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Ya-Nan Zhao,1,* Yu-Dong Yan,1,* Chen-Yao Wang,1 Wei-Min Qu,1 Thomas C Jhou,2 Zhi-Li Huang,1 Su-Rong Yang1 1Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, People’s Republic of China; 2Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA*These authors contributed equally to this workCorrespondence: Su-Rong Yang; Zhi-Li HuangDepartment of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, People’s Republic of ChinaTel/Fax +86-21-54237228; +86-21-54237103Email sryang@shmu.edu.cn; huangzl@fudan.edu.cnAbstract: The rostromedial tegmental nucleus (RMTg), a brake of the dopamine system, is specifically activated by aversive stimuli, such as foot shock. It is principally composed of gamma-aminobutyric acid neurons. However, there is no exact location of the RMTg on the brain stereotaxic atlas. The RMTg can be defined by c-Fos staining elicited by psychostimulants, the position of retrograde-labeled neurons stained by injections into the ventral tegmental area (VTA), the terminal field formed by axons from the lateral habenula, and some molecular markers identified as specifically expressed in the RMTg such as FoxP1. The RMTg receives a broad range of inputs and produces diverse outputs, which indicates that the RMTg has multiple functions. First, the RMTg plays an essential role for non-rapid eye movement sleep. Additionally, the RMTg serves a vital role in response to addiction. Opiates increase the firing rates of dopaminergic neurons in the VTA by acting on μ-opioid receptors on RMTg neurons and their terminals inside the VTA. In this review, we summarize the recent research advances on the anatomical location of the RMTg in rats and mice, its projections, and its regulation of sleep–wake behavior and addiction.Keywords: rostromedial tegmental nucleus, anatomical location, projections, sleep–wake behavior, addiction

Actin dynamics are critical for plant cell morphogenesis, but the underlying signaling mechanisms regulating these dynamics are not well understood. Here, we established that PLEIOTROPIC REGULATORY LOCUS1 (PRL1) modulates leaf pavement cell (PC) morphogenesis in Arabidopsis (Arabidopsis thaliana) by maintaining the dynamic homeostasis of actin microfilaments (MF). Our previous studies indicated that PC shape was determined by antagonistic RHO-RELATED GTPase FROM PLANTS 2 (ROP2) and RHO-RELATED GTPase FROM PLANTS 6 (ROP6) signaling pathways that promote cortical MF and microtubule organization, respectively. Our genetic screen for additional components in ROP6-mediated signaling identified prl1 alleles. Genetic analysis confirmed that PRL1 plays a key role in PC morphogenesis. Mutations in PRL1 caused cortical MF depolymerization, resulting in defective PC morphogenesis. Further genetic analysis revealed that PRL1 is epistatic to ROP2 and ROP6 in PC morphogenesis. Mutations in PRL1 enhanced the effects of ROP2 and ROP6 in PC morphogenesis, leading to a synergistic phenotype in the PCs of ROP2 prl1 and ROP6 prl1. Furthermore, the activities of ROP2 and ROP6 were differentially altered in prl1 mutants, suggesting that ROP2 and ROP6 function downstream of PRL1. Additionally, cortical MF depolymerization in prl1 mutants occurred independently of ROP2 and ROP6, implying that these proteins impact PC morphogenesis in the prl1 mutant through other cellular processes. Our research indicates that PRL1 preserves the structural integrity of actin and facilitates pavement cell morphogenesis in Arabidopsis. PLEIOTROPIC REGULATORY LOCUS1 negatively regulates Rho GTPase-independent and -dependent microfilament integrity-related signaling pathways for pavement cell morphogenesis. [ABSTRACT FROM AUTHOR]

Ping Hua,1 Jianyang Liu,2 Jun Tao,1 Xifeng Lin,1 Rongjun Zou,1 Dingwen Zhang,1 Songran Yang3,4 1Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 2Department of Vascular Surgery, Henan Provincial People’s Hospital, Zhengzhou, 3The Biobank of Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 4Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China Objective: Retrospective studies and a meta-analysis were performed to evaluate the safety and effectiveness of the perioperative administration of recombinant human brain natriuretic peptide (rhBNP) during cardiac surgery under extracorporeal circulation. Methods: Computerized literature searches were performed in Medline, Embase, The Cochrane Library, CNKI, CBM, and WANFANG to find randomized controlled trials (RCTs) related to the perioperative administration of rhBNP during cardiac surgery starting from the database inception until December 2016. Two researchers independently performed study screening, information extraction, and quality evaluation according to the inclusion/exclusion criteria, and a meta-analysis was performed using RevMan 5.2 software. Results: A total of 12 studies were analyzed, including 12 RCTs and 727 patients. The meta-analysis results indicated that the perioperative administration of rhBNP could reduce the occurrence rate of postoperative complications, length of intensive care unit (ICU) stay, length of hospital stay, and serum creatinine (Scr) levels, and increase the 24-hour urine volume; however, it did not affect the postoperative mortality rate. Conclusion: The perioperative administration of rhBNP during cardiac surgery was safe and effective, and could improve the prognosis of the patients. Keywords: recombinant human brain natriuretic peptide, perioperative administration, meta-analysis

As an emerging intelligent construction technique, three-dimensional (3D) printing technology can improve the utilization rate of building materials, reduce labor costs and shorten the construction period. However, in traditional 3D printing, large-size 3D print machines, restricted print sizes of structural components and unstable printing quality limit its application in construction engineering. This paper proposes a mobile 3D printing technique for construction engineering. In this technique, a mobile 3D printing construction robot (M3DPC-Rob) is developed that takes advantage of a movable platform and flexible mechanical arm to cover the printing range of ordinary residential buildings. In order to locate the robot accurately in outdoor environments, an outdoor positioning and navigation method based on reflective columns is proposed. Furthermore, a quality control process is developed and modified to improve the quality of the printed line width. The results of a case study reveal that the outdoor navigation and printing quality control techniques of M3DPC-Rob show sufficient and steady accuracy that meet the requirements of construction engineering. [ABSTRACT FROM AUTHOR]

Radiotherapy could stimulate the immune response and might synergize with PD-1/PD-L1 inhibitors in the clinical treatment of malignancies. Our previous PRaG trial also demonstrated that SBRT/HFRT in combination with PD-1 inhibitors and granulocyte macrophage-colony stimulating factor (GM-CSF) could improve clinical response in patients with advanced refractory solid tumors (ChiCTR1900026175). To further improve the efficacy of immunotherapy combined with radiotherapy, we conducted the PRaG 2.0 trial (ClinicalTrials.gov: NCT04892498) and optimized the PRaG regimen by adding interleukin-2 (IL-2). Preliminary results of PRaG 2.0 had been reported in the 64th ASTRO. Now we report an updated result. The PRaG 2.0 regimen was administered to patients with advanced refractory solid tumors who lacked or were unable to tolerate standard-of-care treatments. A treatment cycle consisted of SBRT or HFRT (5 or 8 Gy×2-3f) delivered for one metastatic lesion, PD-1 inhibitor dosing within one week after completion of radiotherapy, GM-CSF 200μg subcutaneous (SC) injection once daily for 7 days, and then sequentially followed by IL-2 2million IU SC once daily for 7 days. PRaG 2.0 regimen was repeated every 21 days for at least 2 cycles until no appropriate lesions for irradiation or reached the tolerance dose of normal tissues. Patients who could not continue radiotherapy and had not yet developed progression disease (PD) allowed PD-1 inhibitors to be continued as maintenance therapy until PD or unacceptable toxicity but no more than one year. The primary endpoint was Progression-Free Survival (PFS). As of 31st October 2022, 51 patients were enrolled in the study, and 42 completed at least one tumor assessment. The median Progression-Free Survival (PFS) was 5.8 months, and the median overall survival (OS) was 13.5 months. The objective response rate (ORR) was 21.4%, and the disease control rate (DCR) was 61.9% according to RECIST version 1.1. Lower plasma levels of Interleukin (IL)-6 and IL-17 at baseline were found to be associated with improved PFS. Treatment-related adverse events (TRAE) occurred in 34 of 42 (78.6%) patients, Grade ≥ 3 TRAEs occurred in 4 patients (9.5%). TRAEs leading to discontinuation of all study treatments occurred in three patients (7.1%). The PRaG 2.0 trial demonstrates that PD-1 inhibitors in combination with SBRT/HFRT, GM-CSF, and IL-2 could be a potential treatment regimen for patients with advanced refractory solid tumors, with an acceptable benefit/risk profile. [ABSTRACT FROM AUTHOR]

Rationale: Abnormal inflammation and accelerated decline in lung function occur in patients with chronic obstructive pulmonary disease (COPD). Human sirtuin (SIRT1), an antiaging and antiinflammatory protein, is a metabolic NAD(+)-dependent protein/histone deacetylase that regulates proinflammatory mediators by deacetylating histone and nonhistone proteins.Objectives: To determine the expression of SIRT1 in lungs of smokers and patients with COPD, and to elucidate the regulation of SIRT1 in response to cigarette smoke in macrophages, and its impact on nuclear factor (NF)-kappaB regulation.Methods: SIRT1 and NF-kappaB levels were assessed in lung samples of nonsmokers, smokers, and patients with COPD. Human monocyte-macrophage cells (MonoMac6) were treated with cigarette smoke extract (CSE) to determine the mechanism of CSE-mediated regulation of SIRT1 and its involvement in RelA/p65 regulation and IL-8 release.Measurements and Main Results: Peripheral lungs of smokers and patients with COPD showed decreased levels of nuclear SIRT1, as compared with nonsmokers, associated with its post-translational modifications (formation of nitrotyrosine and aldehyde carbonyl adducts). Treatment of MonoMac6 cells with CSE showed decreased levels of SIRT1 associated with increased acetylation of RelA/p65 NF-kappaB. Mutation or knockdown of SIRT1 resulted in increased acetylation of nuclear RelA/p65 and IL-8 release, whereas overexpression of SIRT1 decreased IL-8 release in response to CSE treatment in MonoMac6 cells.Conclusions: SIRT1 levels were reduced in macrophages and lungs of smokers and patients with COPD due to its post-translational modifications by cigarette smoke-derived reactive components, leading to increased acetylation of RelA/p65. Thus, SIRT1 plays a pivotal role in regulation of NF-kappaB-dependent proinflammatory mediators in lungs of smokers and patients with COPD. [ABSTRACT FROM AUTHOR]

MET fusions (MET-Fs) are oncogenic drivers that remain poorly characterized. Analysis of 56 MET-F-positive tumors from an institutional cohort of 91,119 patients (79,864 DNA-seq plus 11,255 RNA-seq) uncovered two forms of MET-F pathobiology. The first group featured 5' partners with homodimerization domains fused in-frame with MET-tyrosine kinase domain (TKD), primarily originated from translocations, frequently excluded MET exon 14, mediated oncogenesis through cytoplasmic aggregation and constitutive activation, and were markedly sensitive to MET tyrosine kinase inhibitors (TKI) in pre-clinical models and patients with lung cancer. The second group lacked partner homodimerization motifs and retained MET transmembrane and extracellular domains. Their pathogenesis involved intrachromosomal rearrangements, resulting in partner selection for promoter hijacking and fusion allele amplification. Membrane-bound fusions were enriched in gliomas with RTK co-alterations. We provide a framework to comprehend the heterogeneous landscape of MET-Fs, supporting that fusion oncogenicity and MET-TKI sensitivity are determined by structural topology and pathogenomic context.

