Molecular subtypes of breast cancer predicting clinical benefits of radiotherapy after breast-conserving surgery: a propensity-score-matched cohort study.

BACKGROUND: Based on the molecular expression of cancer cells, molecular subtypes of breast cancer have been applied to classify patients for predicting clinical outcomes and prognosis. However, further evidence is needed regarding the influence of molecular subtypes on the efficacy of radiotherapy (RT) after breast-conserving surgery (BCS), particularly in a population-based context. Hence, the present study employed a propensity-score-matched cohort design to investigate the potential role of molecular subtypes in stratifying patient outcomes for post-BCS RT and to identify the specific clinical benefits that may emerge. METHODS: From 2006 to 2019, the present study included 59,502 breast cancer patients who underwent BCS from the Taiwan National Health Insurance Research Database. Propensity scores were utilized to match confounding variables between patients with and without RT within each subtype of breast cancer, namely luminal A, luminal B/HER2-negative, luminal B/HER2-positive, basal-like, and HER2-enriched ones. Several clinical outcomes were assessed, in terms of local recurrence (LR), regional recurrence (RR), distant metastasis (DM), disease-free survival (DFS), and overall survival (OS). RESULTS: After post-BCS RT, patients with luminal A and luminal B/HER2-positive breast cancers exhibited a decrease in LR (adjusted hazard ratio [aHR] = 0.18, p < 0.0001; and, 0.24, p = 0.0049, respectively). Furthermore, reduced RR and improved DFS were observed in patients with luminal A (aHR = 0.15, p = 0.0004; and 0.29, p < 0.0001), luminal B/HER2-negative (aHR = 0.06, p = 0.0093; and, 0.46, p = 0.028), and luminal B/HER2-positive (aHR = 0.14, p = 0.01; and, 0.38, p < 0.0001) breast cancers. Notably, OS benefits were found in patients with luminal A (aHR = 0.62, p = 0.002), luminal B/HER2-negative (aHR = 0.30, p < 0.0001), basal-like (aHR = 0.40, p < 0.0001), and HER2-enriched (aHR = 0.50, p = 0.03), but not luminal B/HER2-positive diseases. Remarkably, when considering DM, luminal A patients who received RT demonstrated a lower cumulative incidence of DM than those without RT (p = 0.02). CONCLUSION: In patients with luminal A breast cancer who undergo BCS, RT could decrease the likelihood of tumor metastasis. After RT, the tumor's hormone receptor status may predict tumor control regarding LR, RR, and DFS. Besides, the HER2 status of luminal breast cancer patients may serve as an additional predictor of OS after post-BCS RT. However, further prospective studies are required to validate these findings.

Concurrent Imaging and Clinical Study of the Efficacy of Hyaluronic Acid Injection for Knee Osteoarthritis: A Synovial Membrane Investigation with Ultrasound Imaging.

We investigated whether hyaluronic acid (HA) injections can ameliorate ultrasound-detected synovitis in knee osteoarthritis (OA). We recruited 103 patients with symptomatic knee OA and ultrasound-detected synovitis and performed two ultrasound-guided fluid drainage procedures, followed by the administration of a low-molecular-weight HA injection (2.5 mL) in the subpatellar bursa, at a 2-week interval. Knee ultrasound imaging evaluations were performed before injection (baseline) and at 1 and 6 months after the second injection and included the measurements of synovial vascularity by using color Doppler ultrasound, synovial fluid depth over the suprapatellar bursa (SF), and synovial hypertrophy (SH). Initial clinical assessments included a visual analog scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). VAS scores decreased significantly at both 1-month and 6-month evaluations (p < 0.001). WOMAC scores also significantly decreased at 1 month (p < 0.001), but not at 6 months (p = 0.23). The ultrasound parameters did not significantly change, except color Doppler grading, which tended to decrease at the 6-month evaluation (p = 0.059). Our findings revealed that two ultrasound-guided HA injections following fluid drainage improved pain and knee function but did not considerably influence imaging-detected synovitis in patients with knee OA.

High Sensitivity SERS Substrate of a Few Nanometers Single-Layer Silver Thickness Fabricated by DC Magnetron Sputtering Technology.

