemorrhage is unclear and may be a spontaneous episode. In discussion with the patient and the ophthalmologist, dulaglutide was restarted at 1.5 mg once weekly. After 4 weeks of reinitiation, the patient denied any recurrent symptoms of vitreous hemorrhage or worsening diabetic retinopathy. The most recent ophthalmology evaluation indicated no change in diabetic retinopathy. PRACTICE IMPLICATIONS: This case report adds to the limited body of evidence available for the incidence of vitreous hemorrhage in the setting of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) therapy and pre-existing diabetic retinopathy. The case report illustrates that a history of diabetic retinopathy should not automatically preclude the use of GLP-1 RAs.

Generation of genetically engineered mice for lung cancer with mutant EGFR.

Although epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have shown dramatic response and improvement in treating lung cancer with mutant EGFR, the emergence of drug resistance remains a major problem. In particular, some mutations including T790 M and C797S have been recognized as mechanisms of acquired resistance because they weaken binding affinity to drugs. To date, many attempts have been made to develop a new drug for overcoming acquired resistance to EGFR-TKIs, including secondary mutations. However, an appropriate animal model to evaluate in vivo efficacy during novel drug development remains lacking. In this study, we generated a novel transgenic mouse model that conditionally expresses human EGFRL858R/T790M/C797S and firefly luciferase using Cas9-mediated homology-independent targeted integration. Using a lung-specific Sftpc-CreERT2 mouse line, we induced expression of both the human EGFRL858R/T790M/C797S transgene and firefly luciferase in the lungs of adult mice. The expression of these genes and lung cancer occurrence was monitored using an in vivo imaging system and magnetic resonance imaging, respectively. Overall, our mouse model can be utilized to develop new drugs for overcoming C797S-mediated resistance to osimertinib; further, such knock-in systems for expressing oncogenes may be applied to study tumorigenesis and the development of other targeted agents.

Dynamic regulation of lipid metabolism in the placenta of in vitro and in vivo models of gestational diabetes mellitus†.

The purpose of this study was to investigate lipid metabolism in the placenta of gestational diabetes mellitus individuals and to evaluate its effect on the fetus. We examined the expression of lipogenesis- and lipolysis-related proteins in the in vitro and in vivo gestational diabetes mellitus placenta models. The levels of sterol regulatory element binding protein-1c were increased, and fat accumulated more during early hyperglycemia, indicating that lipogenesis was stimulated. When hyperglycemia was further extended, lipolysis was activated due to the phosphorylation of hormone-sensitive lipase and expression of adipose triglyceride lipase. In the animal model of gestational diabetes mellitus and in the placenta of gestational diabetes mellitus patients during the extended stage of gestational diabetes mellitus, the expression of sterol regulatory element binding protein-1c decreased and the deposition of fat increased. Similar to the results obtained in the in vitro study, lipolysis was enhanced in the animal and human placenta of extended gestational diabetes mellitus. These results suggest that fat synthesis may be stimulated by lipogenesis in the placenta when the blood glucose level is high. Subsequently, the accumulated fat can be degraded by lipolysis and more fat and its metabolites can be delivered to the fetus when the gestational diabetes mellitus condition is extended at the late stage of gestation. Imbalanced fat metabolism in the placenta and fetus of gestational diabetes mellitus patients can cause metabolic complications in the fetus, including fetal macrosomia, obesity, and type 2 diabetes mellitus.

Reconstruction of Extensive Oromandibular Defect With Simultaneous Dual Free Flap Transfer.

ABSTRACT: Complex oromandibular defects are usually too extensive or complex to be reconstructed with a single free flap. In this situation, dual free flaps can provide an adequate amount of tissues and a three-dimensional structure for large composite defects.In our institution, a total of 6 patients underwent immediate dual free-flap reconstruction between December 2013 and February 2020. In all patients, oromandibular defects were reconstructed with a combination of a fibula free flap and a vertical rectus abdominis myocutaneous, anterolateral thigh, or radial forearm free flap. All 6 patients showed tolerable flap status without any major complications, and could transit a diet from a dysphagia diet to a general diet on the final visit. Dual free flaps can be considered an optimal reconstructive option with favorable functional and aesthetic outcomes for complex oromandibular defects involving the bone, oral lining, external skin, or soft tissue.

Crystal Structure of H227A Mutant of Arginine Kinase in Daphnia magna Suggests the Importance of Its Stability.