Uterine leiomyomas, or fibroids, are common benign tumors that affect a significant percentage of women, with treatment options ranging from medication to surgery. Carbobenzoxyl-L-leucyl-L-leucyl-L-leucine (MG132), a proteasome inhibitor, has exhibited potential in treating various cancers by disrupting key cellular processes such as apoptosis and cell cycle regulation. The present study aimed to evaluate the effects of MG132 on the viability, proliferation, apoptosis, and the production of reactive oxygen species (ROS) in Eker leiomyoma tumor-3 (ELT3) uterine leiomyoma cells and to elucidate the underlying molecular mechanisms involved. Cell viability was evaluated using an MTT assay, while cytotoxicity was assessed using a lactate dehydrogenase (LDH) release assay. Colony formation assays assessed the long-term effects of MG132. Apoptosis and cell cycle distribution were analyzed using flow cytometry with Annexin V staining, and ROS production was also measured by flow cytometry. Western blot analysis was performed to examine key proteins related to the cell cycle and apoptosis. The findings of the present study revealed that MG132 significantly reduced the cell viability and impaired colony formation in ELT3 cells, as evidenced by decreased cell viability and increased LDH activity. MG132 treatment significantly increased apoptosis and induced cell cycle arrest at the G 2 /M phase. Additionally, MG132 increased the levels of ROS, which contributed to ROS-mediated apoptosis. Western blot analysis revealed that MG132 modulated key proteins involved in cell proliferation and apoptosis, including p21, p27, ERK, and caspase-3. Furthermore, MG132 treatment induced autophagy, as indicated by the increased conversion of LC3 I to LC3 II. Overall, MG132 was revealed to exert potent cytotoxic effects on ELT3 uterine leiomyoma cells by inducing ROS-mediated apoptosis and cell cycle arrest, and triggering autophagy. These findings suggest that MG132 provides a proof of concept for targeting the proteasome in uterine leiomyomas., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2025 Joung et al.)

Small cell lung carcinoma (SCLC) is a highly aggressive malignancy that is typically associated with tobacco exposure and inactivation of RB1 and TP53 genes. Here, we performed detailed clinicopathologic, genomic, and transcriptomic profiling of an atypical subset of SCLC that lacked RB1 and TP53 co-inactivation and arose in never/light smokers. We found that most cases were associated with chromothripsis-massive, localized chromosome shattering-recurrently involving chromosome 11 or 12 and resulting in extrachromosomal amplification of CCND1 or co-amplification of CCND2/CDK4/MDM2, respectively. Uniquely, these clinically aggressive tumors exhibited genomic and pathologic links to pulmonary carcinoids, suggesting a previously uncharacterized mode of SCLC pathogenesis via transformation from lower-grade neuroendocrine tumors or their progenitors. Conversely, SCLC in never-smokers harboring inactivated RB1 and TP53 exhibited hallmarks of adenocarcinoma-to-SCLC derivation, supporting two distinct pathways of plasticity-mediated pathogenesis of SCLC in never-smokers. Significance: Here, we provide the first detailed description of a unique SCLC subset lacking RB1/TP53 alterations and identify extensive chromothripsis and pathogenetic links to pulmonary carcinoids as its hallmark features. This work defines atypical SCLC as a novel entity among lung cancers, highlighting its exceptional histogenesis, clinicopathologic characteristics, and therapeutic vulnerabilities. See related commentary by Nadeem and Drapkin, p. 8., (©2024 The Authors; Published by the American Association for Cancer Research.)

Histologic features, including architectural patterns, cytologic features, and 2021 World Health Organization nuclear grade have been shown to have prognostic significance in epithelioid diffuse pleural mesothelioma (DPM). Biphasic and sarcomatoid DPM, regardless of morphology, have worse outcomes. These prognostic findings are well established but the correlation of architectural patterns, cytologic features, and nuclear grade with genetic alterations has not been well studied. To investigate relationships between histologic findings and genomic alterations, 128 treatment-naïve DPM specimens (70% epithelioid, 23% biphasic, and 6.3% sarcomatoid) with next-generation sequencing data were retrospectively reviewed. Alterations in BAP1 were the most common genomic alteration (n = 62, 48%), followed by CDKN2A (n = 49, 38%) and NF2 (n = 38, 30%). NF2 alterations were significantly more frequent in biphasic DPM (53% in biphasic vs 25% in sarcomatoid and 22% in epithelioid DPM; P = .005). In epithelioid DPM, TP53 alterations were associated with the presence of prognostically unfavorable histology, including micropapillary or solid architecture, pleomorphic features, and high nuclear grade. Tumors with low tumor-infiltrating lymphocytes (TILs) had a higher rate of BAP1 alterations than tumors with higher levels of TILs (67% vs 30%; P = .002). The findings of this study enhance our understanding of the relationships among prognostically significant histologic and molecular features of DPM and provide preliminary data to support increased integration of these findings in clinical diagnosis of pleural mesothelioma., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

VISTA is a key immune checkpoint receptor under investigation for cancer immunotherapy; however, its signaling mechanisms remain unclear. Here we identify a conserved four amino acid (NPGF) intracellular motif in VISTA that suppresses cell proliferation by constraining cell-intrinsic growth receptor signaling. The NPGF motif binds to the adapter protein NUMB and recruits Rab11 endosomal recycling machinery. We identify and characterize a class of triple-negative breast cancers with high VISTA expression and low proliferative index. In tumor cells with high VISTA levels, the NPGF motif sequesters NUMB at endosomes, which interferes with epidermal growth factor receptor (EGFR) trafficking and signaling to suppress tumor growth. These effects do not require canonical VISTA ligands, nor a functioning immune system. As a consequence of VISTA expression, EGFR receptor remains abnormally phosphorylated and cannot propagate ligand-induced signaling. Mutation of the VISTA NPGF domain reverts VISTA-induced growth suppression in multiple breast cancer mouse models. These results define a mechanism by which VISTA represses NUMB to control malignant epithelial cell growth and signaling. They also define distinct intracellular residues that are critical for VISTA-induced cell-intrinsic signaling that could be exploited to improve immunotherapy., Competing Interests: Conflicts of Interests: J.J.G. reports contracted research from Curis, Inc., consulting for Sharma Therapeutics, LLC and Guidepoint and research support (to his institution) from Hummingbird Bioscience. J.M.F. has received research support (to his institution) from AstraZeneca, Genentech, Incyte, Merus, Pfizer and PUMA. M.L.T. reports research support (to her institution) from AbbVie, Bayer, Biothera, Calithera Biosciences, EMD Serono, Genentech, Medivation, Novartis, OncoSec, Pfizer, PharmaMar, Tesaro, and Vertex and consulting/advisory fees from AbbVie, Aduro Biotech, AstraZeneca, Blueprint Medicines, Celgene, Daiichi Sankyo, Genentech/Roche, G1 Therapeutics, Guardant, Immunomedics, Lilly, Merck, Natera, and Pfizer. M.M.J. is an employee and shareholder of Guardant Health, Inc. J.D.B.K. and D.T. are employees of and hold equity in Hummingbird Bioscience.

Comprehensive molecular profiling by next-generation sequencing has revolutionized tumor classification and biomarker evaluation. However, routine implementation is challenged by the scant nature of diagnostic material obtained through minimally invasive procedures. Here, we describe our long-term experience in profiling cytology samples with an in-depth assessment of the performance, quality metrics, biomarker identification capabilities, and potential pitfalls. We highlight the impact of several optimization strategies to maximize performance with 4,871 prospectively sequenced clinical cytology samples tested by MSK-IMPACT TM . Special emphasis is given to the use of residual supernatant cell-free DNA (ScfDNA) as a valuable source of tumor DNA. Overall, cytology samples are similar in performance to surgical samples in identifying clinically relevant genomic alterations, achieving success rates up to 93% with full optimization. While cell block (CB) samples have excellent performance overall, low-level cross-contamination is identified in a small proportion of cases (4.7%), a common pitfall intrinsic to the processing of paraffin blocks, suggesting that more stringent precautions and processing modifications should be considered in quality control initiatives. By contrast ScfDNA samples have negligible contamination. Finally, ScfDNA testing exclusively used as a rescue strategy, delivered successful results in 71% of cases where tumor tissue from CB was depleted., Competing Interests: Competing interests: C.V. reports intellectual property rights and equity interest in Paige.AI, Inc. A.R.B. has ownership/equity interests in Johnson and Johnson. M.B. has received advisory or consulting fees from AstraZeneca, Eli Lilly and Company, and PetDx, Inc. M.L. has received advisory or consulting fees from Takeda Oncology, Janssen Pharmaceuticals, AstraZeneca, ADC Therapeutics, Paige.AI, Merck, Bayer, and Lilly Oncology and has received research funding from Loxo Oncology, Helsinn Therapeutics, Merus NV, Elevation Oncology, and Rain Therapeutics. O.L. has received advisory or consulting fees from Hologic and Janssen Research & Development, LLC. M.A. has received advisory or consulting fees from Axis Medical Education, Clinical Education Alliance, LLC, Merck Sharp & Dohme, PeerView Institute for Medical Education (PVI), Physicians’ Education Resource, RMEI Medical Education, LLC, and Roche. The following Authors declare no competing interests: D.K., S.Y., S.N., K.N., R.F., N.R., I.R., J.C., and A.Y., (© 2024. The Author(s).)