Surface-enhanced Raman spectroscopy (SERS) is commonly used for super-selective analysis through nanostructured silver layers in the environment, food quality, biomedicine, and materials science. To fabricate a high-sensitivity but a more accessible device of SERS, DC magnetron sputtering technology was used to realize high sensitivity, low cost, a stable deposition rate, and rapid mass production. This study investigated various thicknesses of a silver film ranging from 3.0 to 12.1 nm by field emission scanning electron microscope, X-ray diffraction, and X-ray photoelectron spectroscopy. In the rhodamine 6G (R6G) testing irradiated by a He-Ne laser beam, the analytical enhancement factor (AEF) of 9.35 × 108, the limit of detection (LOD) of 10-8 M, and the relative standard deviation (RSD) of 1.61% were better than the other SERS substrates fabricated by the same DC sputtering process because the results showed that the 6 nm thickness silver layer had the highest sensitivity, stability, and lifetime. The paraquat and acetylcholine analytes were further investigated and high sensitivity was also achievable. The proposed SERS samples were evaluated and stored in a low humidity environment for up to forty weeks, and no spectrum attenuation could be detected. Soon, the proposed technology to fabricate high sensitivity, repeatability, and robust SERS substrate will be an optimized process technology in multiple applications.

Psychological disorders in patients with orthopaedic oncological diseases and their coping strategies.

BACKGROUND: This study aimed to determine the prevalence and risk factors of anxiety and depression among orthopaedic oncology patients, their quality of life and coping strategies. METHODS: This cross-sectional study recruited patients from the outpatient orthopaedic oncology clinic at a tertiary institution. Data were collected from self-report questionnaires: Hospital Anxiety and Depression Scale Hospital Anxiety Depression Scale, World Health Organization Quality of Life (WHOQOL-BREF) and Brief Coping with Problems Experienced (Brief COPE). Risk factors were analyzed with multiple logistic regression. RESULTS: 191 patients were recruited. The median age was 39.4 years old (IQR 35.0). 29.8% had anxiety, 16.2% had depression, and 15.2% had mixed anxiety and depression. Quality of life median scores differed significantly between patients with anxiety and no anxiety and patients with depression and no depression (p < 0.001). Patients with mixed anxiety and depression had a more inferior quality of life (p < 0.001). Age, psychological health and radiotherapy were inversely associated with anxiety. Physical and psychological health were significantly associated with less depression. Ongoing chemotherapy was significantly associated with anxiety and depression. The commonest coping strategies were denial, behavioural disengagement, venting and self-blame. CONCLUSION: Anxiety and depression are prevalent among orthopaedic oncology patients. Patients with mixed anxiety and depression had a more inferior quality of life. Patients with ongoing chemotherapy had higher risks of anxiety and depression. The commonest coping strategies were denial, behavioural disengagement, venting and self-blame. Psychosocial evaluation followed by appropriate psychiatric referrals and consultations could be established to facilitate orthopaedic oncology patients during their course of treatment.

Sphingosine 1-Phosphate Receptor 4 Promotes Nonalcoholic Steatohepatitis by Activating NLRP3 Inflammasome.

BACKGROUND & AIMS: Sphingosine 1-phosphate receptors (S1PRs) are a group of G-protein-coupled receptors that confer a broad range of functional effects in chronic inflammatory and metabolic diseases. S1PRs also may mediate the development of nonalcoholic steatohepatitis (NASH), but the specific subtypes involved and the mechanism of action are unclear. METHODS: We investigated which type of S1PR isoforms is activated in various murine models of NASH. The mechanism of action of S1PR4 was examined in hepatic macrophages isolated from high-fat, high-cholesterol diet (HFHCD)-fed mice. We developed a selective S1PR4 functional antagonist by screening the fingolimod (2-amino-2-[2-(4- n -octylphenyl)ethyl]-1,3- propanediol hydrochloride)-like sphingolipid-focused library. RESULTS: The livers of various mouse models of NASH as well as hepatic macrophages showed high expression of S1pr4. Moreover, in a cohort of NASH patients, expression of S1PR4 was 6-fold higher than those of healthy controls. S1pr4+/- mice were protected from HFHCD-induced NASH and hepatic fibrosis without changes in steatosis. S1pr4 depletion in hepatic macrophages inhibited lipopolysaccharide-mediated Ca++ release and deactivated the Nod-like receptor pyrin domain-containning protein 3 (NLRP3) inflammasome. S1P increased the expression of S1pr4 in hepatic macrophages and activated NLRP3 inflammasome through inositol trisphosphate/inositol trisphosphate-receptor-dependent [Ca++] signaling. To further clarify the biological function of S1PR4, we developed SLB736, a novel selective functional antagonist of SIPR4. Similar to S1pr4+/- mice, administration of SLB736 to HFHCD-fed mice prevented the development of NASH and hepatic fibrosis, but not steatosis, by deactivating the NLRP3 inflammasome. CONCLUSIONS: S1PR4 may be a new therapeutic target for NASH that mediates the activation of NLRP3 inflammasome in hepatic macrophages.

