E-cigarettes exacerbate allergic inflammation via cytokine induction and MUC5AC/5B expression in a murine asthma model.

The effects of electronic cigarettes (e-cigarettes) vapor on inflammation and mucin secretion on asthmatics remain insufficiently explored. This study investigated the effects of e-cigarette vapor on allergic inflammation, cytokine production, and MUC5AC/5B expression in murine asthma model. Airway hyperresponsiveness was significantly higher in the e-cigarette-exposed ovalbumin (OVA) sensitization group than in the control, e-cigarette exposure, and OVA sensitization groups. The e-cigarette-exposed OVA sensitization group showed significantly greater infiltration of inflammatory cells and Th2-mediated inflammatory cytokines (interleukin-4 and -5) compared to the control, e-cigarette exposure, and OVA sensitization groups. MUC5AC mucin levels were significantly elevated in the e-cigarette exposure, OVA sensitization, and e-cigarette-exposed OVA sensitization groups, whereas MUC5B mucin levels were significantly elevated in the OVA sensitization and e-cigarette-exposed OVA sensitization groups. The results may suggest that the exposure to e-cigarette vapor in an asthmatics promoted allergic inflammation and increased mucin secretion, ultimately leading to the exacerbation of asthma.

Geriatric risk model for older patients with diffuse large B-cell lymphoma (GERIAD): a prospective multicenter cohort study.

Background/Aims: Optimal risk stratification based on simplified geriatric assessment to predict treatment-related toxicity and survival needs to be clarified in older patients with diffuse large B-cell lymphoma (DLBCL). Methods: This multicenter prospective cohort study enrolled newly diagnosed patients with DLBCL (≥ 65 yr) between September 2015 and April 2018. A simplified geriatric assessment was performed at baseline using Activities of Daily Living (ADL), Instrumental ADL (IADL), and Charlson's Comorbidity Index (CCI). The primary endpoint was event-free survival (EFS). Results: The study included 249 patients, the median age was 74 years (range, 65-88), and 125 (50.2%) were female. In multivariable Cox analysis, ADL, IADL, CCI, and age were independent factors for EFS; an integrated geriatric score was derived and the patients stratified into three geriatric categories: fit (n = 162, 65.1%), intermediate-fit (n = 25, 10.0%), and frail (n = 62, 24.9%). The established geriatric model was significantly associated with EFS (fit vs. intermediate-fit, HR 2.61, p < 0.001; fit vs. frail, HR 4.61, p < 0.001) and outperformed each covariate alone or in combination. In 87 intermediate-fit or frail patients, the relative doxorubicin dose intensity (RDDI) ≥ 62.4% was significantly associated with worse EFS (HR, 2.15, 95% CI 1.30-3.53, p = 0.002). It was related with a higher incidence of grade ≥ 3 symptomatic non-hematologic toxicities (63.2% vs. 27.8%, p < 0.001) and earlier treatment discontinuation (34.5% vs. 8.0%, p < 0.001) in patients with RDDI ≥ 62.4% than in those with RDDI < 62.4%. Conclusions: This model integrating simplified geriatric assessment can risk-stratify older patients with DLBCL and identify those who are highly vulnerable to standard dose-intensity chemoimmunotherapy.

Balloon-Expandable Versus Self-Expandable Valve in Transcatheter Aortic Valve Replacement: A Nation-Wide Study.