The progression of chronic obstructive pulmonary disease (COPD) results in irreversible pulmonary damage and sustained inflammatory responses. While alternative approaches have been explored, the specific role of alveolar epithelial cells in the pathogenesis of COPD remains unclear. Additionally, the association between emphysema and DAMP-RAGE signaling in COPD patients are not understood. Therefore, this study demonstrates to determine the therapeutic effect of a RAGE antagonist peptide (RAP), which we previously identified on the pathogenesis of COPD. We assessed the expression of RAGE ligands and RAGE binding signaling in COPD patients using GEO data. PPE-induced emphysema mouse model and AGER -/- mouse were employed, along treated with RAP. The association between RAGE and the development of emphysema was examined in H&E staining and western blot analysis in mouse lung tissue and BALF. We next analyzed the damage caused by oxidative stress and inflammation through CSE and RAP in human alveolar epithelial cell line A549. Our results show that inhibiting of RAGE alleviates emphysema by suppressing inflammation and MMP activity. Inhibition of RAGE in alveolar epithelial cells significantly induced the mitigation of lung injury, independent of macrophage infiltration. Furthermore, it was confirmed that RAP ameliorated CSE-induced oxidative stress, inflammation, and cell cycle arrest in human alveolar epithelial cells. These findings demonstrate that inhibiting RAGE in alveolar epithelial cells suppress lung injury and emphysema by inhibiting oxidative stress-induced inflammation and MMPs, while promoting alveolar epithelial cell proliferation. Furthermore, blocking of the DAMP-RAGE interaction through RAP offers a promising therapeutic approach for mitigating emphysema., 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.)

Objectives: To observe the effect of electroacupuncture (EA) on central nervous inflammatory response in obese rats, so as to explore its mechanisms underlying improvement of obesity., Methods: Male SD rats were randomly allocated to normal control, model, EA and sham-EA groups ( n =15/group). Rats of the normal group were fed with normal diet, and the obesity model was established by feeding the rats with high-fat diet for 8 weeks. EA (2 Hz, 1 mA) was applied to "Zusanli"(ST36), "Zhongwan"(CV12), "Guanyuan"(CV4) and "Fenglong"(ST40), and non-acupuncture points (about 5 mm left to CV4 and CV12 and about 5 mm lateral to ST36 and ST40) for 15 min, once every other day, 3 times a week for 8 weeks (no electrical current was delivered to the non-acupoints). The body weight and anal-nose length in each group were recorded before and after the intervention and Lee's index was calculated. The adipocyte morphology of epididymis was detected after H.E. staining, and the contents of serum tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-10 and free fatty acid (NEFA) were detected by using enzyme-linked immunosorbent assay (ELISA). The expression levels of TNF-α, IL-6, IL-10 and inducible nitric oxide synthase (iNOS) proteins in the hypothalamus tissue were detected by Western blot, and the immunoactivity of ionized calcium-binding adapter molecule 1 (Iba-1) in hypothalamic microglia was detected by immunohistochemistry. The content of Evans blue in the brain tissue samples was detected by Evans blue assay to evaluate the integrality of blood-brain barrier., Results: Compared with the normal group, the body mass (BM), Lee's index, contents of serum TNF-α, IL-6 and NEFA, expression levels of hypothalamic TNF-α, IL-6 and iNOS proteins, the immunoactivity level of Iba-1 and the content of Evans blue were significantly increased ( P <0.01, P <0.05), while the content of serum IL-10 and the expression of hypothalamic IL-10 protein considerably decreased ( P <0.01) in the model group. After the intervention, modeling induced increase of BM, Lee's index, contents of serum TNF-α, IL-6 and NEFA, expression levels of hypothalamic TNF-α, IL-6 and iNOS proteins, the immunoactivity level of Iba-1 and the content of Evans blue, and decrease of serum content and expression level of IL-10 in the hypothalamus were reversed by EA stimulation ( P <0.01, P <0.05) but not by non-acupoint stimulation. H.E. staining showed that the adipocytes of epididymis became larger in size and decreased in the number in the model group relevant to the normal group, and became smaller after EA (not non-acupoint) relevant to the model group., Conclusions: EA can treat obesity, improve body inflammation caused by obesity, and relieve central inflammation by repairing the blood-brain barrier.

Exposure to fine particulate matter (PM 2.5 ) and heavy metals (HMs) in the air is closely associated with the incidence and exacerbation of pulmonary fibrosis. Although the specific responses of alveolar epithelial cells (AECs) and lung fibroblasts to PM 2.5 or HM exposure have been well defined, the cellular responses of lung fibroblasts to PM 2.5 or HM exposure and the subsequent interactions with AECs remain poorly investigated. In this study, we demonstrated that human lung fibroblasts exposed to PM 2.5 or lead (Pb) induced fibrotic changes and apoptosis in AECs. Lung fibroblasts exposed to PM 2.5 induced fibrotic changes in AECs via a paracrine action. We further evaluated the detrimental effects of four HMs (cadmium, lead, arsenic, and manganese) present at the highest levels in the ambient air of South Korea, and investigated their paracrine effects on AECs. We found that long-term (14 passages) exposure to these HMs negatively affected the growth, migration, and survival of lung fibroblasts. Notably, manganese (Mn) significantly upregulated the expression of fibrotic markers with the activation of extracellular signal-regulated kinase (ERK) signaling in lung fibroblasts. However, treatment with conditioned medium (CM) collected from Mn-treated lung fibroblasts did not induce fibrotic changes in AECs. Interestingly, CM from Pb-treated lung fibroblasts significantly upregulated markers for fibrosis and apoptosis in AECs via activation of the ERK signaling pathway. These results suggest that understanding interactions between fibroblasts and AECs may provide useful strategies against PM or HM-induced injuries in alveolar tissue., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In understanding the pathophysiology of pulmonary fibrosis (PF), macrophage plasticity has been implicated with a crucial role in the fibrogenic process. Growing evidence indicates that accumulation of M2 macrophages correlates with the progression of PF, suggesting that targeted modulation of molecules that influence M2 macrophage polarization could be a promising therapeutic approach for PF. Here, we demonstrated a decisive role of C-X-C motif chemokine ligand 11 (CXCL11) in driving M1 macrophage polarization to alleviate PF in the bleomycin-induced murine model., Results: We intravenously administered secretome derived from naïve (M0) and polarized macrophages (M1 and M2) into PF mice and found that lung fibrosis was effectively reversed in only the M1-treated group, with modulation of the M1/M2 ratio toward the ratio of the control group. These findings suggest that the factors secreted from M1 macrophages contribute to alleviating PF by targeting macrophages and reshaping the immunofibrotic environment in a paracrine manner. Secretome analysis of macrophages identified CXCL11 as an M1-specific chemokine, and administration of recombinant CXCL11 effectively improved fibrosis with the reduction of M2 macrophages in vivo. Furthermore, a mechanistic in vitro study revealed that CXCL11 reprogrammed macrophages from M2 to M1 through the activation of pERK, pAKT, and p65 signaling., Conclusions: Collectively, we demonstrate an unprecedented role for M1 macrophage-derived CXCL11 as an inducer of M1 macrophage polarization to revert the fibrogenic process in mice with PF, which may provide a clinically meaningful benefit., Competing Interests: Declarations Ethics approval and consent to participate The experiment was approved by the Institutional Animal Care and Use Committee (IACUC), Kangwon National University (IACUC No. KW-220509-1). Consent for publication Not applicable. Competing interests The authors have declared that no competing interest exists., (© 2024. The Author(s).)

The inherent toxicity and persistence of emerging contaminants such as antibiotics and endocrine disruptors pose substantial threats to the environment. Advanced oxidation processes (AOPs) employed for oxidative degradation could yield toxic oxidation by-products (OBPs), including organic acids and aromatic hydrocarbons. Despite their typically low concentrations, OBPs require scrutiny owing to their potential health risks. Although effective assessment methodologies are available, a comprehensive review focusing on the ecological and environmental effects of these pollutants is lacking. This study offers a succinct overview of existing ecotoxicological exposure assessments for emerging organic pollutants. Further, it encapsulates principal dose-response assessment techniques and provides a comparative analysis of several methods. The straightforward assessment factor method evaluates risk based on exposure and species sensitivity and is suitable for preliminary assessments of single pollutants; Species Sensitivity Distribution (SSD) compares species sensitivities to OBPs, emphasizing the importance of species-specific toxicological responses; microcosm and mesocosm methods simulate and predict the effects of OBPs on aquatic life by considering environmental diversity and biological community structures and are ideal for assessing the toxicity of multiple OBPs; the ecological risk analysis model employs mathematical and probabilistic approaches to comprehensively and accurately assess exposures and effects, accounting for the complexities and uncertainties inherent in ecotoxicological evaluations. Different risk characterization techniques are outlined in this study, including the risk quotient (RQ), which is ideal for quantifying and comparing risks; probabilistic ecological risk assessment (PERA), suitable for managing significant uncertainty; and the Environmental Pollution Index (EPI), the preferred method for quantitative assessment of OBP pollution levels. The merits and limitations of each of these quantitative assessment tools are evaluated, providing a comprehensive view of their applications in risk analysis. In addition, pressing contemporary challenges are identified and trajectories and pivotal issues suggested for future research., 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 B.V. All rights reserved.)

Purpose: Well-differentiated papillary peritoneal mesothelial tumors (WDPMTs) are understudied and discrete from peritoneal mesotheliomas (PMs). We report clinicopathologic characteristics and outcomes of a large prospective WDPMT cohort., Methods: Patients with WDPMT identified between August 2007 and December 2020 were followed through January 2023. Clinical characteristics and outcomes were annotated. Overall survival (OS) was assessed from pathologic diagnosis. Germline variants were analyzed, and targeted next-generation sequencing (NGS; MSK-IMPACT) data were compared to PMs and diffuse pleural mesotheliomas (DPMs)., Results: Among 54 patients, median age at diagnosis was 55 (range 20-76), 50% were female (n = 27), and 46% were smokers (n = 25; median 8 pack/years). Most (94%, n = 51) WDPMTs were found during surgical explorations for other indications, primarily other malignancies. Two patients underwent surgical resection for WDPMT; none received systemic therapy for WDPMT. Median OS was not reached (19/54; median follow up 4.5 years). Somatic NGS was available for 35% (19/54) of patients. TRAF7 alterations were enriched in WDPMT (89%; 17/19) compared with PM (0%; 0/50; p < 0.0001) and DPM (0%; 0/74; p < 0.0001). In WDPMT compared with PM and DPM, there were less BAP1 (0% [0/0] vs. 4% [8/50] vs. 46% [34/74]; p = 0.001 and p < 0.0001, respectively) and NF2 (0% [0/0] vs. 24% [12/50] vs. 31% [23/74]; p = 0.03 and p = 0.001 respectively) alterations. Pathogenic germline variants were present in 23% (4/17) of WDPMTs., Conclusions: Well-differentiated papillary peritoneal mesothelial tumors were primarily incidental findings. There was no WDPMT-related mortality, so there was no distinct role for routine cytoreductive surgery or systemic therapy. Genomic profiles can help to differentiate WDPMT from DPM and PM., (© 2024. The Author(s).)