Arginine kinase (AK) plays a crucial role in the survival of Daphnia magna, a water flea and a common planktonic invertebrate sensitive to water pollution, owing to the production of bioenergy. AK from D. magna (DmAK) has four highly conserved histidine residues, namely, H90, H227, H284, and H315 in the amino acid sequence. In contrast to DmAK WT (wild type), the enzyme activity of the H227A mutant decreases by 18%. To identify the structure-function relationship of this H227A mutant enzyme, the crystal 3D X-ray structure has been determined and an unfolding assay using anilino-1-naphthalenesulfonic acid (ANS) fluorescence has been undertaken. The results revealed that when compared to the DmAK WT, the hydrogen bonding between H227 and A135 was broken in the H227A crystal structure. This suggests that H227 residue, closed to the arginine binding site, plays an important role in maintaining the structural stability and maximizing the enzyme activity through hydrogen bonding with the backbone oxygen of A135.

Short-chain fatty acid butyrate induces IL-10-producing B cells by regulating circadian-clock-related genes to ameliorate Sjögren's syndrome.

OBJECTIVES: Sjögren's syndrome (SS) is an autoimmune disease caused by inflammation of the exocrine gland. The pathological hallmark of SS is the infiltration of lymphocytes into the salivary glands. Increased infiltration of T and B cells into salivary glands exacerbates symptoms of SS. Several recent studies have identified the role of gut microbiota in SS. Butyrate, one of the metabolites of the gut microbiota, regulates T cells; however, its effects on B cells and SS remain unknown. This study determined the therapeutic effect of butyrate on regulating B cells in SS. METHODS: Various concentrations of butyrate were intraperitoneally injected three times per week in NOD/ShiLtJ (NOD) mice, the prototype animal model for SS, and observed for more than 10 weeks. Whole salivary flow rate and the histopathology of salivary glands were investigated. Human submandibular gland (HSG) cells and B cells in mouse spleen were used to confirm the anti-inflammatory and immunomodulatory effects of butyrate. RESULTS: Butyrate increased salivary flow rate in NOD mice and reduced inflammation of salivary gland tissues. It also regulated cell death and the expression of circadian-clock-related genes in HSG cells. Butyrate induced B cell regulation by increasing IL-10-producing B (B10) cells and decreasing IL-17-producing B cells, through the circadian clock genes RAR-related orphan receptor alpha and nuclear receptor subfamily 1 group D member 1. CONCLUSION: The findings of this study imply that butyrate may ameliorate SS via reciprocal regulation of IL-10- and IL-17-producing B cells.

Deep learning reconstruction for contrast-enhanced CT of the upper abdomen: similar image quality with lower radiation dose in direct comparison with iterative reconstruction.

OBJECTIVE: To evaluate the effect of a commercial deep learning algorithm on the image quality of chest CT, focusing on the upper abdomen. METHODS: One hundred consecutive patients who simultaneously underwent contrast-enhanced chest and abdominal CT were collected. The radiation dose was optimized for each scan (mean CTDIvol: chest CT, 3.19 ± 1.53 mGy; abdominal CT, 7.10 ± 1.88 mGy). Three image sets were collected: chest CT reconstructed with an adaptive statistical iterative reconstruction (ASiR-CHT; 50% blending), chest CT with a deep learning algorithm (DLIR-CHT), and abdominal CT with ASiR (ASiR-ABD; 40% blending). Afterwards, the images covering the upper abdomen were extracted, and image noise, the signal-to-noise ratio (SNR), and the contrast-to-noise ratio (CNR) were measured. For subjective evaluation, three radiologists independently assessed noise, spatial resolution, presence of artifacts, and overall image quality. Additionally, readers selected the most preferable reconstruction technique among three image sets for each case. RESULTS: The average measured noise for DLIR-CHT, ASiR-CHT, and ASiR-ABD was 8.01 ± 2.81, 14.8 ± 2.56, and 12.3 ± 2.28, respectively (p < .001). Deep learning-based image reconstruction (DLIR) also showed the best SNR and CNR (p < .001). However, in the subjective analysis, ASiR-ABD showed less subjective noise than DLIR (2.94 ± 0.23 vs. 2.87 ± 0.26; p < .001), while DLIR showed better spatial resolution (2.60 ± 0.34 vs. 2.44 ± 0.31; p = .02). ASiR-ABD showed a better overall image quality (p = .001), but two of the three readers preferred DLIR more frequently. CONCLUSION: With < 50% of the radiation dose, DLIR chest CT showed comparable image quality in the upper abdomen to that of dedicated abdominal CT and was preferred by most readers. KEY POINTS: • With < 50% radiation dose, a deep learning algorithm applied to contrast-enhanced chest CT exhibited better image noise and signal-to-noise ratio than standard abdominal CT with the ASiR technique. • Pooled readers mostly preferred deep learning algorithm-reconstructed contrast-enhanced chest CT reconstructed using a standard ASiR-reconstructed abdominal CT. • Reconstruction algorithm-induced distortion artifacts were more frequently observed on deep learning algorithm-reconstructed images, but diagnostic difficulty was reported in only 0.3% of cases.