A few studies have reported comparative analysis of clinical outcomes between balloon-expandable valve (BEV) and self-expandable valve (SEV) after transcatheter aortic valve replacement (TAVR) in patients with severe aortic stenosis using newer-generation devices. However, those reports were mostly limited to short-term outcomes and Western populations. In the present study, data of patients with severe aortic stenosis who underwent TAVR between March 2016 and December 2018 were obtained from the National Health Insurance Service in Korea. The primary end point, defined as all-cause mortality, was compared in BEV (SAPIEN 3, Edwards Lifesciences, Irvine, California) and SEV (Evolut R, Medtronic, Minneapolis, MN) groups using a propensity-score matching analysis. Cumulative event rates of ischemic stroke, repeat procedures, and permanent pacemaker insertion (PPI) were evaluated as secondary outcomes. All events were followed up to a maximum of 3 years. A total of 1,172 patients underwent transfemoral TAVR, of whom 707 (60.3%) were treated with BEV and 452 (38.6%) with SEV. After 1:1 propensity-score matching, the BEV group showed lower all-cause mortality after a median follow-up of 12.0 months (mean: 13.1 ± 9.3 months) based on Cox proportional hazard model analysis (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.45 to 0.99, p = 0.04). Cumulative incidence of ischemic stroke was not statistically different between the 2 groups (HR 0.68, 95% CI 0.29 to 1.59, p = 0.37). PPI occurred less frequently in the BEV group (HR 0.4, 95% CI 0.25 to 0.64, p < 0.01). Repeat procedures were rare (1 patient in BEV and 2 patients in SEV group). In conclusion, Korean nation-wide data analysis showed that BEV was associated with less all-cause death and incidence of PPI after TAVR than was SEV using a newer-generation device.

Safety and efficacy of a novel anti-CD19 chimeric antigen receptor T cell product targeting a membrane-proximal domain of CD19 with fast on- and off-rates against non-Hodgkin lymphoma: a first-in-human study.

BACKGROUND: Commercial anti-CD19 chimeric antigen receptor T-cell therapies (CART19) are efficacious against advanced B-cell non-Hodgkin lymphoma (NHL); however, most patients ultimately relapse. Several mechanisms contribute to this failure, including CD19-negative escape and CAR T dysfunction. All four commercial CART19 products utilize the FMC63 single-chain variable fragment (scFv) specific to a CD19 membrane-distal epitope and characterized by slow association (on) and dissociation (off) rates. We hypothesized that a novel anti-CD19 scFv that engages an alternative CD19 membrane-proximal epitope independent of FMC63 and that is characterized by faster on- and off-rates could mitigate CART19 failure and improve clinical efficacy. METHODS: We developed an autologous CART19 product with 4-1BB co-stimulation using a novel humanized chicken antibody (h1218). This antibody is specific to a membrane-proximal CD19 epitope and harbors faster on/off rates compared to FMC63. We tested h1218-CART19 in vitro and in vivo using FMC63-CART19-resistant models. We conducted a first-in-human multi-center phase I clinical trial to test AT101 (clinical-grade h1218-CART19) in patients with relapsed or refractory (r/r) NHL. RESULTS: Preclinically, h1218- but not FMC63-CART19 were able to effectively eradicate lymphomas expressing CD19 point mutations (L174V and R163L) or co-expressing FMC63-CAR19 as found in patients relapsing after FMC63-CART19. Furthermore, h1218-CART19 exhibited enhanced killing of B-cell malignancies in vitro and in vivo compared with FMC63-CART19. Mechanistically, we found that h1218-CART19 had reduced activation-induced cell death (AICD) and enhanced expansion compared to FMC63-CART19 owing to faster on- and off-rates. Based on these preclinical results, we performed a phase I dose-escalation trial, testing three dose levels (DL) of AT101 (the GMP version of h1218) using a 3 + 3 design. In 12 treated patients (7 DLBCL, 3 FL, 1 MCL, and 1 MZL), AT101 showed a promising safety profile with 8.3% grade 3 CRS (n = 1) and 8.3% grade 4 ICANS (n = 1). In the whole cohort, the overall response rate was 91.7%, with a complete response rate of 75.0%, which improved to 100% in DL-2 and -3. AT101 expansion correlates with CR and B-cell aplasia. CONCLUSIONS: We developed a novel, safe, and potent CART19 product that recognizes a membrane-proximal domain of CD19 with fast on- and off-rates and showed significant efficacy and promising safety in patients with relapsed B-cell NHL. TRIAL REGISTRATION: NCT05338931; Date: 2022-04-01.

Complete response of metastatic BRAF V600-mutant anaplastic thyroid cancer following adjuvant dabrafenib and trametinib treatment: A case report.