Feasibility of Single-Stage Posterior Passive Correction and Fusion Surgery for Congenital Scoliosis in Adolescent Patients Who Have Attained Skeletal Maturity

Methods@#Patients with congenital scoliosis who underwent SSPPCF using a pedicle screw system were reviewed. We identified the following three surgical indications: (1) hemivertebra or wedge vertebra over the thoracic or thoracolumbar region with structural lumbar curves, (2) hemivertebra or wedge vertebra at the lumbar region with significant pelvic obliquity or sacral slanting, and (3) mixed or complex congenital scoliosis. The demographic, perioperative, and radiographic data of these patients were collected. @*Results@#Thirty-four patients were reviewed. The mean patient age was 14.6±3.4 years. There were 13 hemivertebrae, three wedged vertebrae, two butterfly vertebrae, three hemivertebrae with butterfly vertebra, eight unsegmented bars, and five multiple complex lesions. The average surgical duration was 219.4±68.8 minutes. The average blood loss was 1,208.4±763.5 mL. Seven patients required allogeneic blood transfusion. The mean hospital stay duration was 6.1±2.5 days. The complication rate was 11.8% (4/34): one patient had severe blood loss, one had rod breakage, and two had distal adding-on. The Cobb angle reduced from 65.9°±17.4° to 36.3°±15.3° (p<0.001) with a correction rate (CR) of 44.8%±17.4%. The regional kyphotic angle decreased from 39.9°±20.5° to 27.5°±13.9° (p=0.001) with a CR of 19.3%±49.6%. Radiographic parameters (radiographic shoulder height, clavicle angle, T1 tilt, cervical axis, pelvic obliquity, coronal balance, and apical vertebral translation) showed significant improvement postoperatively. @*Conclusions@#SSPPCF was a feasible option for adolescent patients with congenital scoliosis who were skeletally matured.

Hepatic MIR20B promotes nonalcoholic fatty liver disease by suppressing PPARA.

Background: Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation and imbalances in lipid metabolism in the liver. Although nuclear receptors (NRs) play a crucial role in hepatic lipid metabolism, the underlying mechanisms of NR regulation in NAFLD remain largely unclear. Methods: Using network analysis and RNA-seq to determine the correlation between NRs and microRNA in human NAFLD patients, we revealed that MIR20B specifically targets PPARA. MIR20B mimic and anti-MIR20B were administered to human HepG2 and Huh-7 cells and mouse primary hepatocytes as well as high-fat diet (HFD)- or methionine-deficient diet (MCD)-fed mice to verify the specific function of MIR20B in NAFLD. We tested the inhibition of the therapeutic effect of a PPARα agonist, fenofibrate, by Mir20b and the synergic effect of combination of fenofibrate with anti-Mir20b in NAFLD mouse model. Results: We revealed that MIR20B specifically targets PPARA through miRNA regulatory network analysis of nuclear receptor genes in NAFLD. The expression of MIR20B was upregulated in free fatty acid (FA)-treated hepatocytes and the livers of both obesity-induced mice and NAFLD patients. Overexpression of MIR20B significantly increased hepatic lipid accumulation and triglyceride levels. Furthermore, MIR20B significantly reduced FA oxidation and mitochondrial biogenesis by targeting PPARA. In Mir20b-introduced mice, the effect of fenofibrate to ameliorate hepatic steatosis was significantly suppressed. Finally, inhibition of Mir20b significantly increased FA oxidation and uptake, resulting in improved insulin sensitivity and a decrease in NAFLD progression. Moreover, combination of fenofibrate and anti-Mir20b exhibited the synergic effect on improvement of NAFLD in MCD-fed mice. Conclusions: Taken together, our results demonstrate that the novel MIR20B targets PPARA, plays a significant role in hepatic lipid metabolism, and present an opportunity for the development of novel therapeutics for NAFLD. Funding: This research was funded by Korea Mouse Phenotyping Project (2016M3A9D5A01952411), the National Research Foundation of Korea (NRF) grant funded by the Korea government (2020R1F1A1061267, 2018R1A5A1024340, NRF-2021R1I1A2041463, 2020R1I1A1A01074940, 2016M3C9A394589324), and the Future-leading Project Research Fund (1.210034.01) of UNIST.

