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Mei-Yu Lv, Li-Xia Qiang, Bao-Cai Wang, Yue-Peng Zhang, Zhi-Heng Li, Xiang-Shun Li, Ling-Ling Jin, Shou-De Jin Department of Respiratory Medicine, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, People’s Republic of ChinaCorrespondence: Shou-De Jin, Department of Respiratory Medicine, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, 150001, People’s Republic of China, Tel/Fax +86 0451-85939123, Email jinshoude@163.comPurpose: Pulmonary surfactant proteins A (SP-A) and D (SP-D) are lectins, involved in host defense and regulation of pulmonary inflammatory response. However, studies on the assessment of COPD progress are limited.Patients and Methods: Pulmonary surfactant proteins were obtained from the COPD mouse model induced by cigarette and lipopolysaccharide, and the specimens of peripheral blood and bronchoalveolar lavage (BALF) in COPD populations. H&E staining and RT-PCR were performed to demonstrate the successfully established of the mouse model. The expression of SP-A and SP-D in mice was detected by Western Blot and immunohistochemistry, while the proteins in human samples were measured by ELISA. Pulmonary function test, inflammatory factors (CRP, WBC, NLR, PCT, EOS, PLT), dyspnea index score (mMRC and CAT), length of hospital stay, incidence of complications and ventilator use were collected to assess airway remodeling and progression of COPD.Results: COPD model mice with emphysema and airway wall thickening were more prone to have decreased SP-A, SP-D and increased TNF-α, TGF-β, and NF-kb in lung tissue. In humans, SP-A and SP-D decreased in BALF, but increased in serum. The serum SP-A and SP-D were negatively correlated with FVC, FEV1, FEV1/FVC, and positively correlated with CRP, WBC, NLR, mMRC and CAT scores (P < 0.05, respectively). The lower the SP-A and SP-D in BALF, the worse the lung function and the increased probability of complications and ventilator use. Moreover, the same trend emerged in COPD patients grouped according to GOLD severity grade (Gold 1– 2 group vs Gold 3– 4 group). The worse the patient’s condition, the more pronounced the change.Conclusion: This study suggests that SP-A and SP-D may be related to the progression and prognostic evaluation of COPD in terms of airway remodeling, inflammatory response and clinical symptoms, and emphasizes the necessity of future studies of surfactant protein markers in COPD.Keywords: COPD, pulmonary surfactant protein A and D, airway remodeling

Qiang Shi,1 Shanlian Hu,2 Wesley E Furnback,3 Gregory F Guzauskas,3 Jiejing Shen,1 Bruce CM Wang3 1Lilly Suzhou Pharmaceutical Company, Ltd., Shanghai, People’s Republic of China; 2Shanghai Health Development Research Center, Shanghai, People’s Republic of China; 3Elysia Group, Ltd., Taipei, Taiwan, Republic of China Background: Eli Lilly and the China Primary Health Care Foundation are currently implementing a patient assistance program (PAP) in China, which allows first-line nonsquamous non-small-cell lung cancer (NSCLC) patients who complete four cycles of pemetrexed induction therapy to receive free, continuous pemetrexed maintenance therapy.Objective: To estimate the cost-effectiveness of pemetrexed maintenance therapy vs basic standard care (BSC) and the economic impacts of providing a PAP for pemetrexed maintenance therapy to NSCLC patients who have completed pemetrexed induction therapy in a Chinese health care setting.Methods: We developed a novel decision-analytic model to evaluate the long-term costs and clinical efficacy of pemetrexed plus BSC vs BSC alone. We utilized a three-state (progression-free survival, progressed disease, and dead) partition survival model for both the clinical and economic aspects of the analysis. Cost and health utility estimates were derived from the literature. We performed a scenario analysis to estimate the real-world impact of introducing the PAP in China by comparing the use of the PAP vs non-PAP. Model uncertainty was evaluated using one-way and multivariate probabilistic sensitivity analysis.Results: Compared to BSC, pemetrexed plus BSC resulted in a gain of 0.22 years of life (95% credible range [CR]: 0.04–0.46) and 0.13 quality-adjusted life years (95% CR: 0.04–0.26) per patient, at an increased cost of $28,105 (95% CR: −$22,720 to $48,646) without a PAP and $3,068 (95% CR: −$1,263 to $9,163) with a PAP. The incremental cost-effectiveness ratio for pemetrexed plus BSC vs BSC alone was cost-prohibitive at $222,700 for non-PAP, but cost-effective at $24,319 with a PAP.Conclusion: Our study suggests that maintenance pemetrexed therapy following pemetrexed induction for patients with advanced NSCLC is likely to be highly non-cost-effective in the absence of a PAP, but the pending implementation of the PAP promises to make it cost-effective, with a >90% probability of cost-effectiveness at a Chinese willingness-to-pay threshold per quality-adjusted life year. Keywords: non-small-cell lung cancer, pemetrexed, patient assistance program, cost–utility analysis, basic standard care