BACKGROUND: Anaplastic thyroid cancer (ATC) is a rare but aggressive type of thyroid carcinoma. BRAF V600E-mutation, which is found in 10%-50% of ATCs, is associated with poor prognosis. A recent clinical trial reported a substantial clinical benefit of concomitant treatment of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for treating BRAF V600E-mutant ATC. However, reports on patients with ATC treated with this regimen following surgery are lacking. CASE SUMMARY: We report the case of a 63-year-old female patient diagnosed with BRAF V600E-mutant ATC. Following three surgeries-total thyroidectomy, total laryngectomy, and neck dissection-she was diagnosed with lung metastasis during follow-up. The metastatic ATC was successfully treated with dabrafenib and trametinib. The patient achieved a complete response at the 32-mo follow-up. CONCLUSION: Adjuvant chemotherapy with dabrafenib plus trametinib is efficacious for treatment and prevention of recurrent ATC with BRAF mutation following surgery.

Comparison of first-line treatment with CHOP versus ICED in patients with peripheral T-cell lymphoma eligible for upfront autologous stem cell transplantation.

Introduction: Upfront autologous stem cell transplantation (ASCT) has been recommended for patients who are newly diagnosed with peripheral T-cell lymphoma (PTCL), and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), an anthracycline-based chemotherapy has been the frontline chemotherapy for PTCL. However, it is not clear whether anthracycline-based chemotherapies such as CHOP could be standard induction therapy for PTCL. Methods: We conducted a randomized phase II study to compare CHOP with fractionated ifosfamide, carboplatin, etoposide, and dexamethasone (ICED) for patients eligible for ASCT. The primary endpoint was progression-free survival (PFS) and secondary endpoints included objective response rate, overall survival (OS), and safety profiles. Results: Patients were randomized into either CHOP (n = 69) or ICED (n = 66), and the characteristics of both arms were not different. PTCL-not otherwise specified (NOS, n = 60) and angioimmunoblastic T-cell lymphoma (AITL, n = 53) were dominant. The objective response rate was not different between CHOP (59.4%) and ICED (56.1%), and the 3-year PFS was not different between CHOP (36.7%) and ICED (33.1%). In AITL patients, CHOP was favored over ICED whereas ICED was associated with more cytopenia and reduced dose intensity. Patients who received upfront ASCT after achieving complete response to CHOP or ICED showed 80% of 3-year OS. Discussion: In summary, our study showed no therapeutic difference between CHOP and ICED in terms of response and PFS. Thus, CHOP might remain the reference regimen especially for AITL based on its better outcome in AITL, and upfront ASCT could be recommended as a consolidation of complete response in patients with PTCL.

C-C Motif Chemokine Receptor 3-Mediated Extracellular Signal-Regulated Kinase 1/2 and p38 Mitogen-Activated Protein Kinase Signaling: Promising Targets for Human Airway Epithelial Mucin 5AC Induction by Eotaxin-2 and Eotaxin-3.

INTRODUCTION: Eotaxin-2 and -3 of the C-C chemokine subfamily function as potent chemoattractant factors for eosinophil recruitment and various immune responses in allergic and inflammatory airway diseases. Mucin 5AC (MUC5AC), a major gel-forming secretory mucin, is overexpressed in airway inflammation. However, the association between mucin secretion and eotaxin-2/3 expression in the upper and lower airway epithelial cells has not been fully elucidated. Therefore, in this study, we investigated the effects of eotaxin-2/3 on MUC5AC expression and its potential signaling mediators. METHODS: We analyzed the effects of eotaxin-2 and -3 on NCI-H292 human airway epithelial cells and primary human nasal epithelial cells (HNEpCs) via reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, and western blotting. Along with immunoblot analyses with specific inhibitors and small interfering RNA (siRNA), we explored the signaling pathway involved in MUC5AC expression following eotaxin-2/3 treatment. RESULTS: In HCI-H292 cells, eotaxin-2/3 activated the mRNA expression and protein production of MUC5AC. A specific inhibitor of C-C motif chemokine receptor 3 (CCR3), SB328437, suppressed eotaxin-2/3-induced MUC5AC expression at both the mRNA and protein levels. Eotaxin-2/3 induced the phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 and p38, whereas pretreatment with a CCR3 inhibitor significantly attenuated this effect. Induction of MUC5AC expression with eotaxin-2/3 was decreased by U0126 and SB203580, specific inhibitors of ERK1/2 and p38 mitogen-activated protein kinase (MAPK), respectively. In addition, cell transfection with ERK1/2 and p38 siRNAs inhibited eotaxin-2/3-induced MUC5AC expression. Moreover, specific inhibitors (SB328437, U0126, and SB203580) attenuated eotaxin-2/3-induced MUC5AC expression in HNEpCs. CONCLUSION: Our results imply that CCR3-mediated ERK1/2 and p38 MAPK are involved in the signal transduction of eotaxin-2/3-induced MUC5AC overexpression.