Crosstalk between E-Cadherin/ß-Catenin and NF-κB Signaling Pathways: The Regulation of Host-Pathogen Interaction during Leptospirosis.

Approximately 1 million cases of leptospirosis, an emerging infectious zoonotic disease, are reported each year. Pathogenic Leptospira species express leucine-rich repeat (LRR) proteins that are rarely expressed in non-pathogenic Leptospira species. The LRR domain-containing protein family is vital for the virulence of pathogenic Leptospira species. In this study, the biological mechanisms of an essential LRR domain protein from pathogenic Leptospira were examined. The effects of Leptospira and recombinant LRR20 (rLRR20) on the expression levels of factors involved in signal transduction were examined using microarray, quantitative real-time polymerase chain reaction, and western blotting. The secreted biomarkers were measured using an enzyme-linked immunosorbent assay. rLRR20 colocalized with E-cadherin on the cell surface and activated the downstream transcription factor ß-catenin, which subsequently promoted the expression of MMP7, a kidney injury biomarker. Additionally, MMP7 inhibitors were used to demonstrate that the secreted MMP7 degrades surface E-cadherin. This feedback inhibition mechanism downregulated surface E-cadherin expression and inhibited the colonization of Leptospira. The degradation of surface E-cadherin activated the NF-κB signal transduction pathway. Leptospirosis-associated acute kidney injury is associated with the secretion of NGAL, a downstream upregulated biomarker of the NF-κB signal transduction pathway. A working model was proposed to illustrate the crosstalk between E-cadherin/ß-catenin and NF-κB signal transduction pathways during Leptospira infection. Thus, rLRR20 of Leptospira induces kidney injury in host cells and inhibits the adhesion and invasion of Leptospira through the upregulation of MMP7 and NGAL.

Sphingomyelin synthase 1 mediates hepatocyte pyroptosis to trigger non-alcoholic steatohepatitis.

OBJECTIVE: Lipotoxic hepatocyte injury is a primary event in non-alcoholic steatohepatitis (NASH), but the mechanisms of lipotoxicity are not fully defined. Sphingolipids and free cholesterol (FC) mediate hepatocyte injury, but their link in NASH has not been explored. We examined the role of free cholesterol and sphingomyelin synthases (SMSs) that generate sphingomyelin (SM) and diacylglycerol (DAG) in hepatocyte pyroptosis, a specific form of programmed cell death associated with inflammasome activation, and NASH. DESIGN: Wild-type C57BL/6J mice were fed a high fat and high cholesterol diet (HFHCD) to induce NASH. Hepatic SMS1 and SMS2 expressions were examined in various mouse models including HFHCD-fed mice and patients with NASH. Pyroptosis was estimated by the generation of the gasdermin-D N-terminal fragment. NASH susceptibility and pyroptosis were examined following knockdown of SMS1, protein kinase Cδ (PKCδ), or the NLR family CARD domain-containing protein 4 (NLRC4). RESULTS: HFHCD increased the hepatic levels of SM and DAG while decreasing the level of phosphatidylcholine. Hepatic expression of Sms1 but not Sms2 was higher in mouse models and patients with NASH. FC in hepatocytes induced Sms1 expression, and Sms1 knockdown prevented HFHCD-induced NASH. DAG produced by SMS1 activated PKCδ and NLRC4 inflammasome to induce hepatocyte pyroptosis. Depletion of Nlrc4 prevented hepatocyte pyroptosis and the development of NASH. Conditioned media from pyroptotic hepatocytes activated the NOD-like receptor family pyrin domain containing 3 inflammasome (NLRP3) in Kupffer cells, but Nlrp3 knockout mice were not protected against HFHCD-induced hepatocyte pyroptosis. CONCLUSION: SMS1 mediates hepatocyte pyroptosis through a novel DAG-PKCδ-NLRC4 axis and holds promise as a therapeutic target for NASH.