Chiun-Fang Chiou,1 Bruce CM Wang,2 Ronald Caldwell,3 Wesley Furnback,2 Jung-Sun Lee,4 Nathan Kothandaraman,5 SunKyoung Lee,6 Jin Wang,7 Fan Zhang8 1Regional Market Access, Janssen Asia-Pacific, Singapore; 2Elysia Group, LLC, Taipei, Taiwan; 3Department of Economics, University of Michigan, Ann Arbor, MI, USA; 4Department of Psychiatry, University of Ulsan, College of Medicine, Asan Medical Center, Seoul, Korea; 5Government Affairs, Johnson & Johnson Sdn Bhd, Selangor, Malaysia; 6Market Access, Janssen Korea Ltd, Seoul, Korea; 7Strategy and Development, Xian Janssen Pharmaceutical Co, Ltd, 8Medical Affairs, Xian Janssen Pharmaceutical Co, Ltd, Beijing, People’s Republic of China Background: Schizophrenia results in substantial health care utilization costs. Much of these costs can be attributed to health care use resulting from nonadherence to treatment, relapse, and hospitalization.Aims of the study: The objective of this research is to further estimate the health care resource utilization costs of patients with schizophrenia in the People’s Republic of China, Korea, and Malaysia with a specific focus on the reduction in hospitalization costs associated with the use of long-acting, injectable paliperidone palmitate (PP) relative to alternative treatment medications.Methods: The study focuses exclusively on the estimated reduction in hospitalization days following treatment with PP and the potential associated cost savings. Cost analysis was done using a payer’s perspective and only includes direct health care costs associated with hospitalization. Localized cost data were taken from published sources, and health care utilization was estimated based on a clinical study conducted in countries in the Asia-Pacific region. People’s Republic of China, Korea, and Malaysia had the highest number of patients enrolled in the clinical study, and thus were chosen for this research. Analysis looked at 12-month and 18-month periods following initial treatment with PP relative to a retrospective 12-month period utilizing alternative treatment medications.Results: Results suggest that reductions in hospital utilization cost over 12 months may occur through the use of PP relative to alternatives – ranging from $1,991 for the People’s Republic of China to $6,698 for Korea and $6,716 for Malaysia.Conclusion: Given the substantial costs associated with the treatment of schizophrenia both worldwide and in Asia, it is important to fully understand the costs and outcomes associated with various treatment options. In this research, we have specifically analyzed the direct health care cost savings associated with hospital utilization for patients taking PP relative to alternative treatment methods. The results suggest that reductions in hospital utilization cost were associated with PP treatment, likely largely due to increased adherence to treatment. Keywords: schizophrenia, antipsychotic treatment, health economics, cost savings

Isodesmic reactions, in which chemical bonds are redistributed between substrates and products, provide a general and powerful strategy for both biological and chemical synthesis. However, most isodesmic reactions involve either metathesis or functional-group transfer. Here, we serendipitously discovered a novel isodesmic reaction of indoles and anilines that proceeds intramolecularly under weakly acidic conditions. In this process, the five-membered ring of the indole motif is broken and a new indole motif is constructed on the aniline side, accompanied by the formation of a new aniline motif. Mechanistic studies revealed the pivotal role of σ→π* hyperconjugation on the nitrogen atom of the indole motif in driving this unusual isodesmic reaction. Furthermore, we successfully synthesized a diverse series of polycyclic indole derivatives; among quinolines, potential antitumor agents were identified using cellular and in vivo experiments, thereby demonstrating the synthetic utility of the developed methodology., (© 2024 Wiley-VCH GmbH.)