Automatic prediction of left cardiac chamber enlargement from chest radiographs using convolutional neural network.

OBJECTIVE: To develop deep learning-based cardiac chamber enlargement-detection algorithms for left atrial (DLCE-LAE) and ventricular enlargement (DLCE-LVE), on chest radiographs METHODS: For training and internal validation of DLCE-LAE and -LVE, 5,045 chest radiographs (CRs; 2,463 normal and 2,393 LAE) and 1,012 CRs (456 normal and 456 LVE) matched with the same-day echocardiography were collected, respectively. External validation was performed using 107 temporally independent CRs. Reader performance test was conducted using the external validation dataset by five cardiothoracic radiologists without and with the results of DLCE. Classification performance of DLCE was evaluated and compared with those of the readers and conventional radiographic features, including cardiothoracic ratio, carinal angle, and double contour. In addition, DLCE-LAE was tested on 5,277 CRs from a healthcare screening program cohort. RESULTS: DLCE-LAE showed areas under the receiver operating characteristics curve (AUROCs) of 0.858 on external validation. On reader performance test, DLCE-LAE showed better results than pooled radiologists (AUROC 0.858 vs. 0.651; p < .001) and significantly increased their performance when used as a second reader (AUROC 0.651 vs. 0.722; p < .001). DLCE-LAE also showed a significantly higher AUROC than conventional radiographic findings (AUROC 0.858 vs. 0.535-0.706; all ps < .01). In the healthcare screening cohort, DLCE-LAE successfully detected 71.0% (142/200) CRs with moderate-to-severe LAE (93.5% [29/31] of severe cases), while yielding 11.8% (492/4,184) false-positive rate. DLCE-LVE showed AUROCs of 0.966 and 0.594 on internal and external validation, respectively. CONCLUSION: DLCE-LAE outperformed and improved cardiothoracic radiologists' performance in detecting LAE and showed promise in screening individuals with moderate-to-severe LAE in a healthcare screening cohort. KEY POINTS: • Our deep learning algorithm outperformed cardiothoracic radiologists in detecting left atrial enlargement on chest radiographs. • Cardiothoracic radiologists improved their performance in detecting left atrial enlargement when aided by the algorithm. • On a healthcare-screening cohort, our algorithm detected 71.0% (142/200) radiographs with moderate-to-severe left atrial enlargement while yielding 11.8% (492/4,184) false-positive rate.

Metformin Augments Anti-Inflammatory and Chondroprotective Properties of Mesenchymal Stem Cells in Experimental Osteoarthritis.

Mesenchymal stem cells (MSCs) can protect against cartilage breakdown in osteoarthritis (OA) via their immunomodulatory capacities. However, the optimization strategy for using MSCs remains challenging. This study's objective was to identify the in vivo effects of metformin-stimulated adipose tissue-derived human MSCs (Ad-hMSCs) in OA. An animal model of OA was established by intra-articular injection of monosodium iodoacetate into rats. OA rats were divided into a control group and two therapy groups (treated with Ad-hMSCs or metformin-stimulated Ad-hMSCs). Limb nociception was assessed by measuring the paw withdrawal latency and threshold. Our data show that metformin increased IL-10 and IDO expression in Ad-hMSCs and decreased high-mobility group box 1 protein, IL-1ß, and IL-6 expression. Metformin increased the migration capacity of Ad-hMSCs with upregulation of chemokine expression. In cocultures, metformin-stimulated Ad-hMSCs inhibited the mRNA expression of RUNX2, COL X, VEGF, MMP1, MMP3, and MMP13 in IL-1ß-stimulated OA chondrocytes and increased the expression of TIMP1 and TIMP3. The antinociceptive activity and chondroprotective effects were greater in OA rats treated with metformin-stimulated Ad-hMSCs than in those treated with unstimulated Ad-hMSCs. TGF-ß expression in subchondral bone of OA joints was attenuated more in OA rats treated with metformin-stimulated Ad-hMSCs. Our findings suggest that metformin offers a promising option for the clinical application of Ad-hMSCs as a cell therapy for OA.