The comprehensive expression of BCL2 family genes determines the prognosis of diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a prevalent and aggressive non-Hodgkin's lymphoma, and 40% of patients succumb to death. Despite numerous clinical trials aimed at developing treatment strategies beyond the conventional R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen, there have been no positive results thus far. Although the selective BCL2 inhibitor venetoclax has shown remarkable efficacy in chronic lymphocytic leukemia, its therapeutic effect in DLBCL was limited. We hypothesized that the limited therapeutic effect of venetoclax in DLBCL may be attributed to the complex expression and interactions of BCL2 family members, including BCL2. Therefore, we aimed to comprehensively analyze the expression patterns of BCL2 family members in DLBCL. We analyzed 157 patients with de novo DLBCL diagnosed at Asan Medical Center and Ajou University Hospital. The mRNA expression levels of BCL2 family members were quantified using the NanoString technology. BCL2 family members showed distinct heterogeneous expression patterns both intra- and inter-patient. Using unsupervised hierarchical cluster analysis, we were able to classify patients with similar BCL2 family expression pattern and select groups with clear prognostic features, C1 and C6. In the group with the best prognosis, C1, the expression of pro-apoptotic and pro-apoptotic BH3-only group gene expressions were increased, while anti-apoptotic group expression was significantly increased in both C1 and C6. Based on this, we generated the BCL2 signature score using the expression of pro-apoptotic genes BOK and BCL2L15, and anti-apoptotic gene BCL2. The BCL2 signature score 0 had the best prognosis, score 1/2 had intermediate prognosis, and score 3 had the worst prognosis (EFS, p = 0.0054; OS, p = 0.0011). Multivariate analysis, including COO and IPI, showed that increase in the BCL2 signature score was significantly associated with poor prognosis for EFS, independent of COO and IPI. The BCL2 signature score we proposed in this study provides information on BCL2 family deregulation based on the equilibrium of pro-versus anti-apoptotic BCL2 family, which can aid in the development of new treatment strategies for DLBCL in the future.

Paradoxical vocal fold motion masquerading as post-anesthetic respiratory distress: A case report.

BACKGROUND: Functional vocal cord disorders can be a differential diagnosis for postoperative upper airway obstruction requiring urgent intervention. However, this may be unfamiliar to anesthesiologists who would favor inappropriate airway intervention and increased morbidity. CASE SUMMARY: A 61-year-old woman underwent cervical laminectomy, followed by laparoscopic cholecystectomy 10 mo later. Despite adequate reversal of neuromuscular blockade, the patient experienced repetitive respiratory difficulty with inspiratory stridor after extubation. After the second operation, the patient was diagnosed with paradoxical vocal fold motion (PVFM) by an otolaryngologist based on the clinical features and fiberoptic bronchoscopy results, and the patient was successfully treated. CONCLUSION: PVFM should be considered a differential diagnosis if a patient presents with stridor after general anesthesia.

A non-interventional, post-marketing surveillance study evaluating the safety and effectiveness of biosimilar rituximab (CT-P10) during routine clinical practice in the Republic of Korea.