Introduction: Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UTs) are a recently defined group of aggressive cancers in which the effectiveness of standard treatments for lung cancer is unknown., Methods: We collected clinical, pathologic, and demographic variables from five institutions for patients whose tumors met criteria for SMARCA4-UTs (undifferentiated phenotype and loss of SMARCA4 (BRG1) by immunohistochemistry)., Results: We identified 92 patients with SMARCA4-UTs; 58 (63%) had stage IV disease at diagnosis and 16 (17%) developed recurrent or metastatic disease after initial diagnosis. Median overall survival from metastatic diagnosis was 7.3 (95% confidence interval [CI]: 4.6-12.8) months. Of patients with metastatic disease, 58 (78%) received first-line systemic treatment. Most often, patients received chemo and immunotherapy combination (41%), chemotherapy alone (33%), or immunotherapy alone (16%). Median progression-free survival from start of systemic therapy was 1.9 (95% CI: 1.4-14.5) months for chemo and immunotherapy, 1.6 (95% CI: 1.1-5.8) months for chemotherapy, and 3.3 (95% CI: 1.2-undefined) months for immunotherapy alone. Five patients had durable responses (≥2 y); all received immunotherapy as part of first-line regimens. Nine (16%) of 55 tumor samples tested had programmed death-ligand 1 expression more than or equal to 50%, with 24 (44%) negative samples. Tumor mutational burden was available in 48 cases (52%), and median was 10.5 (range: 2-48) mutations per megabase., Conclusions: This multi-institution retrospective cohort analysis revealed a population of patients with short progression-free survival to standard therapies and poor overall survival. A few patients had remarkable response to regimens including immunotherapy. Prospective clinical studies are urgently needed to identify better therapeutic approaches to treat this aggressive malignancy, and this analysis may serve as a benchmark for future clinical trial design., Competing Interests: Dr. Cooper has received honoraria from MJH Life Sciences, Ideology Health, Intellisphere LLC, and MedStar Health; consulting fees from 10.13039/100005564Gilead Sciences, Inc.; and research funding to institution from Merck, Monte Rosa, AbbVie, Roche, and Amgen. Dr. Ricciuti has received consulting fees from AstraZeneca, Bayer, Amgen, Regeneron, Capvision, and Guidepoint; speaker fees from AstraZeneca; and honoraria from SITC and Targeted Oncology. Dr. Sholl reports receiving research and consulting income to institution from Genentech; consulting income to institution from Eli Lilly; and research support from 10.13039/100002491Bristol-Myers Squibb. Dr. Di Federico has served on advisory boards for Hanson-Wade, Novartis, and IQVIA and has received honoraria from SITC. Dr. Awad reports receiving consulting fees from AstraZeneca, Blueprint Medicines Corporation, Bristol-Myers Squibb, EMD Serono, Inc., Genentech Inc., Merck & Co., Inc., Mirati Therapeutics, Inc., Novartis Pharmaceuticals Corporation, and Janssen and Affini-T research support to institution from AstraZeneca, Bristol-Myers Squibb, Genentech, Inc., Amgen, and Eli Lilly. Dr. Aldea reports receiving research funding from 10.13039/100002429Amgen, 10.13039/100011218Sandoz, and AstraZeneca and providing consulting for Viatris. Dr. Grecea has received financial support from AstraZeneca, Eli Lilly, Magna Pharm, Pfizer, and Bristol-Myers Squibb. Dr. Chaft has received research funds to institution from AstraZeneca, Bristol-Myers Squibb, Genentech, Beigene, and Merck and consulting fees from 10.13039/100004325AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Guardant Health, Janssen, Merck, Roche, and Sanofi-Regeneron. Dr. Kris has received consulting fees from AstraZeneca, Bergenbio, Bristol-Myers Squibb, Daiichi Sankyo, Merus, Pfizer, and Sanofi. Dr. Riely has been an uncompensated consultant to Lilly, Pfizer, Merck, Novartis, Verastem, and Mirati; has received institutional research support from Mirati, Eli Lilly, Takeda, 10.13039/100004334Merck, Roche, Pfizer, and Novartis. This work was supported, in part, by grants to Memorial Sloan Kettering Cancer Center from John and Georgia DallePezze and the Ge Li and Ning Zhao Family Foundation. Dr. Rudin reports providing consulting services regarding oncology drug development with AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Jazz, Mariana, and Scorpion Therapeutics; receiving licensing fees for DLL3-directed therapies; and serving on the scientific advisory boards of Auron, DISCO, Earli, and Harpoon Therapeutics. Dr. Dagogo-Jack has received honoraria from Foundation Medicine, Creative Education Concepts, OncLive, ASCO Post, DAVA Oncology, Medscape, Research to Practice, Total Health, Aptitude Health, American Lung Association, and PeerView; consulting fees from AstraZeneca, Boehringer Ingelheim, Bayer, BostonGene, Bristol-Myers Squibb, Catalyst, Genentech, Gilead, Janssen, Eli Lilly, Merus, Novocure, Pfizer, Roche, Sanofi-Genzyme, Syros, ThermoFisher Scientific, and Xcovery; research support from 10.13039/100007174Array, 10.13039/100004328Genentech, 10.13039/100004336Novartis, 10.13039/100004319Pfizer, and Guardant Health; and travel support from Array and Pfizer. Dr. Mino-Kenudson reports receiving compensation from consulting or advisory board from AstraZeneca, Pfizer, Repare, Boehringer Ingelheim, Sanofi, AbbVie, Daiichi Sankyo, and Roche; royalties from Elsevier; and salary partially supported by NIH R01CA240317. Dr. Vokes reports receiving consulting or advisory fees from Oncocyte, Eli Lilly, Sanofi-Genzyme, Regeneron, Amgen, Xencor, AstraZeneca, Tempus, Pfizer, Summit Therapeutics, OncoHost, Guardant, and Merus; travel reimbursement from Regeneron; research grants from Circulogene and Mirati; funding from Circulogene; and honoraria from Nebraska Oncology Society, Scienomics Group, Grace, OncLive, OMNI-Oncology, and Guardant. She acknowledges R01CA276178, Rexana’s Foundation for Fighting Lung Cancer. Ms. Bowman holds IP for MSK-ACCESS licensed to SOPHiA Genetics. Dr. Yang has received speaking fees from Medscape, Medical Learning Institute, and PRIME Education; consulting fees from AstraZeneca, AbbVie, Merus, Roche, Amgen, and Sanofi. Dr. Schoenfeld reports having consulting or advising role to J&J, KSQ Therapeutics, Bristol-Myers Squibb, Merck, Enara Bio, Perceptive Advisors, Oppenheimer and Co., Umoja Biopharma, Legend Biotech, Iovance Biotherapeutics, Obsidian Therapeutics, Prelude Therapeutics, Immunocore, Lyell Immunopharma, Amgen, and Heat Biologics; receiving research funding from 10.13039/100004330GlaxoSmithKline (inst), PACT pharma (inst), Iovance Biotherapeutics (inst), Achilles Therapeutics (inst), Merck (inst), Bristol-Myers Squibb (inst), Harpoon Therapeutics (inst), AffiniT Therapeutics (inst), Legend Therapeutics (inst), and Amgen (inst). The remaining authors declare no conflict of interest., (© 2024 The Authors.)

Oxidative stress and excitotoxicity are the major causes of neuronal death/loss in the brain following ischemia and reperfusion (IR). Hyperthermia is known to exacerbate ischemic neuronal damage; however, the underlying mechanisms remain unclear. This study investigated the mechanisms underlying neuronal damage caused by IR injury (IRI) under hyperthermic conditions in the gerbil hippocampal CA1 region. Gerbils were controlled at normothermia (37.5±0.2°C) or hyperthermia (39.5±0.2°C). After temperature control for 30 min, the animals received IRI (following 5 min of transient forebrain ischemia) or sham ischemia, and were subsequently sacrificed at 0, 3, 6, 12, 24, 48, and 120h after IRI. Neuronal death was examined using neuronal nuclear antigen immunohistochemistry and Fluoro-Jade B histofluorescence. Oxidative stress was analyzed by immunohistochemistry for 8-Hydroxy-2'-deoxyguanosine (8OHdG) and superoxide dismutase 2 (SOD2). Excitotoxicity was investigated by immunohistochemistry and western blotting for glutamate transporter 1 (GLT1). Immunohistochemical staining for glial fibrillary acidic proteins (GFAP) was performed to detect reactive astrogliosis. Loss of pyramidal neurons was detected earlier (48h post-IRI) in the hyperthermia-IRI group than in the normothermia-IRI group (120h post-IRI). Further, 8OHdG and SOD2 immunoreactivity in the hyperthermia-IRI group was significantly higher than that in the normothermia-IRI group. Changes in GLT1 immunoreactivity in both groups were biphasic, indicating that the immunoreactivity and protein levels were significantly lower in the hyperthermia-IRI group. GFAP immunoreactivity was enhanced following neuronal loss, indicating that the immunoreactivity was significantly higher in the hyperthermia-IRI group. Taken together, these results suggest that brain IR under hyperthermic conditions can aggravate neuronal damage in the hippocampal CA1 region through severe oxidative stress and excitotoxicity., (©The Author(s) 2024. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

Owing to the rapid progress in artificial intelligence (AI) and the widespread use of generative learning, the problem of sparse data has been solved effectively in various research fields. The application of AI technologies has resulted in important transformations in healthcare, particularly in radiology. To ensure the high quality, safety, and effectiveness of AI and machine learning (ML) medical devices, the US Food and Drug Administration (FDA) has established regulatory guidelines to support the performance evaluation of medical devices. Furthermore, the FDA has proposed continuous surveillance requirements for AI/ML medical devices. This paper presents a summary of SaMD products that have passed the FDA 510 (k) AI/ML pathway, the challenges associated with the current AI/ML software-as-a-medical-device, and solutions for promoting the development of AI technologies in medicine. We hope to provide valuable information pertaining to medical-device design, development, and monitoring to ultimately achieve safer and more effective personalized medical services., (© 2024 The Authors.)