The identification of structurally novel and potently active BET inhibitors represents a significant advancement in the field of anticancer therapeutics. In the present investigation, leveraging the outcomes of previous screening endeavors, we successfully optimized and synthesized a novel series of bromodomain and extra-terminal (BET) inhibitors with a 4-morpholinothieno[3,2-d]pyrimidine structure. Among the synthesized compounds, compound 6c emerged as a promising candidate, exhibiting exceptional inhibitory activities against various BET isoform proteins, with IC 50 values ranging from 3.3 to 42.0 nM. In cellular assays, compound 6c demonstrated robust antiproliferative effects in SU-DHL-4 cells, achieving an IC 50 value of 8.6 ± 3.3 nM. Further mechanistic studies revealed that compound 6c effectively decreased the expression of c-Myc, a critical oncogenic driver regulated by the BET protein, and induced cell cycle arrest at the G1 phase, as well as cell apoptosis, in a dose-dependent manner. Moreover, in-silico prediction of the physiochemical and pharmacokinetic properties clarified that compound 6c has acceptable drug-like profiles. Taken these findings together, compound 6c represents a novel and potent BET inhibitor, thus positioning it as a promising candidate for subsequent pre-clinical evaluations in the realm of cancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Human-in-the-loop for reinforcement learning (RL) is usually employed to overcome the challenge of sample inefficiency, in which the human expert provides advice for the agent when necessary. The current human-in-the-loop RL (HRL) results mainly focus on discrete action space. In this article, we propose a Q value-dependent policy (QDP)-based HRL (QDP-HRL) algorithm for continuous action space. Considering the cognitive costs of human monitoring, the human expert only selectively gives advice in the early stage of agent learning, where the agent implements human-advised action instead. The QDP framework is adapted to the twin delayed deep deterministic policy gradient algorithm (TD3) in this article for the convenience of comparison with the state-of-the-art TD3. Specifically, the human expert in the QDP-HRL considers giving advice in the case that the difference between the twin Q -networks' output exceeds the maximum difference in the current queue. Moreover, to guide the update of the critic network, the advantage loss function is developed using expert experience and agent policy, which provides the learning direction for the QDP-HRL algorithm to some extent. To verify the effectiveness of QDP-HRL, the experiments are conducted on several continuous action space tasks in the OpenAI gym environment, and the results demonstrate that QDP-HRL greatly improves learning speed and performance.

Scaling up quantum dots to two-dimensional (2D) arrays is a crucial step for advancing semiconductor quantum computation. However, maintaining excellent tunability of quantum dot parameters, including both nearest-neighbor and next-nearest-neighbor couplings, during 2D scaling is challenging, particularly for silicon quantum dots due to their relatively small size. Here, we present a highly controllable and interconnected 2D quantum dot array in planar silicon, demonstrating independent control over electron fillings and the tunnel couplings of nearest-neighbor dots. More importantly, we also demonstrate the wide tuning of tunnel couplings between next-nearest-neighbor dots, which play a crucial role in 2D quantum dot arrays. This excellent tunability enables us to alter the coupling configuration of the array as needed. These results open up the possibility of utilizing silicon quantum dot arrays as versatile platforms for quantum computing and quantum simulation.