Radial Probe Endobronchial Ultrasound Using Guide Sheath-Guided Transbronchial Lung Biopsy in Peripheral Pulmonary Lesions without Fluoroscopy / 결핵및호흡기질환

Background@#Radial probe endobronchial ultrasound-guided transbronchial lung biopsy (RP-EBUS-TBLB) has improved the diagnostic yield of bronchoscopic biopsy of peripheral pulmonary lesions (PPLs). The diagnostic yield and complications of RP-EBUS-TBLB for PPLs vary depending on the technique, such as using a guide sheath (GS) or fluoroscopy. In this study, we investigated the utility of RP-EBUS-TBLB using a GS without fluoroscopy for diagnosing PPLs. @*Methods@#We retrospectively reviewed data from 607 patients who underwent RP-EBUS of PPLs from January 2019 to July 2020. TBLB was performed using RP-EBUS with a GS without fluoroscopy. The diagnostic yield and complications were assessed. Multivariable logistic regression analyses were used to identify factors affecting the diagnostic yields. @*Results@#The overall diagnostic accuracy was 76.1% (462/607). In multivariable analyses, the size of the lesion (≥20 mm; odds ratio [OR], 2.06; 95% confidence interval [CI], 1.27–3.33; p=0.003), positive bronchus sign in chest computed tomography (OR, 2.30; 95% CI, 1.40–3.78; p=0.001), a solid lesion (OR, 2.40; 95% CI, 1.31–4.41; p=0.005), and an EBUS image with the probe within the lesion (OR, 6.98; 95% CI, 4.38–11.12; p<0.001) were associated with diagnostic success. Pneumothorax occurred in 2.0% (12/607) of cases and chest tube insertion was required in 0.5% (3/607) of patients. @*Conclusion@#RP-EBUS-TBLB using a GS without fluoroscopy is a highly accurate diagnostic method in diagnosing PPLs that does not involve radiation exposure and has acceptable complication rates.

Utility of Radial Probe Endobronchial Ultrasound Guided Transbronchial Lung Biopsy in Bronchus Sign Negative Peripheral Pulmonary Lesions

Background@#The presence of the bronchus sign on chest computed tomography is associated with an increased diagnostic yield of radial probe endobronchial ultrasound– guided transbronchial lung biopsy (RP-EBUS-TBLB). However, the utility of RP-EBUS-TBLB for bronchus sign negative peripheral pulmonary lesions (PPLs) remains unknown. We investigated the utility of RP-EBUS-TBLB in bronchus sign negative PPLs. @*Methods@#We retrospectively reviewed data from 109 patients who underwent RP-EBUS for bronchus sign negative PPLs from January 2019 to August 2020. TBLB was performed using RP-EBUS with a guide sheath and without fluoroscopy. The EBUS visualization and TBLB diagnostic yields were assessed. Multivariable logistic regression analyses were used to identify factors affecting the EBUS visualization and diagnostic yields. @*Results@#The EBUS visualization yield was 74.1% (68/109). Of the 109 lung lesions, 92 were definitively diagnosed. The overall diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 50.5% (55/109), 34.9% (29/83), 100% (26/26), 100% (29/29), and 32.5% (26/80), respectively. In multivariable analyses, the size of the lesion (≥ 20 mm; odds ratio [OR], 2.62; 95% confidence interval [CI], 1.16–5.93; P = 0.021) and the distance from the pleura (> 10 mm; OR, 2.37; 95% CI, 1.02–5.52; P = 0.045) were associated with EBUS visualization. Regarding diagnostic yield, having the probe within the lesion (OR, 28.50; 95% CI, 6.26–129.85; P < 0.001) and a solid lesion (OR, 14.58; 95% CI, 2.64–80.38; P = 0.002) were associated with diagnostic success. Pneumothorax and hemoptysis occurred in 3.7% (4/109) and 0.9% (1/109), respectively, of the patients. @*Conclusion@#RP-EBUS-TBLB using a GS can be considered a diagnostic method in bronchus sign negative solid PPLs. Having the probe within the lesion and a solid lesion were important for diagnostic success. Complication rates were acceptable.

