We investigate the impact of the diabatic heating (Q1) over the Indian subcontinent and Tibetan Plateau (TP) sensible heat on the heat waves in South Korea in July and August over a recent 42‐year ...period. In particular, we emphasize the role of the convective activity across the region from northeastern Pakistan to northwestern India (PWI) induced by the heat from the TP, especially over the western and eastern TP. A composite analysis indicates that the composite differences between the heat‐wave summers (HWS) and non‐heat‐wave summers (NHWS) resemble the circum‐global teleconnection (CGT) pattern, which generates a high‐pressure anomaly over the Korean Peninsula, producing favourable conditions for heat waves in South Korea. The first coupled mode of the geopotential height at 250 hPa with the daily maximum temperature (TM) for July and August in South Korea is consistent with the composite pattern, suggesting that the diabatic heating over the Indian subcontinent induces a high‐pressure anomaly over the Korean Peninsula through a CGT‐like mechanism. The regression analysis of the wind vectors in the upper troposphere also indicates that the diabatic heating over the PWI region and associated TP sensible heating generates the strong convection over the PWI region, which corresponds to the anomalous anticyclonic circulation at 250 hPa over the western TP and the cyclonic circulation at 850 hPa over the PWI region. Moreover, the correlation patterns of the 250‐hPa geopotential height with the normalized rainfall amount index (IMRI) over the PWI region and the wave activity flux pattern confirm that the strong convective activity over the PWI region contributes to the anomalous high pressure and heat waves over the Korean Peninsula.
It is found that the PWI diabatic heating triggers anomalous South Asian High shifted to the western TP and then it stimulates stationary Rossby wave propagation and finally generates anomalous high pressures over the Korean Peninsula through stationary Rossby wave propagation, which contribute to the heat waves in South Korea.
Osteoclasts are specialized cells for bone-resorption originated from precursors of macrophage/monocyte lineage. The receptor activator of NFκB ligand (RANKL) initiates osteoclast differentiation, in ...which nuclear factor of activated T cell cytoplasmic 1 (NFATc1) plays a key role as a master transcription factor. In the present report, we show that microRNA-124 (miR-124) regulates osteoclastogenesis of mouse bone marrow macrophages (BMMs) by suppressing NFATc1 expression. On the other hand, synthetic inhibitor that binds specifically to miR-124 enhanced osteoclast differentiation and NFATc1 expression. The overexpression of a constitutively active form of NFATc1 prevented the inhibitory effect of miR-124 on osteoclastogenesis. Finally, miR-124 also affected the proliferation and motility of osteoclast precursors, the latter coinciding with the reduced expression of RhoA and Rac1. These findings not only reveal unprecedented role of miR-124 in osteoclastogenesis but also suggest a novel mode of regulation of NFATc1 in osteoclasts.
Abstract
Investigations concerning oxygen deficiency will increase our understanding of those factors that govern the overall material properties. Various studies have examined the relationship ...between oxygen deficiency and the phase transformation from a nonpolar phase to a polar phase in HfO
2
thin films. However, there are few reports on the effects of oxygen deficiencies on the switching dynamics of the ferroelectric phase itself. Herein, we report the oxygen- deficiency induced enhancement of ferroelectric switching properties of Si-doped HfO
2
thin films. By controlling the annealing conditions, we controlled the oxygen deficiency concentration in the ferroelectric orthorhombic HfO
2
phase. Rapid high-temperature (800 °C) annealing of the HfO
2
film accelerated the characteristic switching speed compared to low-temperature (600 °C) annealing. Scanning transmission electron microscopy and electron energy-loss spectroscopy (EELS) revealed that thermal annealing increased oxygen deficiencies, and first-principles calculations demonstrated a reduction of the energy barrier of the polarization flip with increased oxygen deficiency. A Monte Carlo simulation for the variation in the energy barrier of the polarization flipping confirmed the increase of characteristic switching speed.
Objectives
The optimal sequence for the administration of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for treating non‐small cell lung cancer (NSCLC) is still unclear. ...This study aimed to evaluate the efficacy of sequential afatinib and osimertinib treatment in patients with NSCLC harboring EGFR mutations.
Materials and methods
Electronic records of patients with EGFR‐mutated NSCLC, who were administered afatinib and osimertinib (group A) or other chemotherapy (group B) between October 2014 and 2019, across 16 hospitals in South Korea were reviewed. The primary outcome, time on treatment (TOT), secondary outcome, and overall survival (OS) were estimated using the Kaplan–Meier method and log‐rank test. Multivariate analyses were performed using the Cox proportional hazards model.