Introduction: No definitive answers currently exist regarding optimal first-line therapy for HER2-mutant NSCLC. Access to rapid tissue sequencing is a major barrier to precision drug development in the first-line setting. ctDNA analysis has the potential to overcome these obstacles and guide treatment., Methods: We retrospectively analyzed patients with metastatic HER2-mutant NSCLC who underwent prospective clinical ctDNA sequencing and received systemic therapy at Memorial Sloan Kettering Cancer Center (MSK) from January 2016 to September 2022. HER2 mutations were identified by next-generation sequencing through MSK-IMPACT, MSK-ACCESS or Resolution ctDx LungTM assay. Primary endpoints were time to the next treatment (TTNT) and overall survival (OS)., Results: Sixty-three patients were included in the primary analysis. Chemoimmunotherapy (33/63, 52.4 %) was the predominant first-line treatment with a median TTNT of 5.1 months (95 %CI 4.1 - 6.1) whereas 55.0 % (22/40) of patients who received second-line T-DXd obtained a median TTNT of 9.2 m (95 % CI, 0-22.2). Plasma ctDNA was tested before first-line therapy in 40 patients with a median OS of 28.0 months (95 % CI 21-34), in whom 31 patients (78.0 %) had detectable ctDNA. HER2 mutations were detected on ctDNA with a median turnaround time of 13 days, occasionally co-occurred with EGFR and MET alterations and were tracked longitudinally correlating with treatment response. Patients with detectable baseline ctDNA had significantly shorter OS (hazard ratio (HR), 5.25; 95 % CI, 1.2-23.9; p = 0.019)., Conclusion: Chemoimmunotherapy remains a major treatment option for metastatic HER2-mutant NSCLC. ctDNA can rapidly detect HER2 and co-mutations, and it has the potential to guide and monitor optimal first-line therapy. As a negative prognostic biomarker, detectable ctDNA at baseline would need to be taken into account for patient selection in future studies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Bob T. Li has served as an uncompensated advisor and consultant to Amgen, AstraZeneca, Boehringer Ingelheim, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, and Lilly. He has received research grants to his institution from Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Jiangsu Hengrui Pharmaceuticals, Lilly, Nuvalent, and Revolution Medicines. He has received academic travel support from Amgen. He is an inventor on three institutional patents at MSK (US62/685,057, US62/514,661, US63/424,813) and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. Alexander Drilon declared as follows: Honoraria: 14ner/Elevation Oncology, Amgen, Abbvie, ArcherDX, AstraZeneca, Beigene, BergenBio, Blueprint Medicines, Bristol Myers Squibb, Chugai Pharmaceutical, EcoR1, EMD Serono, Entos, Exelixis, Helsinn, Hengrui Therapeutics, Ignyta/Genentech/Roche, Janssen, Loxo/Bayer/Lilly, Merus, Monopteros, MonteRosa, Novartis, Nuvalent, Pfizer, Prelude, Regeneron, Repare RX, Springer Healthcare, Takeda/Ariad/Millenium, Treeline Bio, TP Therapeutics, Tyra Biosciences, Verastem. Advisory Boards: Bayer, MonteRosa, Abbvie, EcoR1 Capital, LLC, Amgen, Helsinn, Novartis, Lilly, AnHeart Therapeutics. Consulting: MonteRosa, Innocare, Boundless Bio, Treeline Bio, Nuvalent, 14ner/Elevation Oncology, Entos, Prelude. Associated Research Paid to Institution: Foundatin Medicine, GlaxoSmithKlein, Teva, Taiho, PharmaMar. Equity: mBrace. Copyright: Selpercatinib-Osimertinib (filed/pending). Royalties: Wolters Kluwer; Other (Food/Beverage): Merck, Puma, Merus, Boehringer Ingelheim; CME Honoraria: Answers in CME, Applied Pharmaceutical Science, Inc, AXIS, Clinical Care Options, Doc Congress, EPG Health, Harborside Nexus, I3 Health, Imedex, Liberum, Medendi, Medscape, Med Learning, MedTalks, MJH Life Sciences, MORE Health, Ology, OncLive, Paradigm, Peerview Institute, PeerVoice, Physicians Education, Projects in Knowledge, Resources, Remedica Ltd, Research to Practice, RV More, Targeted Oncology, TouchIME, WebMD. Sarat Chandarlapaty has received institutional grant/funding from Daiichi-Sankyo, AstraZeneca, and Lilly, Shares/Ownership interests in Odyssey Biosciences, Effector Therapeutics, and Totus Medicines, and consultation/Ad board/Honoraria from AstraZeneca, Daiichi-Sankyo, Novartis, Neogenomics, Nuvalent, Blueprint, SAGA Diagnostics, and Effector Therapeutics. Jiannan Guo is a former employee of Resolution Bioscience. Eric Gagne, Kavita Garg and Frederick Baehner are employees of Exact Sciences. All remaining authors have declared no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

IgA nephropathy (IgAN) is the most common type of glomerulonephritis that frequently progresses to kidney failure. However, the molecular pathogenesis underlying IgAN remains largely unknown. Here, we investigated the role of galectin-3 (Gal-3), a galactoside-binding protein in IgAN pathogenesis, and showed that Gal-3 expression by the kidney was significantly enhanced in patients with IgAN. In both TEPC-15 hybridoma-derived IgA-induced, passive, and spontaneous "grouped" ddY IgAN models, Gal-3 expression was clearly increased with disease severity in the glomeruli, peri-glomerular regions, and some kidney tubules. Gal-3 knockout (KO) in the passive IgAN model had significantly improved proteinuria, kidney function and reduced severity of kidney pathology, including neutrophil infiltration and decreased differentiation of Th17 cells from kidney-draining lymph nodes, despite increased percentages of regulatory T cells. Gal-3 KO also inhibited the NLRP3 inflammasome, yet it enhanced autophagy and improved kidney inflammation and fibrosis. Moreover, administration of 6-de-O-sulfated, N-acetylated low-molecular-weight heparin, a competitive Gal-3 binding inhibitor, restored kidney function and improved kidney lesions in passive IgAN mice. Thus, our results suggest that Gal-3 is critically involved in IgAN pathogenesis by activating the NLRP3 inflammasome and promoting Th17 cell differentiation. Hence, targeting Gal-3 action may represent a new therapeutic strategy for treatment of this kidney disease., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Lipopolysaccharide (LPS), a gut-derived endotoxin, is a recognized risk factor for both Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). Rocaglamide-A (Roc-A), a natural compound derived from the genus Aglaia, is known for its pharmacological and immunosuppressive effects on various cell types. Although our recent investigations have unveiled Roc-A's anti-adipogenic role in adipocytes, its mechanism in hepatic inflammation remains elusive. This study delves into Roc-A's protective effects on LPS-induced hepatic inflammation. Our results demonstrated that Roc-A treatment significantly reduced the LPS-induced production of inflammatory cytokines in hepatocytes. Intriguingly, Roc-A decreased LPS-induced production of reactive oxygen species (ROS), upregulated antioxidant gene expression, and downregulated endoplasmic reticulum (ER) stress-related gene expression. Mechanistically, Roc-A significantly attenuated LPS-induced phosphorylation of c-Jun N-terminal kinase (JNK) and activator protein-1 (AP-1). Notably, this effect was abolished by the JNK activator Anisomycin, while the JNK inhibitor SP600125 enhanced it. Furthermore, Roc-A suppressed the expression of NF-κB target genes, including inducible nitric oxide synthase (iNOS), thereby alleviating iNOS-derived nitric oxide (NO) production. These findings collectively indicate that Roc-A has the potential to alleviate LPS-induced nitrosative/oxidative stress and hepatic inflammation by inhibiting JNK phosphorylation. Thus, Roc-A emerges as a promising anti-inflammatory intervention for LPS-induced hepatic inflammation., Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-024-00263-y., Competing Interests: Conflict of interestThe authors declare that they have no competing financial interests., (© The Author(s) under exclusive licence to Korean Society of Toxicology 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Objectives: To observe the effect of electroacupuncture (EA) on the expressions of high mobility group protein 1(HMGB1) and myeloid differentiation factor 88 (MyD88) in the small intestine and intestinal flora of obese rats, so as to explore the potential mechanism of EA to improve obesity in rats., Methods: After 1 week of acclimatization, 10 rats were randomly selected from 50 Wistar male rats as the normal group, and the rest rats were fed with high-fat diet for 8 weeks to establish the obese model. The successfully modeling rats were randomly divided into model group, EA group and sham EA group, with 10 rats in each group. Rats in the EA group were given EA (2 Hz, 1 mA) at "Zhongwan"(CV12), "Guanyuan"(CV4), "Zusanli" (ST36)and "Fenglong"(ST40). Rats in the sham EA group were given shallow stabs at acupoints of the EA group about 5 mm outwardly and the electrodes were clamped without being energized. Both groups were intervened for 10 min each time, 3 times (Monday, Wednesday and Friday) a week for 8 weeks. The body weights of the rats were measured before and after 8 weeks of intervention, respectively. The contents of serum lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-α were measured by ELISA, and the protein and mRNA expressions of HMGB1 and MyD88 in the small intestine were detected by Western blot and real-time quantitative PCR, respectively. 16S rRNA sequencing was performed to determine the relative abundance and diversity of the bacterial flora in the fresh feces of rats., Results: Compared with the normal group, the body weight, serum LPS and TNF-α contents, small intestinal HMGB1 and MyD88 protein and mRNA expression levels of rats in the model group were significantly increased ( P <0.01), while the relative abundance of Lactobacillus , Muri and Bifidobacterium was decreased ( p <0.01), Collinsella , Prevotella and Ruminococcus was increased ( P <0.01). Compared with model group, the body weight, serum LPS and TNF-α contents, protein and mRNA expression levels of HMGB1 and MyD88 in both EA and sham EA groups were decreased ( P <0.01, P <0.05), while the relative abundance of Lactobacillus , Muri and Bifidobacterium was increased ( P <0.01) and Collinsella , Prevotella and Ruminococcus decreased ( P <0.01). Comparison between EA group and sham EA group showed that, the contents of LPS and TNF-α in serum of rats in sham EA group were increased ( P <0.01, P <0.05), the relative abundance of Lactobacillus , Muri and Bifidobacterium was lower ( P <0.05, P <0.01), and Collinsella , Prevotella and Ruminococcus was higher ( P <0.01)., Conclusions: EA can reduce the body weight of obese rats, which may be related to the regulation of the structure of intestinal flora and the reduction of inflammatory reactions in the small intestine.