Radial Probe Endobronchial Ultrasound Using Guide Sheath-Guided Transbronchial Lung Biopsy in Peripheral Pulmonary Lesions without Fluoroscopy / 결핵및호흡기질환

Background@#Radial probe endobronchial ultrasound-guided transbronchial lung biopsy (RP-EBUS-TBLB) has improved the diagnostic yield of bronchoscopic biopsy of peripheral pulmonary lesions (PPLs). The diagnostic yield and complications of RP-EBUS-TBLB for PPLs vary depending on the technique, such as using a guide sheath (GS) or fluoroscopy. In this study, we investigated the utility of RP-EBUS-TBLB using a GS without fluoroscopy for diagnosing PPLs. @*Methods@#We retrospectively reviewed data from 607 patients who underwent RP-EBUS of PPLs from January 2019 to July 2020. TBLB was performed using RP-EBUS with a GS without fluoroscopy. The diagnostic yield and complications were assessed. Multivariable logistic regression analyses were used to identify factors affecting the diagnostic yields. @*Results@#The overall diagnostic accuracy was 76.1% (462/607). In multivariable analyses, the size of the lesion (≥20 mm; odds ratio [OR], 2.06; 95% confidence interval [CI], 1.27–3.33; p=0.003), positive bronchus sign in chest computed tomography (OR, 2.30; 95% CI, 1.40–3.78; p=0.001), a solid lesion (OR, 2.40; 95% CI, 1.31–4.41; p=0.005), and an EBUS image with the probe within the lesion (OR, 6.98; 95% CI, 4.38–11.12; p<0.001) were associated with diagnostic success. Pneumothorax occurred in 2.0% (12/607) of cases and chest tube insertion was required in 0.5% (3/607) of patients. @*Conclusion@#RP-EBUS-TBLB using a GS without fluoroscopy is a highly accurate diagnostic method in diagnosing PPLs that does not involve radiation exposure and has acceptable complication rates.

Utility of Radial Probe Endobronchial Ultrasound Guided Transbronchial Lung Biopsy in Bronchus Sign Negative Peripheral Pulmonary Lesions

Background@#The presence of the bronchus sign on chest computed tomography is associated with an increased diagnostic yield of radial probe endobronchial ultrasound– guided transbronchial lung biopsy (RP-EBUS-TBLB). However, the utility of RP-EBUS-TBLB for bronchus sign negative peripheral pulmonary lesions (PPLs) remains unknown. We investigated the utility of RP-EBUS-TBLB in bronchus sign negative PPLs. @*Methods@#We retrospectively reviewed data from 109 patients who underwent RP-EBUS for bronchus sign negative PPLs from January 2019 to August 2020. TBLB was performed using RP-EBUS with a guide sheath and without fluoroscopy. The EBUS visualization and TBLB diagnostic yields were assessed. Multivariable logistic regression analyses were used to identify factors affecting the EBUS visualization and diagnostic yields. @*Results@#The EBUS visualization yield was 74.1% (68/109). Of the 109 lung lesions, 92 were definitively diagnosed. The overall diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 50.5% (55/109), 34.9% (29/83), 100% (26/26), 100% (29/29), and 32.5% (26/80), respectively. In multivariable analyses, the size of the lesion (≥ 20 mm; odds ratio [OR], 2.62; 95% confidence interval [CI], 1.16–5.93; P = 0.021) and the distance from the pleura (> 10 mm; OR, 2.37; 95% CI, 1.02–5.52; P = 0.045) were associated with EBUS visualization. Regarding diagnostic yield, having the probe within the lesion (OR, 28.50; 95% CI, 6.26–129.85; P < 0.001) and a solid lesion (OR, 14.58; 95% CI, 2.64–80.38; P = 0.002) were associated with diagnostic success. Pneumothorax and hemoptysis occurred in 3.7% (4/109) and 0.9% (1/109), respectively, of the patients. @*Conclusion@#RP-EBUS-TBLB using a GS can be considered a diagnostic method in bronchus sign negative solid PPLs. Having the probe within the lesion and a solid lesion were important for diagnostic success. Complication rates were acceptable.