Xylan is one of the major hemicelluloses in plant cell walls and its xylosyl backbone is often decorated at O-2 with glucuronic acid (GlcA) and/or methylglucuronic acid (MeGlcA) residues. The GlcA/MeGlcA side chains may be further substituted with 2-O-arabinopyranose (Arap) or 2-O-galactopyranose (Gal) residues in some plant species, but the enzymes responsible for these substitutions remain unknown. During our endeavor to investigate the enzymatic activities of Arabidopsis MUR3-clade members of the GT47 glycosyltransferase family, we found that one of them was able to transfer Arap from UDP-Arap onto O-2 of GlcA side chains of xylan, and thus it was named xylan 2-O-arabinopyranosyltransferase 1 (AtXAPT1). The function of AtXAPT1 was verified in planta by its T-DNA knockout mutation showing a loss of the Arap substitution on xylan GlcA side chains. Further biochemical characterization of XAPT close homologs from other plant species demonstrated that while the poplar ones had the same catalytic activity as AtXAPT1, those from Eucalyptus, lemon-scented gum, sea apple, 'Ohi'a lehua, duckweed and purple yam were capable of catalyzing both 2-O-Arap and 2-O-Gal substitutions of xylan GlcA side chains albeit with differential activities. Sequential reactions with XAPTs and glucuronoxylan methyltransferase 3 (GXM3) showed that XAPTs acted poorly on MeGlcA side chains, whereas GXM3 could efficiently methylate arabinosylated or galactosylated GlcA side chains of xylan. Furthermore, molecular docking and site-directed mutagenesis analyses of Eucalyptus XAPT1 revealed critical roles of several amino acid residues at the putative active site in its activity. Together, these findings establish that XAPTs residing in the MUR3 clade of family GT47 are responsible for 2-O-arabinopyranosylation and 2-O-galactosylation of GlcA side chains of xylan., (© 2024 The Author(s). The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.)

Background: Early detection of T790M mutation in exon 20 of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) patients with brain metastasis is crucial for optimizing treatment strategies. In this study, we developed radiomics models to distinguish NSCLC patients with T790M-positive mutations from those with T790M-negative mutations using multisequence MR images of brain metastasis despite an imbalanced dataset. Various resampling techniques and classifiers were employed to identify the most effective strategy., Methods: Radiomic analyses were conducted on a dataset comprising 125 patients, consisting of 18 with EGFR T790M-positive mutations and 107 with T790M-negative mutations. Seventeen first- and second-order statistical features were selected from CET1WI, T2WI, T2FLAIR, and DWI images. Four classifiers (logistic regression, support vector machine, random forest [RF], and extreme gradient boosting [XGBoost]) were evaluated under 13 different resampling conditions., Results: The area under the curve (AUC) value achieved was 0.89, using the SVM-SMOTE oversampling method in combination with the XGBoost classifier. This performance was measured against the AUC reported in the literature, serving as an upper-bound reference. Additionally, comparable results were observed with other oversampling methods paired with RF or XGBoost classifiers., Conclusions: Our study demonstrates that, even when dealing with an imbalanced EGFR T790M dataset, reasonable predictive outcomes can be achieved by employing an appropriate combination of resampling techniques and classifiers. This approach has significant potential for enhancing T790M mutation detection in NSCLC patients with brain metastasis., (© 2024. The Author(s).)

Background: Susceptibility-weighted imaging (SWI) is a common imaging technique used to identify cerebral microbleeds. Given that spinal cord injury (SCI) often creates an environment that favors ferroptosis, a type of cell death driven by iron, this study aimed to explore the relationship between microbleeds on SWI and ferroptosis, and explore the effect of deferoxamine on SCI., Methods: Thirty-six rabbits were divided into three groups: sham, SCI, and SCI with deferoxamine (DFO, a ferroptosis inhibitor) treatment (SCI+DFO). Following 48 hours of SCI modeling, the rabbits underwent magnetic resonance imaging (MRI) and SWI examinations. Ferroptosis markers and spinal cord tissue morphology were examined, and the modified Tarlov's score was used to assess neurological function., Results: SWI analysis revealed that rabbits in the SCI group exhibited lower signal intensities and larger microbleed areas compared to the those in the SCI+DFO group ( p < 0.05). The SCI+DFO group demonstrated significantly decreased iron and malondialdehyde (MDA) levels, coupled with increased glutathione (GSH) and glutathione peroxidase 4 (GPX4) levels, along with attenuated ferroptosis ( p < 0.05). This group also displayed greater Neuronal Nuclei (NeuN) expression, Tarlov's scores, and neurological recovery rates (all p < 0.05). A significant positive correlation was found between the microbleed area and iron content (r = 0.59, p = 0.04), MDA (r = 0.75, p = 0.01), and mitochondrial damage (r = 0.90, p < 0.01). Conversely, a negative correlation was established between the microbleed area and GPX4 levels (r = -0.87, p < 0.01), as well as neurological function recovery (r = -0.62, p = 0.03)., Conclusion: The extent of microbleeds on SWI following SCI is closely correlated with ferroptosis, and the inhibition of ferroptosis could improve neurologic function. These findings suggest that the area of microbleeds on SWI could potentially serve as a predictive marker for ferroptosis in spinal cord injury.