Purpose: Even though BRAF fusions are increasingly detected in standard multigene next-generation sequencing panels, few reports have explored their structure and impact on clinical course., Experimental Design: We collected data from patients with BRAF fusion-positive cancers identified through a genotyping protocol of 97,024 samples. Fusions were characterized and reviewed for oncogenic potential (in-frame status, non-BRAF partner gene, and intact BRAF kinase domain)., Results: We found 241 BRAF fusion-positive tumors from 212 patients with 82 unique 5' fusion partners spanning 52 histologies. Thirty-nine fusion partners were not previously reported, and 61 were identified once. BRAF fusion incidence was enriched in pilocytic astrocytomas, gangliogliomas, low-grade neuroepithelial tumors, and acinar cell carcinoma of the pancreas. Twenty-four patients spanning multiple histologies were treated with MAPK-directed therapies, of which 20 were evaluable for RECIST. Best response was partial response (N = 2), stable disease (N = 11), and progressive disease (N = 7). The median time on therapy was 1 month with MEK plus BRAF inhibitors [(N = 11), range 0-18 months] and 8 months for MEK inhibitors [(N = 14), range 1-26 months]. Nine patients remained on treatment for longer than 6 months [pilocytic astrocytomas (N = 6), Erdheim-Chester disease (N = 1), extraventricular neurocytoma (N = 1), and melanoma (N = 1)]. Fifteen patients had acquired BRAF fusions., Conclusions: BRAF fusions are found across histologies and represent an emerging actionable target. BRAF fusions have a diverse set of fusion partners. Durable responses to MAPK therapies were seen, particularly in pilocytic astrocytomas. Acquired BRAF fusions were identified after targeted therapy, underscoring the importance of postprogression biopsies to optimize treatment at relapse in these patients., (©2024 American Association for Cancer Research.)

Obesity, a widespread global health issue, is frequently linked to disrupted lipid metabolism, resulting in excessive accumulation of adipose tissue and associated health complications. Acupuncture, a traditional Chinese medical modality, has exhibited potential as a viable intervention for addressing obesity. The underlying mechanism proposed involves the stimulation of specific acupoints to exert a regulatory influence on hepatic function. The liver has a central role in lipid metabolism, including processes such as lipid synthesis, storage and distribution. Acupuncture is believed to enhance the liver's efficiency in processing lipids, thereby reducing lipid accumulation and improving metabolic functions. Research indicates that acupuncture can influence the expression of certain genes and proteins involved in lipid metabolism in the liver. This includes upregulating genes that promote lipid breakdown and oxidation, and downregulating those involved in lipid synthesis. Additionally, acupuncture has been shown to improve insulin sensitivity, which is crucial for the regulation of lipid metabolism. Furthermore, the potential anti-inflammatory effects of acupuncture may play a significant role in its efficacy for the treatment of obesity. The presence of chronic inflammation has been strongly associated with metabolic disorders such as obesity. Through its ability to mitigate inflammation, acupuncture can potentially aid in the restoration of lipid metabolism and the reduction of body weight. Moreover, the amelioration of hepatic oxidative stress represents another mechanism by which acupuncture may contribute to the reduction of lipid deposition. Notably, the liver, being the primary site of lipid metabolism, maintains communication with various organs including the brain, adipose tissue, skeletal muscle and intestines. This perspective opens new avenues for the treatment of obesity, emphasizing the importance of holistic approaches in managing complex metabolic disorders. Please cite this article as: Yang SR, Chen L, Luo D, Wang YY, Liang FX. Unlocking the potential: How acupuncture reshapes the liver-centered lipid metabolism pattern to fight obesity. J Integr Med. 2024; 22(5): 523-532., (Copyright © 2024 Shanghai Yueyang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine. Published by Elsevier B.V. All rights reserved.)

Background: While NTRK fusion-positive cancers can be exquisitely sensitive to first-generation TRK inhibitors, resistance inevitably occurs, mediated in many cases by acquired NTRK mutations. Next-generation inhibitors (e.g., selitrectinib, repotrectinib) maintain activity against these TRK mutant tumors; however, there are no next-generation TRK inhibitors approved by the FDA and select trials have stopped treating patients. Thus, the identification of novel, potent and specific next-generation TRK inhibitors is a high priority., Methods: In silico modeling and in vitro kinase assays were performed on TRK wild type (WT) and TRK mutant kinases. Cell viability and clonogenic assays as well as western blots were performed on human primary and murine engineered NTRK fusion-positive TRK WT and mutant cell models. Finally, zurletrectinib was tested in vivo in human xenografts and murine orthotopic glioma models harboring TRK-resistant mutations., Results: In vitro kinase and in cell-based assays showed that zurletrectinib, while displaying similar potency against TRKA, TRKB, and TRKC WT kinases, was more active than other FDA approved or clinically tested 1 st - (larotrectinib) and next-generation (selitrectinib and repotrectinib) TRK inhibitors against most TRK inhibitor resistance mutations (13 out of 18). Similarly, zurletrectinib inhibited tumor growth in vivo in sub-cute xenograft models derived from NTRK fusion-positive cells at a dose 30 times lower when compared to selitrectinib. Computational modeling suggests this stronger activity to be the consequence of augmented binding affinity of zurletrectinib for TRK kinases. When compared to selitrectinib and repotrectinib, zurletrectinib showed increased brain penetration in rats 0.5 and 2 h following a single oral administration. Consistently, zurletrectinib significantly improved the survival of mice harboring orthotopic NTRK fusion-positive, TRK-mutant gliomas (median survival = 41.5, 66.5, and 104 days for selitrectinib, repotrectinib, and zurletrectinib respectively; P < 0.05)., Conclusion: Our data identifies zurletrectinib as a novel, highly potent next-generation TRK inhibitor with stronger in vivo brain penetration and intracranial activity than other next-generation agents., (© 2024. The Author(s).)

Combining exogenous and endogenous antibacterial mechanisms has been demonstrated to enhance therapeutic efficacy significantly. This study constructs an innovative type of exogenous and endogenous antibacterial nanocomposite hydrogels with injectable dual-crosslinked networks and dual-stimuli responsiveness. The primary network establishes imine bonds between the functionalized dextran featuring norbornenes and aldehydes (NorAld-Dex) and the quaternized chitosan (QCS). The imine bonds provide self-healing, injectability, and pH-responsiveness to the hydrogel network. The secondary network is established by integrating thiolated mesoporous silica-coated titanium dioxide nanoparticles (TiO 2 @MS-SH) into the hydrogel network via an ultrasound-activated thiol-norbornene reaction with NorAld-Dex. The microstructures and properties of NorAld-Dex/QCS/TiO 2 @MS-SH hydrogels can be fine-tuned by adjusting the sonication time to increase the amount of thiol-norbornene crosslinks in the network. Effective antibacterial performance of NorAld-Dex/QCS/TiO 2 @MS-SH hydrogels at low pH has been demonstrated with the synergistic effect of the acid-induced dissociation of the hydrogel network, protonated QCS, and the reactive oxygen species (ROS) generated by TiO 2 @MS-SH nanoparticles under ultrasound irradiation. In summary, NorAld-Dex/QCS/TiO 2 @MS-SH nanocomposite hydrogel is an advanced dual stimuli-responsive antibacterial platform with customizable microstructures and properties, offering great potential for biomedical applications., (© 2024 Wiley-VCH GmbH.)

Comprehensive molecular profiling by next generation sequencing (NGS) has revolutionized tumor classification and biomarker evaluation. However, routine implementation is challenged by the scant nature of diagnostic material obtained through minimally invasive procedures. Here, we describe our long-term experience in profiling cytology samples with an in-depth assessment of the performance, quality metrics, biomarker identification capabilities, and potential pitfalls. We highlight the impact of several optimization strategies to maximize performance with 4,871 prospectively sequenced clinical cytology samples tested by MSK-IMPACT ™ . Special emphasis is given to the use of residual supernatant cell free DNA (ScfDNA) as a valuable source of tumor DNA. Overall, cytology samples were similar in performance to surgical samples in identifying clinically relevant genomic alterations, achieving success rates up to 93% with full optimization. While cell block (CB) samples had excellent performance overall, low-level cross-contamination was identified in a small proportion of cases (4.7%), a common pitfall intrinsic to the processing of paraffin blocks, suggesting that more stringent precautions and processing modifications should be considered in quality control initiatives. By contrast ScfDNA samples had negligible contamination. Finally, ScfDNA testing exclusively used as a rescue strategy delivered successful results in 71% of cases where tumor tissue from CB was depleted.

Solution styrene-butadiene rubber (SSBR) is widely used to improve the properties of tire tread compounds. Tire wear particles (TWPs), which are generated on real roads as vehicles traverse, represent one of significant sources of microplastics. In this study, four SSBR compounds were prepared using two SSBRs with high styrene (STY samples) and 1,2-unit (VIN samples) contents, along with dicyclopentadiene resin. The abrasion behaviors were investigated using four different abrasion testers: cut and chip (CC), Lambourn, DIN, and laboratory abrasion tester (LAT100). The abrasion rates observed in the Lambourn and LAT100 abrasion tests were consistent with each other, but the results of CC and DIN abrasion tests differed from them. The addition of the resin improved the abrasion rate and resulted in the generation of large wear particles. The abrasion rates of STY samples in the Lambourn and LAT100 abrasion tests were lower than those of VIN samples, whereas the values in the CC and DIN abrasion tests were higher than those of VIN samples. The wear particles were predominantly larger than 1000 μm, except for the VIN sample in the DIN abrasion test. However, TWPs > 1000 μm are rarely produced on real roads. The size distributions of wear particles > 1000 μm were 74.0-99.5%, 65.9-93.4%, 7.2-95.1%, and 37.5-83.0% in the CC, Lambourn, DIN, and LAT100 abrasion tests, respectively. The size distributions of wear particles in the Lambourn and LAT100 abrasion tests were broader than those in the other tests, whereas the distributions in the CC abrasion test were narrower. The abrasion patterns and the morphologies and size distributions of wear particles generated by the four abrasion tests varied significantly, attributable to differences in the bound rubber contents, crosslink densities, and tensile properties.