BACKGROUND: CT-P10 was the first licensed rituximab biosimilar. This Korean post-marketing surveillance study evaluated CT-P10 safety and effectiveness in approved indications. RESEARCH DESIGN AND METHODS: This prospective, open-label, observational, phase 4 study collected routine clinical practice data across 27 centers in the Republic of Korea. Patients received their first CT-P10 treatment, per prescribing information, for non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), or microscopic polyangiitis (MPA) during the surveillance period (16 November 2016-15 November 2020). Safety (including adverse events [AEs] and adverse drug reactions [ADRs]) and disease-specific clinical response (by best overall response [NHL/CLL], Disease Activity Score in 28-joints [RA], or Birmingham Vasculitis Activity Score for Wegener's Granulomatosis [GPA/MPA]) were assessed for ≤1 year (NHL/CLL) or ≤24 weeks (RA/GPA/MPA). RESULTS: The safety population comprised 677 patients (604 NHL, 16 CLL, 42 RA, 7 GPA, 8 MPA). AEs/ADRs were reported for 68.4%/27.7% (NHL/CLL), 31.0%/14.3% (RA), and 86.7%/13.3% (GPA/MPA) of patients. Serious AEs and unexpected ADRs did not raise new safety signals. Pneumonia was the most frequent serious ADR overall. Positive effectiveness outcomes were observed. CONCLUSIONS: Findings were consistent with the known CT-P10/reference rituximab safety profile, with high effectiveness observed in NHL/CLL and RA.

Outcomes in Refractory Diffuse Large B-Cell Lymphoma: Results from Two Prospective Korean Cohorts.

PURPOSE: Diffuse large B-cell lymphoma (DLBCL) is the most common hematologic malignancy worldwide. Although substantial improvement has been achieved by the frontline rituximab-based chemoimmunotherapy, up to 40%-50% of patients will eventually have relapsed or refractory disease, whose prognosis is extremely dismal. MATERIALS AND METHODS: We have carried out two prospective cohort studies that include over 1,500 DLBCL patients treated with rituximab plus CHOP (#NCT01202448 and #NCT02474550). In the current report, we describe the outcomes of refractory DLBCL patients. Patients were defined to have refractory DLBCL if they met one of the followings, not achieving at least partial response after 4 or more cycles of R-CHOP; not achieving at least partial response after 2 or more cycles of salvage therapy; progressive disease within 12 months after autologous stem cell transplantation. RESULTS: Among 1,581 patients, a total of 260 patients met the criteria for the refractory disease after a median time to progression of 9.1 months. The objective response rate of salvage treatment was 26.4%, and the complete response rate was 9.6%. The median overall survival (OS) was 7.5 months (95% confidence interval, 6.4 to 8.6), and the 2-year survival rate was 22.1%±2.8%. The median OS for each refractory category was not significantly different (p=0.529). CONCLUSION: In line with the previous studies, the outcomes of refractory DLBCL patients were extremely poor, which necessitates novel approaches for this population.

Ghrelin Downregulates Lipopolysaccharide/ Leptin-Induced MUC5AC Expression in Human Nasal Epithelial Cells.

OBJECTIVES: Obesity, which induces chronic low-grade systemic inflammation in the human body, is a known risk factor for various diseases. Recent studies have shown associations between various otorhinolaryngological diseases and obesity. In particular, inflammatory sinonasal diseases have been found to be strongly associated with obesity-related proinflammatory mediators. Many studies have been conducted to identify therapeutic agents for controlling obesity-related inflammatory airway diseases. Ghrelin, an endogenous peptide from the stomach, has anti-inflammatory and antioxidative effects in a wide range of tissues. However, the effect of ghrelin on the regulation of mucus secretion has not yet been studied in the human nasal mucosa. Therefore, we investigated the effects of ghrelin on lipopolysaccharide (LPS)/leptin-mediated MUC5AC expression and mechanisms involved in human nasal epithelial cells (HNEpCs). METHODS: In HNEpCs, the effect and signaling pathways of ghrelin on LPS/leptin-induced MUC5AC expression were examined using reverse transcription polymerase chain reaction, real-time polymerase chain reaction, enzyme immunoassays, Western blotting, and immunofluorescence staining. RESULTS: Growth hormone secretagogue receptor 1a (GHSR1a) was expressed in the HNEpCs. Ghrelin downregulated LPS/leptin-induced MUC5AC expression, which was abolished by D-Lys-3-growth hormone-releasing peptide 6 (D-Lys-3-GHRP-6). Ghrelin significantly inhibited LPS/leptin-activated extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinases (MAPKs). These ghrelin-mediated changes in MAPK activation were abolished by D-Lys-3-GHRP-6. These. RESULTS: showed that ghrelin inhibits LPS/leptin-induced MUC5AC overexpression by modulating the ERK1/2 and p38 MAPK pathways in HNEpCs. CONCLUSION: These findings suggest that ghrelin is a potential therapeutic agent for treating obesity-related inflammatory sinonasal diseases.