Results
Of the 737 patients who received frontline afatinib treatment, 324 with complete records were selected (group A: 126, group B: 198). All patients in group A were T790M positive after afatinib, while patients in group B were all negative or unknown. The median TOT was 35.4 months (95% confidence interval CI: 27.7−45.6) in group A and 20.8 months (95% CI: 19.4−24.0) in group B. The median TOT with afatinib was 13.0 months (95% CI: 12.0−13.9) overall and 15.7 months (95% CI: 13.9−17.3) in group A. The 2‐ and 3‐year survival rates were 86.0 and 69.3% in group A and 75.9 and 55.3% in group B, respectively.
Conclusion
Sequential afatinib and osimertinib treatment resulted in better survival rates than treatment with afatinib followed by other chemotherapies.
Our study evaluated the real‐world efficacy of sequential treatment of afatinib and osimertinib, and compared it with other chemotherapies as a second‐line treatment. Promising real‐world data on first‐line afatinib and second‐line osimertinib may maximize sustained clinical benefit with avoiding chemotherapy and may warrant consideration, though tailored personalized approaches are necessary.
The orientation of magnetic flux ropes in the solar wind is an important component that affects interactions with the Earth's magnetosphere and ionosphere. In this study, we performed global ...magnetohydrodynamic (MHD) simulations on the responses of the magnetosphere and ionosphere to the impact of small‐scale magnetic flux ropes (SMFRs). We considered four types of SMFR structures according to the alignment direction of the flux rope axis in the plane perpendicular to the Sun‐Earth line. The flux rope axis of the two types is oriented in the north‐south direction, while the flux rope axis of the other two types is oriented along the dusk‐dawn direction. Accordingly, the By and Bz profiles of the SMFR types vary as the SMFR passes through the Earth. The main features of the response are as follows: (i) The magnetic reconnection on both the dayside and nightside is well organized by the specific profiles of By and Bz. (ii) One type of SMFRs where Bz turns from south to north and By remains duskward leads to plasmoid formation in the tail, distinguishing it from the other types. (iii) The temporal responses of the tail plasma flow, cross‐tail electric field, tail plasma pressure, and cross‐polar cap potential depend on the specific profiles of By and Bz, causing different response times. (iv) The evolution of ionospheric convection pattern sensitively depends on the magnetic field variation within SMFRs. (v) The peak value of cross‐polar cap potential ranges from 25 kV to >50 kV, providing energy storage suitable for substorm expansion.
Key Points
MHD simulations are undertaken on the magnetospheric and ionospheric responses to four types of small‐scale magnetic flux rope (SMFR)
Magnetospheric responses in terms of reconnection, plasma flow, electric field, and pressure are well distinguished among four SMFRs
The ionospheric convection pattern and cross‐polar cap potential evolve in different ways depending on the impact of specific SMFRs
This study aimed to evaluate treatment outcomes and safety of afatinib in patients with squamous cell carcinoma of the lung (LSCC) who progressed after chemotherapy and immunotherapy. We recruited ...patients both retrospectively and prospectively and collected the outcomes and safety data. Additionally, we performed next-generation sequencing using tumor tissue and/or plasma to explore potential molecular biomarkers. Altogether, 42 patients were included in the final analysis. The median number of prior treatments was three (range 1-8), and the median TTF was 2.1 months. Objective response rate and disease control rate were 16.2% and 59.5%, respectively, and median duration of response was 4.0 months among response evaluable patients (
= 37). Treatment-related adverse events (TRAEs, including diarrhea, stomatitis, and paronychia) occurred in 22 (52.3%) patients; however, most were grade 2 or lower, and only 5 cases were grade 3. TRAEs led to dose modification in 17 (40.5%) and discontinuation in 4 (9.5%) patients. The TTF in patients with
mutations was significantly longer than that in patients without (6.8 vs. 2.1 months,
= 0.045). Our results highlight that afatinib is a reasonable treatment option in terms of effectiveness and safety, and
mutation can be used as a predictive biomarker in clinical settings.
Abstract
In this study, we aimed to investigate the feasibility of serum Krebs von den Lungen-6 (KL-6) as a potential biomarker for treatment-related ILD (TR-ILD) in lung cancer. We recruited ...patients with lung cancer in whom KL-6 was measured to differentiate between pneumonia and ILD (category 1), diagnose and assess the severity of suspicious ILD (category 2), or evaluate baseline levels before cancer treatment (category 3). Among 1,297 patients who underwent KL-6 testing, 422 had lung cancer, and TR-ILD was detected in 195 patients. In categories 1–2, median KL-6 level was higher in drug-induced ILD or acute exacerbation of underlying ILD than in no ILD or radiation-induced pneumonitis, and it was correlated with the severity of TR-ILD. High KL-6 level (cut-off: > 436U/mL) was an independent risk factor for severe TR-ILD, and low KL-6 level with high procalcitonin level (> 0.5 ng/mL) could exclude severe TR-ILD. Patients with severe TR-ILD had worse overall survival than those without, whereas high baseline KL-6 level was associated with worse survival, especially in patients without severe TR-ILD. Therefore, serum KL-6 may be a surrogate marker for predicting the occurrence and assessing the severity of TR-ILD at the time of suspected ILD and before lung cancer treatment.