Computed tomography arthrography of the shoulder with tin filter-based spectral shaping at 100 kV and 140 kV.

BACKGROUND: Tin filter-based spectral shaping has been used for low-dose and ultra-low-dose computed tomography (CT) in several body parts. However, studies of shoulder CT arthrography with spectral shaping are limited. PURPOSE: To investigate image quality and radiation dose of shoulder CT arthrography with tin filter-based spectral shaping at 100 kV (Sn 100 kV) and 140 kV (Sn 140 kV) in comparison with the conventional protocol. MATERIAL AND METHODS: Ninety-nine shoulder CT arthrographies with protocols of Sn 100 kV (n = 32), Sn 140 kV (n = 25), and conventional 120 kV (n = 42) were retrospectively evaluated. Qualitative image quality, CT attenuations of intra-articular contrast mixture and tissues, background noise, contrast-to-noise ratios (CNRs), and figures of merit were assessed. Radiation doses were compared. RESULTS: CT arthrographies with Sn 100 kV and Sn 140 kV yielded approximately 70% and 60% radiation dose reduction, respectively, compared with the conventional 120 kV (P < 0.001). Qualitative image noise and quantitative background noise of Sn 100 kV and Sn 140 kV were significantly less than those of the conventional protocol. Qualitative image contrast, CT attenuations of intra-articular contrast mixture and tissues, and CNRs for Sn 100 were similar to those of the conventional 120 kV. However, Sn 140 kV showed significantly lower qualitative contrast and CNRs than 120 kV. Sn 100 kV was the most dose efficient among the three protocols. CONCLUSION: Shoulder CT arthrography with Sn 100 kV substantially reduced radiation dose and image noise and maintained image contrast, compared with the conventional protocol.

Establishment and Long-Term Expansion of Small Cell Lung Cancer Patient-Derived Tumor Organoids.

Differential chemo-sensitivity of cancer cells, which is attributed to the cellular heterogeneity and phenotypic variation of cancer cells, is considered to be the main reason for tumor recurrence after chemotherapy. Here, we generated small cell lung cancer patient-derived tumor organoids and subjected them to long-term expansion with the addition of WNT3A or R-spondin1. We confirmed that the organoids have similar genetic profiles, molecular characteristics, and morphological architectures to the corresponding patient tumor tissue during and after long-term expansion. Interestingly, the cellular heterogeneity of organoids is reflected in their differential response to cisplatin or etoposide. We propose to utilize the organoids as small cell lung cancer patient avatar models that would be ideal for investigating the mechanisms underlying tumor recurrence after chemotherapy, and would ultimately help to develop personalized medicine.

NAB2-STAT6 fusion protein mediates cell proliferation and oncogenic progression via EGR-1 regulation.

Solitary fibrous tumors are rare mesenchymal tumors derived from soft tissues and vascular walls. NAB2-STAT6 fusion gene serves as a marker gene for this disease and consists of the truncated repressor domain of NGFI-A-Binding protein 2 (NAB2) and the intact activation domain of STAT6. In this study, we found that EGR-1 and the proliferation-related EGR-1 target gene IGF2 were upregulated in NIH-3T3 cells transfected with NAB2-STAT6. Additionally, p-Rb (Ser795) and cyclin D1 levels were upregulated, and cell proliferation was also enhanced. We identified that treatment with the IGF2 inhibitor reduced cell proliferation in NIH-3T3 cells transfected with NAB2-STAT6. The oncogenic progression was enhanced in NIH-3T3 cells transfected with NAB2-STAT6 compared with those transfected with the empty vector. Taken together, our study suggests that the NAB2-STAT6 fusion gene is associated with cell proliferation through EGR-1 transcriptional expression and IGF2 can be a drug target for the treatment of solitary fibrous tumors.

Deep learning algorithm for surveillance of pneumothorax after lung biopsy: a multicenter diagnostic cohort study.