Bendamustine Plus Rituximab for Mantle Cell Lymphoma: A Korean, Multicenter Retrospective Analysis.

BACKGROUND/AIM: The combination of bendamustine and rituximab (BR) is highly effective in both treatment-naïve and relapsed or refractory mantle cell lymphoma (MCL). Due to the rarity of MCL and limited accessibility of BR, clinical outcome from BR in the routine clinical practice in Korean patients are limited. PATIENTS AND METHODS: To evaluate the real-world outcomes of BR treatment for MCL in Korea, medical records from 37 patients were retrospectively analyzed. RESULTS: Twenty-five patients received BR as first-line treatment, and ten, eight, and seven patients were classified as low-, intermediate-, and high-risk by MIPI-classification, respectively. With the follow-up duration of 24.3 months, the three-year progression-free survival (PFS) rate was 80.5%±11.8%. PFS significantly differed according to MIPI-classification (p=0.002) and TP53 status (p=0.042). The three-year overall survival (OS) rate was 92.0%±5.4%. In 12 patients who received BR as salvage treatment, the median age was 66. The median PFS was 12.8 months, and the three-year OS rate was 66.8%±16.2%. CONCLUSION: BR is an effective regimen for both newly-diagnosed and relapsed or refractory MCL patients in Korea, with favorable response rates and outcomes.

Clinical benefit of long-term use of dual antiplatelet therapy for acute myocardial infarction patients with the PEGASUS-TIMI 54 criteria.

Background: We evaluated the effectiveness of extended dual antiplatelet therapy (DAPT) usage after 2nd-generation drug elution stent implantation in acute myocardial infarction (AMI) survivors with high ischemic risk characteristics who had no major bleeding for 24 months under at least 1 year of DAPT maintenance. Materials and methods: The primary ischemic and bleeding endpoints were the risk of mortality and the risk of BARC 3 or 5 (major) bleeding. We investigated the event rates for 2-5 years after the index procedure. Results: Of 3382 post-AMI survivors who met the PEGASUS-TIMI 54 (PEGASUS) criteria and without major bleeding until 2 years, 2281 (67.4%) maintained DAPT over 24 months, and 1101 (32.5%) switched DAPT to a single antiplatelet agent. The >24 M DAPT group showed a lower risk of mortality than the 12-24 M DAPT group (7.2 vs. 9.2%; adjusted hazard ratio: 0.648; 95% confidence interval: 0.595-0.976; p < 0.001). The mortality risk was significantly greater as the number of PEGASUS criteria increased (p < 0.001). DAPT > 24 months was not significantly associated with a decreased risk for major bleeding in the population meeting the PEGASUS criteria (2.0 vs. 1.1%; p = 0.093). The results were consistent after propensity-score matching and inverse probability weighting to adjust for baseline differences. Conclusion: Extended DAPT over 24 months was associated with a lower risk of mortality without increasing the risk of major bleeding among 2 years survivors after AMI who met the PEGASUS criteria and had no major bleeding events before 24 months.

Saponin attenuates diesel exhaust particle (DEP)-induced MUC5AC expression and pro-inflammatory cytokine upregulation via TLR4/TRIF/NF-κB signaling pathway in airway epithelium and ovalbumin (OVA)-sensitized mice.