Macrophorins H ( 4 ) and L ( 5 ), two rare HMG-conjugate macrophorins along with three known macrophorins ( 1 - 3 ), three DMOA-derived meroterpenoids ( 6 - 8 ) and two ergosterol derivates ( 9 - 10 ) were isolated from sterilized rice medium cultured Penicillium sp. NX-05-G-3. Their structures were elucidated by 1D and 2D NMR. The cytotoxicities of all compounds were evaluated, and compounds 1 and 2 showed extensive cytotoxicity against human cancer cell lines Hela, SCC15, MDA-MB-453 and A549, with IC 50 values ranging from 17.6 to 32.8 µM.

Leptomeningeal metastases (LMs) remain a devastating complication of non-small cell lung cancer (NSCLC), particularly following osimertinib resistance. We conducted single-cell RNA sequencing on cerebrospinal fluid (CSF) from EGFR-mutant NSCLC with central nervous system metastases. We found that macrophages of LMs displayed functional and phenotypic heterogeneity and enhanced immunosuppressive properties. A population of lipid-associated macrophages, namely RNASE1&#95;M, were linked to osimertinib resistance and LM development, which was regulated by Midkine (MDK) from malignant epithelial cells. MDK exhibited significant elevation in both CSF and plasma among patients with LMs, with higher MDK levels correlating to poorer outcomes in an independent cohort. Moreover, MDK could promote macrophage M2 polarization with lipid metabolism and phagocytic function. Furthermore, malignant epithelial cells in CSF, particularly after resistance to osimertinib, potentially achieved immune evasion through CD47-SIRPA interactions with RNASE1&#95;M. In conclusion, we revealed a specific subtype of macrophages linked to osimertinib resistance and LM development, providing a potential target to overcome LMs., Competing Interests: Declaration of interests Y.-L.W. has received honoraria from AstraZeneca, Eli Lilly, Roche, Pierre Fabre, Pfizer, and Sanofi and has consulting or advisory roles with AstraZeneca, Roche, Merck, Boehringer Ingelheim, and Roche outside the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Plant cell walls are largely composed of polysaccharide polymers, including cellulose, hemicelluloses (xyloglucan, xylan, mannan, and mixed-linkage β-1,3/1,4-glucan), and pectins. Among these cell wall polysaccharides, xyloglucan, xylan, mannan, and pectins are often O -acetylated, and polysaccharide O -acetylation plays important roles in cell wall assembly and disease resistance. Genetic and biochemical analyses have implicated the involvement of three groups of proteins in plant cell wall polysaccharide O -acetylation: trichome birefringence-like (TBL)/domain of unknown function 231 (DUF231), reduced wall acetylation (RWA), and altered xyloglucan 9 (AXY9). Although the exact roles of RWAs and AXY9 are yet to be identified, members of the TBL/DUF231 family have been found to be O -acetyltransferases responsible for the O -acetylation of xyloglucan, xylan, mannan, and pectins. Here, we provide a comprehensive overview of the occurrence of O -acetylated cell wall polysaccharides, the biochemical properties, structural features, and evolution of cell wall polysaccharide O -acetyltransferases, and the potential biotechnological applications of manipulations of cell wall polysaccharide acetylation. Further in-depth studies of the biochemical mechanisms of cell wall polysaccharide O -acetylation will not only enrich our understanding of cell wall biology, but also have important implications in engineering plants with increased disease resistance and reduced recalcitrance for biofuel production.