Pulmonary arteriovenous malformation (PAVM) is a rare pulmonary disease. Although most patients with PAVMs are asymptomatic, cerebral complications associated with PAVMs are often fatal. This study ...aimed to evaluate the risk factors for cerebral complications in patients with PAVMs.
We retrospectively reviewed the medical charts of patients with PAVMs between 2003 and 2021 at two tertiary referral hospitals and one secondary hospital.
Fifty-five patients diagnosed with PAVMs were enrolled in this study. Most patients were female (89.1%), and the median age was 53 years. Thirty patients (54.5%) had incidentally detected PAVMs without symptoms. Twenty-four patients (43.7%) with PAVMs were treated with embolotherapy or surgery. Thirteen patients (23.6%) had cerebral complications. There was no significant difference in the development of cerebral complications according to treatment; however, older age (≥ 65 years) was associated with the development of new cerebral complications in untreated patients with PAVMs (odds ratio, 17.09; 95% confidence interval, 1.16-250.31; P = 0.038).
Older age (≥ 65 years) was a risk factor for the development of cerebral complications in patients with PAVMs; therefore, treatment should be considered in older patients with PAVMs.
Pneumocystis jirovecii pneumonia (PCP) is a fatal respiratory infection, mostly associated with immunocompromised conditions. Several reports have described PCP development in patients who were not ...immunocompromised, but the clinical course and prognosis of PCP are not well understood. We compared the clinical characteristics and prognoses between patients with and without immunocompromised conditions who developed PCP.
We retrospectively analyzed patients who had been treated for PCP from three hospitals. We defined immunocompromised (IC) status as following: human immunodeficiency virus (HIV) infection; hematological malignancy; solid organ tumor under chemotherapy; rheumatic disease; medication with immunosuppressive agents. Patients without immunocompromised status were defined as being non-immunocompromised (non-IC).
The IC and non-IC groups comprised 173 and 14 patients. The median ages were 62.0 and 74.0 years in the IC and the non-IC group, respectively. The median interval between admission and anti-PCP treatment was significantly longer for patients in the non-IC group than that for patients in the IC group (7 vs. 2 days). The in-hospital mortality rates were significantly higher for patients in the non-IC group than that for patients in the IC group (71.4% vs. 43.9%; P = 0.047). A longer interval between admission and anti-PCP therapy was associated with increased 90-day mortality rate in patients with PCP (hazard ratio, 1.082; 95% confidence interval, 1.015-1.153; P = 0.016).
Patients with PCP with no predisposing illnesses were older and had higher mortality rates than IC patients with PCP. Delayed anti-PCP treatment was associated with increased 90-day mortality.
Nuclear factor E2 p45-related factor 2 (Nrf2) is a transcription factor involved in the expression of cytoprotective genes induced by external stresses. We investigated the role of Nrf2 in osteoclast ...and osteoblast differentiation. Nrf2 knockdown or deletion increased osteoclastic differentiation from bone marrow-derived macrophages (BMMs) through the upregulation of NF-κB, c-Fos, and NFATc1 transcription factors. Nrf2 also inhibited osteoblast differentiation and mineralization via suppression of key regulatory proteins, such as Runx2, osteocalcin, and osterix. Micro-computed tomography and histomorphometric analyses showed an increase in bone mass of Nrf2 knockout compared to that of wild type mice. In addition, the mineral apposition rate and the number of osteoblasts in bone were higher in Nrf2 knockout mice. However, bone resorption parameters, namely DPD and CTX levels, were not affected by Nrf2 deletion. In a coculture condition where calvarial osteoblasts and BMMs from wild type and Nrf2 knockout mice were grown, deletion of Nrf2 in osteoblasts markedly reduced osteoclast formation. This effect was due to an increase in OPG expression in Nrf2 knockout osteoblasts. Taken as a whole, these results indicate that Nrf2 is intrinsically inhibitory to both osteoblast and osteoclast differentiation but its effect on osteoblasts is dominant to its effect on osteoclasts in vivo.
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