Background: Diesel exhaust particle (DEP) is a harmful kind of particulate matter known to exacerbate pre-existing respiratory diseases. Although their adverse effects on airway pathologies have been widely studied, the mechanistic analysis of signaling pathways and potential targets in reducing DEP-induced mucin secretion and pro-inflammatory cytokine production remain elusive. We, for the first time, investigated the effects of Korean Red Ginseng (KRG) extracts on mucin overproduction and airway inflammation induced by DEP. Methods: The effects of KRG and saponin on DEP-induced expression of MUC5AC and interleukin (IL)-6/8 were examined by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) in human airway epithelial NCI-H292 cells. We conducted Western blotting analysis to analyze the associated signaling pathways. To evaluate the effects of saponin treatment on DEP-induced MUC5AC expression and inflammatory cell infiltrations in ovalbumin (OVA)-sensitized mice, immunohistochemical (IHC) staining and real-time PCR were implemented. Results: The KRG extracts markedly attenuated DEP-induced MUC5AC expression in vitro by inhibiting the TLR4/TRIF/NF-κB pathway. Furthermore, KRG and saponin inhibited DEP-induced pro-inflammatory cytokine IL-6/8 production. The in vivo study revealed that saponin blocked DEP-induced inflammation, mucin production and MUC5AC expression. Conclusion: Our study revealed that KRG extracts have inhibitory effects on DEP-induced expression of MUC5AC and the production of pro-inflammatory cytokines. This finding provides novel insights into the mechanism by which saponin alleviates diesel-susceptible airway inflammation, elucidating its potential as a phytotherapeutic agent for inflammatory pathologies of airway.

SARS-CoV-2 Induces Expression of Cytokine and MUC5AC/5B in Human Nasal Epithelial Cell through ACE 2 Receptor.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a novel infectious respiratory disease called COVID-19, which is threatening public health worldwide. SARS-CoV-2 spike proteins connect to the angiotensin converting enzyme 2 (ACE2) receptor through the receptor binding domain and are then activated by the transmembrane protease serine subtype 2 (TMPRSS2). The ACE2 receptor is highly expressed in human nasal epithelial cells. Nasal ciliated cells are primary targets for SARS-CoV-2 replication. However, the effect of SARS-CoV-2 on the upper respiratory tract remains unknown, thus leading to the purpose of our study. We investigate the effects of SARS-CoV-2 on cytokines and mucin expression in human nasal epithelial cells. Methods: We investigated the effects of the SARS-CoV-2 spike protein receptor binding domain (RBD) on cytokines (IL-1ß, IL-6, and IL-8) and MUC5AC/5B expression via real-time PCR, ELISA, periodic acid-Schiff (PAS) staining, and immunofluorescence staining in cultured human nasal epithelial cells. Results: The mRNA expression and protein production of cytokines (IL-1ß, IL-6, and IL-8) and MUC5AC/5B were increased by SARS-CoV-2 spike protein RBD. ACE2 receptor inhibitor suppressed the expression of cytokines (IL-1ß, IL-6, and IL-8) and MUC5AC/5B induced by SARS-CoV-2 spike protein RBD. Conclusions: SARS-CoV-2 induced cytokines (IL-1ß, IL-6, and IL-8) and MUC5AC/5B expression through the ACE 2 receptor in human nasal epithelial cells. Therefore, ACE2 receptor inhibitors can be an effective therapeutic option for SARS-CoV-2 infection.

POEMS Syndrome: Presented as Idiopathic Multicentric Castleman Disease of Plasma Cell Variant for Eight Years and Dramatic Treatment with Siltuximab Followed by Autologous Peripheral Blood Stem Cell Transplantation.

BACKGROUND: POEMS syndrome (POEMS) is a rare plasma cell clonal paraneoplastic syndrome consisting of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes presenting with idiopathic multicentric Castleman disease (iMCD) histology, the treatment of which has not yet been well established. iMCD is also a distinctive rare non-clonal lymphoproliferative disorder, of which dramatic response to Siltuximab, a monoclonal anti-IL-6 antibody, has been reported recently. METHODS: the differential diagnosis between POEMS and iMCD can be very challenging because of the identical histology, overlapping similar symptoms such as polyneuropathy, and vital signs insidiously presented to diagnose POEMS. RESULTS: here, we report the case of a 53-year-old man with iMCD treated for 8 years developing sequential polyneuropathy, monoclonal gammopathy, and bone lytic lesions, all of which were confirmed after his iMCD achieved complete remission resulting from siltuximab administration and finally confirmed as POEMS. CONCLUSIONS: we describe the clinical ambiguity of disease presenting that we can face in the real world between iMCD and POEMS and emphasise careful, enduring observation lasting several years.