Mucosal Associated Invariant T (MAIT) Cell Responses Differ by Sex in COVID-19

Sexual dimorphisms in immune responses contribute to coronavirus disease 2019 (COVID-19) outcomes, yet the mechanisms governing this disparity remain incompletely understood. We carried out sex-balanced sampling of peripheral blood mononuclear cells from confirmed COVID-19 inpatients and outpatients, uninfected close contacts, and healthy controls for 36-color flow cytometry and single cell RNA-sequencing. Our results revealed a pronounced reduction of circulating mucosal associated invariant T (MAIT) cells in infected females. Integration of published COVID-19 airway tissue datasets implicate that this reduction represented a major wave of MAIT cell extravasation during early infection in females. Moreover, female MAIT cells possessed an immunologically active gene signature, whereas male counterparts were pro-apoptotic. Collectively, our findings uncover a female-specific protective MAIT profile, potentially shedding light on reduced COVID-19 susceptibility in females.

Chebulic Acid Prevents Methylglyoxal-Induced Mitochondrial Dysfunction in INS-1 Pancreatic ß-Cells.

To investigate the anti-diabetic properties of chebulic acid (CA) associated with the prevention of methyl glyoxal (MG)-induced mitochondrial dysfunction in INS-1 pancreatic ß-cells, INS-1 cells were pre-treated with CA (0.5, 1.0, and 2.0 µM) for 48 h and then treated with 2 mM MG for 8 h. The effects of CA and MG on INS-1 cells were evaluated using the following: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay; glyoxalase 1 (Glo-1) expression via Western blot and enzyme activity assays; Nrf-2, nuclear factor erythroid 2-related factor 2 protein expression via Western blot assay; reactive oxygen species (ROS) production assay; mRNA expression of mitochondrial dysfunction related components (UCP2, uncoupling protein 2; VDAC1, voltage-dependent anion-selective channel-1; cyt c, cytochrome c via quantitative reverse transcriptase-PCR; mitochondrial membrane potential (MMP); adenosine triphosphate (ATP) synthesis; glucose-stimulated insulin secretion (GSIS) assay. The viability of INS-1 cells was maintained upon pre-treating with CA before exposure to MG. CA upregulated Glo-1 protein expression and enzyme activity in INS-1 cells and prevented MG-induced ROS production. Mitochondrial dysfunction was alleviated by CA pretreatment; this occurred via the downregulation of UCP2, VDAC1, and cyt c mRNA expression and the increase of MMP and ATP synthesis. Further, CA pre-treatment promoted the recovery from MG-induced decrease in GSIS. These results indicated that CA could be employed as a therapeutic agent in diabetes due to its ability to prevent MG-induced development of insulin sensitivity and oxidative stress-induced dysfunction of ß-cells.

Anti-hyperglycemic and hypolipidemic effects of black ginseng extract containing increased Rh4, Rg5, and Rk1 content in muscle and liver of type 2 diabetic db/db mice.

Black ginseng (BG), which is produced by repeated steaming and drying of fresh ginseng, has various pharmacological and therapeutic properties. This study investigated the anti-hyperglycemic and hypolipidemic effects of BG ethanolic extract in type 2 diabetic db/db mice. The levels of fasting blood glucose, HbA1c, insulin levels and thiobarbituric acid reactive substances values were decreased in the groups fed BG extract (BG) (100 and 900 mg/kg BW/day), compared to the control group (CON). In the BG compared with the CON, hepatic steatosis in the liver and the size of adipocytes in muscle tissue were improved. The administration of BG regulated the glucose transporter type (GLUT) 4 and 2, and peroxisome proliferator-activated receptor (PPAR) α and γ in muscle and liver. Moreover, ginsenosides (Rh4, Rg5, and Rk1), which profiled by HPLC, regulated the markers for lipid metabolism and glucose metabolism; PPARs and GLUTs in muscle and C2C12 rather than liver cells and tissue. These findings suggested that ginsenosides (Rh4, Rg5, and Rk1) from BG extract can ameliorate type 2 diabetes through their anti-hyperglycemic and hypolipidemic effects.

Inhibition of Ceramide Accumulation in Podocytes by Myriocin Prevents Diabetic Nephropathy.