Purpose: Diffuse pleural mesotheliomas (DPM) with genomic near-haploidization (GNH) represent a novel subtype first recognized by The Cancer Genome Atlas project; however, its clinicopathologic and molecular features remain poorly defined., Experimental Design: We analyzed clinical genomic profiling data from 290 patients with DPM using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay. Allele-specific copy number analysis was performed using the Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing (FACETS) algorithm., Results: A total of 210 patients were evaluable for loss of heterozygosity (LOH) analysis using FACETS from MSK-IMPACT tumor:normal sequencing data. In this cohort, GNH, defined as LOH across >80% of the genome, was detected in 10 cases (4.8%). Compared with non-GNH tumors, GNH DPMs were associated with younger age and less frequent self-reported history of occupational asbestos exposure. Histologically, GNH DPMs were enriched in biphasic subtype (80% vs. 14.5%) and showed abundant tumor-infiltrating lymphocytes (TILs). Genomic analysis revealed a higher frequency of TP53 alterations, whereas SETDB1 mutations were present in nearly all and only in this subset. The clinicopathologic and molecular findings were further validated in a separate cohort. Despite the younger age, patients with GNH DPMs had a shorter overall survival (10.9 vs. 25.4 months, P = 0.004); the poor prognostic impact of GNH remained significant after controlling for biphasic histology. Of three patients with GNH DPMs who received immune checkpoint blockade, two achieved a clinician-assessed partial response., Conclusions: GNH defines an aggressive subtype of mainly biphasic DPMs in younger patients with recurrent alterations in SETDB1 and TP53. The enrichment in biphasic histology and TILs, together with our preliminary immune checkpoint blockade response data and anecdotal clinical trial data, suggests that further evaluation of immunotherapy may be warranted in this subset., (©2024 American Association for Cancer Research.)

Objective: SET domain-containing protein 1A (SETD1A) histone lysine N-methyltransferase may serve as a biomarker for the auxiliary diagnosis and treatment assessment of schizophrenia (SCZ). The aim of this study was to compare serum levels of SETD1A protein between patients with SCZ and health controls., Methods: Patients with SCZ and health controls were recruited from the Sixth Hospital of Changchun and the 'Survey on Chronic Diseases and Risk Factors among Adults in Jilin Province', respectively. The quantifications of lysine N-methyltransferase in peripheral serum were conducted by the ELISA method, and data was analyzed using the R software., Results: Forty patients with SCZ (mean age: 33.97 ± 5.99 years) and forty healthy controls (mean age: 39.07 ± 4.62 years) were included. There was significantly lower concentration of SETD1A protein in the SCZ group compared with the control group (P < 0.001). This significant difference still exists after stratification by sex (P < 0.05)., Conclusion: Our study demonstrates that decreased levels of serum SETD1A protein may be utilized as a possible peripheral biomarker for schizophrenia., 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 B.V. All rights reserved.)

Lung cancer in never smokers (LCINS) accounts for up to 25% of all lung cancers and has been associated with exposure to secondhand tobacco smoke and air pollution in observational studies. Here, we evaluate the mutagenic exposures in LCINS by examining deep whole-genome sequencing data from a large international cohort of 871 treatment-naïve LCINS recruited from 28 geographical locations within the Sherlock- Lung study. KRAS mutations were 3.8-fold more common in adenocarcinomas of never smokers from North America and Europe, while a 1.6-fold higher prevalence of EGFR and TP53 mutations was observed in adenocarcinomas from East Asia. Signature SBS40a, with unknown cause, was found in most samples and accounted for the largest proportion of single base substitutions in adenocarcinomas, being enriched in EGFR -mutated cases. Conversely, the aristolochic acid signature SBS22a was almost exclusively observed in patients from Taipei. Even though LCINS exposed to secondhand smoke had an 8.3% higher mutational burden and 5.4% shorter telomeres, passive smoking was not associated with driver mutations in cancer driver genes or the activities of individual mutational signatures. In contrast, patients from regions with high levels of air pollution were more likely to have TP53 mutations while exhibiting shorter telomeres and an increase in most types of somatic mutations, including a 3.9-fold elevation of signature SBS4 (q-value=3.1 × 10 -5 ), previously linked mainly to tobacco smoking, and a 76% increase of clock-like signature SBS5 (q-value=5.0 × 10 -5 ). A positive dose-response effect was observed with air pollution levels, which correlated with both a decrease in telomere length and an elevation in somatic mutations, notably attributed to signatures SBS4 and SBS5. Our results elucidate the diversity of mutational processes shaping the genomic landscape of lung cancer in never smokers., Competing Interests: COMPETING INTERESTS LBA is a co-founder, CSO, scientific advisory member, and consultant for io9, has equity and receives income. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. LBA is also a compensated member of the scientific advisory board of Inocras. LBA’s spouse is an employee of Biotheranostics. ENB and LBA declare U.S. provisional patent application filed with UCSD with serial numbers 63/269,033. LBA also declares U.S. provisional applications filed with UCSD with serial numbers: 63/366,392; 63/289,601; 63/483,237; 63/412,835; and 63/492,348. LBA is also an inventor of a US Patent 10,776,718 for source identification by non-negative matrix factorization. SRY has received consulting fees from AstraZeneca, Sanofi, Amgen, AbbVie, and Sanofi; received speaking fees from AstraZeneca, Medscape, PRIME Education, and Medical Learning Institute. All other authors declare that they have no competing interests.

In this study, the porous carbon material (FeN-BC) with ultra-high catalytic activity was obtained from waste biomass through Fe-N co-doping. The prominent degradation rate (> 96.8%) of naproxen (NAP) was achieved over a wide pH range (pH 3.0-9.0) in FeN-BC/PAA system. Unlike previously reported iron-based peracetic acid (PAA) systems with • OH or RO • as the dominated reactive species, the degradation of contaminants was attributed to singlet oxygen ( 1 O 2 ) produced by organic radicals (RO • ) decomposition, which was proved to be thermodynamically feasible and favorable by theoretical calculations. Combining the theoretical calculations, characteristic and experimental analysis, the synergistic effects of Fe and N were proposed and summarized as follows: i) promoted the formation of extensive defects and Fe 0 species that facilitated electron transfer between FeN-BC and PAA and continuous Fe(II) generation; ii) modified the specific surface area (SSA) and the isoelectric point of FeN-BC in favor of PAA adsorption on the catalyst surface. This study provides a strategy for waste biomass reuse to construct a heterogeneous catalyst/PAA system for efficient water purification and reveals the synergistic effects of typical metal-heteroatom for PAA activation., 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 B.V. All rights reserved.)

Photothermal therapy is favored by cancer researchers due to its advantages such as controllable initiation, direct killing and immune promotion. However, the low enrichment efficiency of photosensitizer in tumor site and the limited effect of single use limits the further development of photothermal therapy. Herein, a photo-responsive multifunctional nanosystem was designed for cancer therapy, in which myeloid-derived suppressor cell (MDSC) membrane vesicle encapsulated decitabine-loaded black phosphorous (BP) nanosheets (BP@ Decitabine @MDSCs, named BDM). The BDM demonstrated excellent biosafety and biochemical characteristics, providing a suitable microenvironment for cancer cell killing. First, the BDM achieves the ability to be highly enriched at tumor sites by inheriting the ability of MDSCs to actively target tumor microenvironment. And then, BP nanosheets achieves hyperthermia and induces mitochondrial damage by its photothermal and photodynamic properties, which enhancing anti-tumor immunity mediated by immunogenic cell death (ICD). Meanwhile, intra-tumoral release of decitabine induced G2/M cell cycle arrest, further promoting tumor cell apoptosis. In vivo, the BMD showed significant inhibition of tumor growth with down-regulation of PCNA expression and increased expression of high mobility group B1 (HMGB1), calreticulin (CRT) and caspase 3. Flow cytometry revealed significantly decreased infiltration of MDSCs and M2-macrophages along with an increased proportion of CD4 + , CD8 + T cells as well as CD103 + DCs, suggesting a potentiated anti-tumor immune response. In summary, BDM realizes photothermal therapy/photodynamic therapy synergized chemotherapy for cancer., (© 2024. The Author(s).)

Porphyran, a sulfated polysaccharide found in various species of marine red algae, has been demonstrated to exhibit diverse bioactivities, including anti-inflammatory effects. However, the protective effects of porphyran against cerebral ischemia and reperfusion (IR) injury have not been investigated. The aim of this study was to examine the neuroprotective effects of porphyran against brain IR injury and its underlying mechanisms using a gerbil model of transient forebrain ischemia (IR in the forebrain), which results in pyramidal cell (principal neuron) loss in the cornu ammonis 1 (CA1) subregion of the hippocampus on day 4 after IR. Porphyran (25 and 50 mg/kg) was orally administered daily for one week prior to IR. Pretreatment with 50 mg/kg of porphyran, but not 25 mg/kg, significantly attenuated locomotor hyperactivity and protected pyramidal cells located in the CA1 area from IR injury. The pretreatment with 50 mg/kg of porphyran significantly suppressed the IR-induced activation and proliferation of microglia in the CA1 subregion. Additionally, the pretreatment significantly inhibited the overexpressions of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing protein-3 (NLRP3) inflammasome complex, and pro-inflammatory cytokines (interleukin 1 beta and interleukin 18) induced by IR in the CA1 subregion. Overall, our findings suggest that porphyran exerts neuroprotective effects against brain IR injury, potentially by reducing the reaction (activation) and proliferation of microglia and reducing NLRP3 inflammasome-mediated neuroinflammation.

We computed the phase diagram of zigzag graphene nanoribbons as a function of on-site repulsion, doping, and disorder strength. The topologically ordered phase undergoes topological phase transitions into crossover phases, which are new disordered phases with non-universal topological entanglement entropy that exhibits significant variance. We explored the nature of non-local correlations in both the topologically ordered and crossover phases. In the presence of localization effects, strong on-site repulsion and/or doping weaken non-local correlations between the opposite zigzag edges of the topologically ordered phase. In one of the crossover phases, bothe-/2solitonic fractional charges and spin-charge separation were absent; however, charge-transfer correlations between the zigzag edges were possible. Another crossover phase contains solitonice-/2fractional charges but lacks charge transfer correlations. We also observed properties of non-topological, strongly disordered, and strongly repulsive phases. Each phase on the phase diagram exhibits a different zigzag-edge structure. Additionally, we investigated the tunneling of solitonic fractional charges under an applied voltage between the zigzag edges of undoped topologically ordered zigzag ribbons, and found that it may lead to a zero-bias tunneling anomaly., (© 2024 IOP Publishing Ltd.)