Pegfilgrastim Prophylaxis Is Effective in the Prevention of Febrile Neutropenia and Reduces Mortality in Patients Aged ≥ 75 Years with Diffuse Large B-Cell Lymphoma Treated with R-CHOP: A Prospective Cohort Study.

PURPOSE: Febrile neutropenia (FN) can cause suboptimal treatment and treatment-related mortality (TRM) in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). MATERIALS AND METHODS: We conducted a prospective cohort study to evaluate the effectiveness of pegfilgrastim prophylaxis in DLBCL patients receiving R-CHOP, and we compared them with the PROCESS cohort (n=485). RESULTS: Since January 2015, 986 patients with DLBCL were enrolled. Pegfilgrastim was administered at least once in 930 patients (94.3%), covering 90.3% of all cycles. FN developed in 137 patients (13.9%) in this cohort (23.7% in the PROCESS cohort, p<0.001), and 4.2% of all cycles (10.2% in the PROCESS cohort, p<0.001). Dose delay was less common (≥3 days: 18.1% vs. 23.7%, p=0.015; ≥5 days: 12.0% vs. 18.3%, p=0.023) in this cohort than in the PROCESS cohort. The incidence of TRM (3.2% vs. 5.6%, p=0.047) and infection-related death (1.8% vs. 4.5%, p=0.004) was lower in this cohort than in the PROCESS cohort. The 4-year overall survival (OS) and progression-free survival (PFS) rates of the two cohorts were not different (OS: 73.0% vs. 71.9%, p=0.545; PFS: 69.5% vs. 68.8%, p=0.616). However, in patients aged ≥75 years, the 4-year OS and PFS rates were higher in this cohort than in the PROCESS cohort (OS: 49.6% vs. 33.7%, p=0.032; PFS: 44.2% vs. 30.3% p=0.047). CONCLUSION: Pegfilgrastim prophylaxis is effective in the prevention of FN and infection-related death in DLBCL patients receiving R-CHOP, and it also improves OS in patients aged ≥75 years.

BCL2 super-expressor diffuse large B-cell lymphoma: a distinct subgroup associated with poor prognosis.

Overexpression of the BCL2 protein has been reported as a poor prognostic factor for diffuse large B-cell lymphoma (DLBCL). However, there are currently no standardized criteria for evaluating BCL2 protein expression. We aimed to evaluate the prognostic value of BCL2 expression determined by immunohistochemistry (IHC), incorporating both the staining intensity and proportion, in patients with de novo DLBCL who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as first-line treatment. We defined tumors with BCL2 expression in nearly all tumor cells with a uniformly strong intensity by IHC as BCL2 super-expressor. The BCL2 super-expressors (n = 35) showed significantly worse event-free survival (EFS; HR, 1.903; 95% CI, 1.159-3.126, P = 0.011) and overall survival (OS; HR, 2.467; 95% CI, 1.474-4.127, P = 0.001) compared with the non-BCL2 super-expressors (n = 234) independent of the international prognostic index (IPI), cell of origin (COO), and double expressor status in the training set (n = 269). The adverse prognostic impact of BCL2 super-expression was confirmed in the validation set (n = 195). When the survival outcomes were evaluated in the entire cohort (n = 464), BCL2 super-expressor group was significantly associated with inferior EFS and OS regardless of IPI, COO, MYC expression, and stages. BCL2 super-expressors had genetic aberrations enriched in the NOTCH and TP53 signaling pathways. This study suggests that the BCL2 super-expressor characterizes a distinct subset of DLBCL with a poor prognosis and warrants further investigation as a target population for BCL-2 inhibitors.