OBJECTIVES: Pneumothorax is the most common and potentially life-threatening complication arising from percutaneous lung biopsy. We evaluated the performance of a deep learning algorithm for detection of post-biopsy pneumothorax in chest radiographs (CRs), in consecutive cohorts reflecting actual clinical situation. METHODS: We retrospectively included post-biopsy CRs of 1757 consecutive patients (1055 men, 702 women; mean age of 65.1 years) undergoing percutaneous lung biopsies from three institutions. A commercially available deep learning algorithm analyzed each CR to identify pneumothorax. We compared the performance of the algorithm with that of radiology reports made in the actual clinical practice. We also conducted a reader study, in which the performance of the algorithm was compared with those of four radiologists. Performances of the algorithm and radiologists were evaluated by area under receiver operating characteristic curves (AUROCs), sensitivity, and specificity, with reference standards defined by thoracic radiologists. RESULTS: Pneumothorax occurred in 17.5% (308/1757) of cases, out of which 16.6% (51/308) required catheter drainage. The AUROC, sensitivity, and specificity of the algorithm were 0.937, 70.5%, and 97.7%, respectively, for identification of pneumothorax. The algorithm exhibited higher sensitivity (70.2% vs. 55.5%, p < 0.001) and lower specificity (97.7% vs. 99.8%, p < 0.001), compared with those of radiology reports. In the reader study, the algorithm exhibited lower sensitivity (77.3% vs. 81.8-97.7%) and higher specificity (97.6% vs. 81.7-96.0%) than the radiologists. CONCLUSION: The deep learning algorithm appropriately identified pneumothorax in post-biopsy CRs in consecutive diagnostic cohorts. It may assist in accurate and timely diagnosis of post-biopsy pneumothorax in clinical practice. KEY POINTS: • A deep learning algorithm can identify chest radiographs with post-biopsy pneumothorax in multicenter consecutive cohorts reflecting actual clinical situation. • The deep learning algorithm has a potential role as a surveillance tool for accurate and timely diagnosis of post-biopsy pneumothorax.

Suberoylanilide Hydroxamic Acid Attenuates Autoimmune Arthritis by Suppressing Th17 Cells through NR1D1 Inhibition.

Rheumatoid arthritis (RA) is a type of systemic autoimmune arthritis that causes joint inflammation and destruction. One of the pathological mechanisms of RA is known to involve histone acetylation. Although the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) can attenuate arthritis in animal models of RA, the mechanism underlying this effect is poorly understood. This study was performed to examine whether SAHA has therapeutic potential in an animal model of RA and to investigate its mechanism of action. Collagen-induced arthritis (CIA) mice were orally administered SAHA daily for 8 weeks and examined for their arthritis score and incidence of arthritis. CD4+ T cell regulation following SAHA treatment was confirmed in splenocytes cultured under type 17 helper T (Th17) cell differentiation conditions. Clinical scores and the incidence of CIA were lower in mice in the SAHA treatment group compared to the controls. In addition, SAHA inhibited Th17 cell differentiation, as well as decreased expression of the Th17 cell-related transcription factors pSTAT3 Y705 and pSTAT3 S727. In vitro experiments showed that SAHA maintained regulatory T (Treg) cells but specifically reduced Th17 cells. The same results were obtained when mouse splenocytes were cultured under Treg cell differentiation conditions and then converted to Th17 cell differentiation conditions. In conclusion, SAHA was confirmed to specifically inhibit Th17 cell differentiation through nuclear receptor subfamily 1 group D member 1 (NR1D1), a factor associated with Th17 differentiation. The results of the present study suggested that SAHA can attenuate CIA development by inhibition of the Th17 population and maintenance of the Treg population through NR1D1 inhibition. Therefore, SAHA is a potential therapeutic candidate for RA.

Perilla frutescens Britton: A Comprehensive Study on Flavor/Taste and Chemical Properties During the Roasting Process.

This study investigated changes of volatile compounds, sniffing test-assisted sensory properties, taste associated-constituent and free amino acid compositions, taste description by electronic-tongue, and chemical characteristics in Perilla frutescens Britton var. acuta Kudo after roasting at 150 °C for 0⁻8 min. A total of 142 volatile compounds were identified, among which methyl benzoate and limonene were predominant, regardless of roasting time, and these were also detected as the major compounds in the sniffing test by GC-olfactometry. For constituent amino acids analyzed by the acid hydrolysis method using hydrochloric acid (HCl), the concentration of glutamic acid, aspartic acid, and leucine showed an increase pattern with increased roasting time, which results in umami taste, sour taste, and bitter taste, respectively. For free amino acids, valine and hydroxylysine eliciting bitter and bitter and sweet tastes, respectively, also tend to increase by roasting. The pattern of amino acid concentration by roasting was readily matched to the taste description by electronic-tongue but that of sweetness and sourness by electronic-tongue did not coincide with the amino acid composition. For the chemical properties, total phenolic content, antioxidative capacity, and browning intensity tend to increase with roasting but decreased by 8 min. The results of this study provide fundamental information on perilla in both the food industry and cooking environment for the sake of increasing the utilization of perilla as a food source and ingredient.