Background: The poor prognosis of anaplastic thyroid cancer (ATC) patients is associated with limited effective therapeutic strategies. Multiple antiangiogenesis tyrosine kinase inhibitors (TKIs) have been applied in later-line treatment of ATC; however, the results reported in clinical trials were controversial. In this study, we reconstructed the patient-level data to pooled-analyze the survival data, responses, and adverse events., Methods: Online databases (PubMed, Web of Science, Embase, and Cochrane CENTRAL) were searched on September 03, 2023. R software combined with the "metaSurvival" and "meta" packages were used to reconstruct the survival curves and summarize the response rates. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints were survival rate, objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events., Results: Six prospective clinical trials involving 140 ATC patients were enrolled. Four types of TKIs (imatinib, pazopanib, sorafenib, and lenvatinib) were included. When advanced ATC patients were treated with the TKIs, the median OS was 4.8 months and the median PFS was 2.6 months. The pooled ORR and DCR were 9% and 53%. Hypertension, decreased appetite, rash, and lymphopenia were the most common grade ≥ 3 treatment-related adverse events., Conclusion: Mono-anitangiogenesis TKI therapy showed limited improvements in treating advanced ATC patients. Combining antiangiogenesis TKI therapy with chemotherapy, radiotherapy, or immunotherapy could be the direction of future studies., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

The goal of constrained multiobjective evolutionary optimization is to obtain a set of well-converged and well-distributed feasible solutions. To achieve this goal, a delicate tradeoff must be struck among feasibility, diversity, and convergence. However, balancing these three elements simultaneously through a single tradeoff model is nontrivial, mainly because the significance of each element varies in different evolutionary phases. As an alternative approach, we adapt distinct tradeoff models in various phases and introduce a novel algorithm named adaptive tradeoff model with reference points (ATM-R). In the infeasible phase, ATM-R takes the tradeoff between diversity and feasibility into account, aiming to move the population toward feasible regions from diverse search directions. In the semi-feasible phase, ATM-R promotes the transition from "the tradeoff between feasibility and diversity" to "the tradeoff between diversity and convergence." This transition is instrumental in discovering an adequate number of feasible regions and accelerating the search for feasible Pareto optima in succession. In the feasible phase, ATM-R places an emphasis on balancing diversity and convergence to obtain a set of feasible solutions that are both well-converged and well-distributed. It is worth noting that the merits of reference points are leveraged in ATM-R to accomplish these tradeoff models. Also, in ATM-R, a multiphase mating selection strategy is developed to generate promising solutions beneficial to different evolutionary phases. Systemic experiments on a diverse set of benchmark test functions and real-world problems demonstrate that ATM-R is effective. When compared to eight state-of-the-art constrained multiobjective optimization evolutionary algorithms, ATM-R consistently demonstrates its competitive performance.

(1) Background: Identifying acute aortic syndrome (AAS) and thoracic aortic aneurysm (TAA) in busy emergency departments (EDs) is crucial due to their life-threatening nature, necessitating timely and accurate diagnosis. (2) Methods: This retrospective case-control study was conducted in the ED of three hospitals. Adult patients visiting the ED between 1 January 2010 and 1 January 2020 with a chief complaint of chest or back pain were enrolled in the study. The collected chest radiography (CXRs) data were divided into training (80%) and testing (20%) datasets. The training dataset was trained by four different convolutional neural network (CNN) models. (3) Results: A total of 1625 patients were enrolled in this study. The InceptionV3 model achieved the highest F1 score of 0.76. (4) Conclusions: Analysis of CXRs using a CNN-based model provides a novel tool for clinicians to interpret ED patients with chest pain and suspected AAS and TAA. The integration of such imaging tools into ED could be considered in the future to enhance the diagnostic workflow for clinically fatal diseases.

Background: For patients with anaplastic thyroid cancer (ATC) without mutational driver genes, chemotherapy is suggested to be the first-line treatment option. However, the benefits of chemotherapy in treating ATC are limited. In this analysis, we collected the prospective data reported since 2010 to analyze the emerging chemotherapy-based treatments in ATC comprehensively., Methods: For this updated analysis, we searched PubMed (MEDLINE), Web of Science, Embase, and Cochrane CENTRAL databases from 1 January 2010 to 7 February 2024 for prospective clinical studies that contained chemotherapy-based treatments. This analysis was done to pool overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), disease control rates (DCRs), and grade 3 or worse treatment-related adverse events (TRAEs)., Results: Six prospective clinical trials with 232 patients were included. Chemotherapy was commonly combined with targeted therapy or radiotherapy. The pooled median OS was 6.0 months (95% CI 4.1-9.7), and the median PFS was 3.2 months (95% CI 1.9-6.0) in patients with ATC who received chemotherapy-based strategies. The integrated ORR and DCR were 21% (95% CI 15%-27%) and 64% (95% CI 55%-72%), respectively. Regarding the grade 3 or worse TRAE, the pooled incidence was 68% (95% CI 47%-86%)., Conclusion: Although the emerging chemotherapy-based treatments showed antitumor activity in patients with ATC, these strategies failed to prolong the survival time substantially. More practical, safe, and novel therapeutic regimens for patients with ATC warrant further investigations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Lin, Kuang and Cao.)