BACKGROUND: Ceramides are associated with metabolic complications including diabetic nephropathy in patients with diabetes. Recent studies have reported that podocytes play a pivotal role in the progression of diabetic nephropathy. Also, mitochondrial dysfunction is known to be an early event in podocyte injury. Thus, we tested the hypothesis that ceramide accumulation in podocytes induces mitochondrial damage through reactive oxygen species (ROS) production in patients with diabetic nephropathy. METHODS: We used Otsuka Long Evans Tokushima Fatty (OLETF) rats and high-fat diet (HFD)-fed mice. We fed the animals either a control- or a myriocin-containing diet to evaluate the effects of the ceramide. Also, we assessed the effects of ceramide on intracellular ROS generation and on podocyte autophagy in cultured podocytes. RESULTS: OLETF rats and HFD-fed mice showed albuminuria, histologic features of diabetic nephropathy, and podocyte injury, whereas myriocin treatment effectively treated these abnormalities. Cultured podocytes exposed to agents predicted to be risk factors (high glucose, high free fatty acid, and angiotensin II in combination [GFA]) showed an increase in ceramide accumulation and ROS generation in podocyte mitochondria. Pretreatment with myriocin reversed GFA-induced mitochondrial ROS generation and prevented cell death. Myriocin-pretreated cells were protected from GFA-induced disruption of mitochondrial integrity. CONCLUSION: We showed that mitochondrial ceramide accumulation may result in podocyte damage through ROS production. Therefore, this signaling pathway could become a pharmacological target to abate the development of diabetic kidney disease.

Diagnosis and treatment of multidrug-resistant tuberculosis / 영남의대학술지

Tuberculosis (TB) is still a major health problem worldwide. Especially, multidrug-resistant TB (MDR-TB), which is defined as TB that shows resistance to both isoniazid and rifampicin, is a barrier in the treatment of TB. Globally, approximately 3.4% of new TB patients and 20% of the patients with a history of previous treatment for TB were diagnosed with MDR-TB. The treatment of MDR-TB requires medications for a long duration (up to 20–24 months) with less effective and toxic second-line drugs and has unfavorable outcomes. However, treatment outcomes are expected to improve due to the introduction of a new agent (bedaquiline), repurposed drugs (linezolid, clofazimine, and cycloserine), and technological advancement in rapid drug sensitivity testing. The World Health Organization (WHO) released a rapid communication in 2018, followed by consolidated guidelines for the treatment of MDR-TB in 2019 based on clinical trials and an individual patient data meta-analysis. In these guidelines, the WHO suggested reclassification of second-line anti-TB drugs and recommended oral treatment regimens that included the new and repurposed agents. The aims of this article are to review the treatment strategies of MDR-TB based on the 2019 WHO guidelines regarding the management of MDR-TB and the diagnostic techniques for detecting resistance, including phenotypic and molecular drug sensitivity tests.

Clinical Features and Outcomes of 98 PatientsHospitalized with SARS-CoV-2 Infection in Daegu,South Korea: A Brief Descriptive Study

Although some information on the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and a few selectedcases has been reported, data on the clinical characteristics and outcomes of patients hospitalized therewith in South Koreaare lacking. We conducted a retrospective single-center study of 98 consecutive hospitalized patients with confirmed SARS-CoV-2infection at Yeungnam University Medical Center in Daegu, South Korea. Sixty patients were women (61.2%), and the mean agewas 55.4±17.1 years. Thirteen patients (13.3%) were treated in the intensive care unit (ICU). The mean interval from symptom onsetto hospitalization was 7.7±4.5 days. Patients who received ICU care were significantly older and were more likely to have diabetesmellitus. The National Early Warning Score on the day of admission was significantly higher in patients requiring ICU care. Acuterespiratory distress syndrome (13/13 patients; 100%), septic shock (9/13; 69.2%), acute cardiac injury (9/13; 69.2%), and acute kidneyinjury (8/13; 61.5%) were more common in patients who received ICU care. All patients received antibiotic therapy, and most(97/98 patients; 99.0%) received antiviral therapy (lopinavir/ritonavir). Hydroxychloroquine was used in 79 patients (80.6%), andglucocorticoid therapy was used in 18 patients (18.4%). In complete blood counts, lymphopenia was the most common finding(40/98 patients; 40.8%). Levels of all proinflammatory cytokines were significantly higher in ICU patients. As of March 29, 2020, themortality rate was 5.1%. Here, we report the clinical characteristics and laboratory findings of SARS-CoV-2 patients in South Koreaup to March 29, 2020.