Objectives: Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is a subtype of lung carcinoma associated with the Epstein-Barr virus (EBV). The clinical predictive biomarkers of immune checkpoint blockade (ICB) in PLELC require further investigation., Methods: We prospectively analysed EBV levels in the blood and immune tumor biomarkers of 31 patients with ICB-treated PLELC. Viral EBNA-1 and BamHI-W DNA fragments in the plasma were quantified in parallel using quantitative polymerase chain reaction., Results: Progression-free survival (PFS) was significantly longer in EBNA-1 high or BamHI-W high groups. A longer PFS was also observed in patients with both high plasma EBNA-1 or BamHI-W and PD-L1 ≥ 1%. Intriguingly, the tumor mutational burden was inversely correlated with EBNA-1 and BamHI-W . Plasma EBV load was negatively associated with intratumoral CD8 + immune cell infiltration. Dynamic changes in plasma EBV DNA level were in accordance with the changes in tumor volume. An increase in EBV DNA levels during treatment indicated molecular progression that preceded the imaging progression by several months., Conclusions: Plasma EBV DNA could be a useful and easy-to-use biomarker for predicting the clinical activity of ICB in PLELC and could serve to monitor disease progression earlier than computed tomography imaging., Competing Interests: The authors declare that this study was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (© 2024 The Author(s). Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Objective: Atherosclerosis is a chronic inflammatory disease of the arteries, and its pathogenesis is related to endothelial dysfunction. It has been found that the protein convertase subtilin/kexin9 type (PCSK9) plays an important role in AS, but its specific mechanism is still unclear., Methods: In this study, we first cultured human umbilical vein endothelial cells (HUVECs) with 50 or 100μg/ml oxidized low-density lipoprotein (ox-LDL) for 24 hours to establish a coronary atherosclerosis cell model., Results: The results showed that ox-LDL induced HUVEC injury and autophagy and upregulated PCSK9 protein expression in HUVECs in a concentration-dependent manner. Silencing PCSK9 expression with siRNA inhibited ox-LDL-induced HUVEC endothelial dysfunction, inhibited the release of inflammatory factors, promoted HUVEC proliferation and inhibited apoptosis. In addition, ox-LDL increased the expression of LC3B-I and LC3B-II and decreased the expression of p62. However, these processes are reversed by sh-PCSK9. In addition, sh-PCSK9 can inhibit PI3K, AKT and mTOR phosphorylation and promote autophagy., Conclusion: Taken together, our research shows that silencing PCSK9 inhibits the PI3K/ATK/mTOR pathway to activate ox-LDL-induced autophagy in vascular endothelial cells, alleviating endothelial cell injury and inflammation.

Analyzing polysorbate 20 (PS20) composition and the impact of each component on stability and safety is crucial due to formulation variations and individual tolerance. The similar structures and polarities of PS20 components make accurate separation, identification, and quantification challenging. In this work, a high-resolution quantitative method was developed using single-dimensional high-performance liquid chromatography (HPLC) with charged aerosol detection (CAD) to separate 18 key components with multiple esters. The separated components were characterized by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) with an identical gradient as the HPLC-CAD analysis. The polysorbate compound database and library were expanded over 7-time compared to the commercial database. The method investigated differences in PS20 samples from various origins and grades for different dosage forms to evaluate the composition-process relationship. UHPLC-Q-TOF-MS identified 1329 to 1511 compounds in 4 batches of PS20 from different sources. The method observed the impact of 4 degradation conditions on peak components, identifying stable components and their tendencies to change. HPLC-CAD and UHPLC-Q-TOF-MS results provided insights into fingerprint differences, distinguishing quasi products., Competing Interests: The authors declare that there are no conflicts of interest., (© 2024 The Authors.)