This study introduces Sn-substituted higher manganese silicides (MnSi 1.75 , HMS) synthesized via an arc-melting process followed by spark plasma sintering (SPS). The influences of Sn concentrations on the thermoelectric performance of Mn(Si 1-x Sn x ) 1.75 (x = 0, 0.001, 0.005, 0.01, 0.015) are systematically investigated. Our findings reveal that metallic Sn precipitates within the Mn(Si 1-x Sn x ) 1.75 matrix at x ≥ 0.005, with a determined solubility limit of approximately x = 0.001. In addition, substituting Si with Sn effectively reduces the lattice thermal conductivity of HMS by introducing point defect scattering. In contrast to the undoped HMS, the lattice thermal conductivity decreases to a minimum value of 2.0 W/mK at 750 K for the Mn(Si 0.999 Sn 0.001 ) 1.75 sample, marking a substantial 47.4% reduction. Consequently, a figure of merit (ZT) value of ~0.31 is attained at 750 K. This considerable enhancement in ZT is primarily attributed to the suppressed lattice thermal conductivity resulting from Sn substitution.

9p21 deletions involving MTAP/CDKN2A genes are detected in diffuse pleural mesotheliomas (DPM) but are absent in benign mesothelial proliferations. Loss of MTAP expression by immunohistochemistry (IHC) is well accepted as a surrogate for 9p21 deletion to support a diagnosis of DPM. Accurate interpretation can be critical in the diagnosis of DPM, but variations in antibody performance may impact interpretation. The objectives of this study were to compare the performance of MTAP monoclonal antibodies (mAbs) EPR6893 and 1813 and to compare MTAP expression by IHC with 9p21 copy number status in DPM. Cytoplasmic expression of MTAP IHC with mAbs EPR6893 (ab126770; Abcam) and 1813 (NBP2-75730, Novus Biologicals) was evaluated in 56 DPM (47 epithelioid, 7 biphasic, and 2 sarcomatoid) profiled by targeted next-generation sequencing. 9p21 Copy number status was assessed by Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing (FACETS) analysis and also by CDKN2A fluorescence in situ hybridization in discrepant cases when material was available. MTAP mAb 1813 showed stronger immunoreactivity, more specific staining, and no equivocal interpretations compared to mAb EPR6893 which showed equivocal staining in 19 (34%) of cases due to weak or heterogenous immunoreactivity, lack of definitive internal positive control, and/or nonspecific background staining. MTAP expression with mAb 1813 showed near perfect agreement with 9p21 copy number by combined FACETS/fluorescence in situ hybridization calls (κ = 0.85; 95% CI, 0.71-0.99; P < .001). MTAP IHC with mAb 1813 was 96% sensitive, 86% specific, and 93% accurate for 9p21 homozygous deletion. The findings of this study suggest that interpretation of MTAP IHC is improved with mAb 1813 because mAb EPR6893 was often limited by equivocal interpretations. We show that MTAP IHC and molecular assays are complementary in detecting 9p21 homozygous deletion. MTAP IHC may be particularly useful for low tumor purity samples and in low-resource settings., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Microsatellite instability (MSI) and mismatch repair (MMR) deficiency represent a distinct oncogenic process and predict response to immune checkpoint inhibitors (ICIs). The clinicopathologic features of MSI-high (MSI-H) and MMR deficiency (MMR-D) in lung cancers remain poorly characterized., Methods: MSI status from 5171 patients with NSCLC and 315 patients with SCLC was analyzed from targeted next-generation sequencing data using two validated bioinformatic pipelines., Results: MSI-H and MMR-D were identified in 21 patients with NSCLC (0.41%) and six patients with SCLC (1.9%). Notably, all patients with NSCLC had a positive smoking history, including 11 adenocarcinomas. Compared with microsatellite stable cases, MSI-H was associated with exceptionally high tumor mutational burden (37.4 versus 8.5 muts/Mb, p < 0.0001), MMR mutational signatures (43% versus 0%, p < 0.0001), and somatic biallelic alterations in MLH1 (52% versus 0%, p < 0.0001). Loss of MLH1 and PMS2 expression by immunohistochemistry was found in MLH1 altered and wild-type cases. Similarly, the majority of patients with MSI-H SCLC had evidence of MLH1 inactivation, including two with MLH1 promoter hypermethylation. A single patient with NSCLC with a somatic MSH2 mutation had Lynch syndrome as confirmed by the presence of a germline MSH2 mutation. Among patients with advanced MSI-H lung cancers treated with ICIs, durable clinical benefit was observed in three of eight patients with NSCLC and two of two patients with SCLC. In NSCLC, STK11, KEAP1, and JAK1 were mutated in nonresponders but wild type in responders., Conclusions: We present a comprehensive clinicogenomic landscape of MSI-H lung cancers and reveal that MSI-H defines a rare subset of lung cancers associated with smoking, high tumor mutational burden, and MLH1 inactivation. Although durable clinical benefit to ICI was observed in some patients, the broad range of responses suggests that clinical activity may be modulated by co-mutational landscapes., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Diffuse pleural mesothelioma (DPM) is a highly aggressive malignant neoplasm arising from the mesothelial cells lining the pleural surfaces. While DPM is a well-recognized disease linked to asbestos exposure, recent advances have expanded our understanding of molecular pathogenesis and transformed our clinical practice. This comprehensive review explores the current concepts and emerging trends in DPM, including risk factors, pathobiology, histologic subtyping, and therapeutic management, with an emphasis on a multidisciplinary approach to this complex disease.

Chronic respiratory diseases such as idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and respiratory infections injure the alveoli; the damage evoked is mostly irreversible and occasionally leads to death. Achieving a detailed understanding of the pathogenesis of these fatal respiratory diseases has been hampered by limited access to human alveolar tissue and the differences between mice and humans. Thus, the development of human alveolar organoid (AO) models that mimic in vivo physiology and pathophysiology has gained tremendous attention over the last decade. In recent years, human pluripotent stem cells (hPSCs) have been successfully employed to generate several types of organoids representing different respiratory compartments, including alveolar regions. However, despite continued advances in three-dimensional culture techniques and single-cell genomics, there is still a profound need to improve the cellular heterogeneity and maturity of AOs to recapitulate the key histological and functional features of in vivo alveolar tissue. In particular, the incorporation of immune cells such as macrophages into hPSC-AO systems is crucial for disease modeling and subsequent drug screening. In this review, we summarize current methods for differentiating alveolar epithelial cells from hPSCs followed by AO generation and their applications in disease modeling, drug testing, and toxicity evaluation. In addition, we review how current hPSC-AOs closely resemble in vivo alveoli in terms of phenotype, cellular heterogeneity, and maturity.

Mesenchymal stromal/stem cells (MSCs) possess immunoregulatory properties and their regulatory functions represent a potential therapy for acute lung injury (ALI). However, uncertainties remain with respect to defining MSCs-derived immunomodulatory pathways. Therefore, this study aimed to investigate the mechanism underlying the enhanced effect of human recombinant bone morphogenic protein-2 (rhBMP-2) primed ES-MSCs (MSC BMP2 ) in promoting Tregs in ALI mice. MSC were preconditioned with 100 ng/ml rhBMP-2 for 24 h, and then administrated to mice by intravenous injection after intratracheal injection of 1 mg/kg LPS. Treating MSCs with rhBMP-2 significantly increased cellular proliferation and migration, and cytokines array reveled that cytokines release by MSC BMP2 were associated with migration and growth. MSC BMP2 ameliorated LPS induced lung injury and reduced myeloperoxidase activity and permeability in mice exposed to LPS. Levels of inducible nitric oxide synthase were decreased while levels of total glutathione and superoxide dismutase activity were further increased via inhibition of phosphorylated STAT1 in ALI mice treated with MSC BMP2 . MSC BMP2 treatment increased the protein level of IDO1, indicating an increase in Treg cells, and Foxp3 + CD25 + Treg of CD4 + cells were further increased in ALI mice treated with MSC BMP2 . In co-culture assays with MSCs and RAW264.7 cells, the protein level of IDO1 was further induced in MSC BMP2 . Additionally, cytokine release of IL-10 was enhanced while both IL-6 and TNF-α were further inhibited. In conclusion, these findings suggest that MSC BMP2 has therapeutic potential to reduce massive inflammation of respiratory diseases by promoting Treg cells., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest., (Copyright © 2023. The Korean Association of Immunologists.)

Aberrant communication in alveolar epithelium is a major feature of inflammatory response for the airway remodeling leading to chronic obstructive pulmonary disease (COPD). In this study, we investigated the effect of protein transduction domains (PTD) conjugated Basic Fibroblast Growth Factor (FGF2) (PTD-FGF2) in response to cigarette smoke extract (CSE) in MLE-12 cells and porcine pancreatic elastase (PPE)-induced emphysematous mice. When PPE-induced mice were intraperitoneally treated with 0.1-0.5 mg/kg PTD-FGF2 or FGF2, the linear intercept, infiltration of inflammatory cells into alveoli and pro-inflammatory cytokines were significantly decreased. In western blot analysis, phosphorylated protein levels of c-Jun N-terminal Kinase 1/2 (JNK1/2), extracellular signal-regulated kinase (ERK1/2) and p38 mitogen-activated protein kinases (MAPK) were decreased in PPE-induced mice treated PTD-FGF2. In MLE-12 cells, PTD-FGF2 treatment decreased reactive oxygen species (ROS) production and further decreased Interleukin-6 (IL-6) and IL-1b cytokines in response to CSE. In addition, phosphorylated protein levels of ERK1/2, JNK1/2 and p38 MAPK were reduced. We next determined microRNA expression in the isolated exosomes of MLE-12 cells. In reverse transcription-polymerase chain reaction (RT-PCR) analysis, level of let-7c miRNA was significantly increased while levels of miR-9 and miR-155 were decreased in response to CSE. These data suggest that PTD-FGF2 treatment plays a protective role in regulation of let-7c, miR-9 and miR-155 miRNA expressions and MAPK signaling pathways in CSE-induced MLE-12 cells and PPE-induced emphysematous mice.

RET alterations, such as fusions or mutations, drive the growth of multiple tumor types. These alterations are found in canonical (lung and thyroid) and non-canonical (e.g., gastrointestinal, breast, gynecological, genitourinary, histiocytic) cancers. RET alterations are best identified via comprehensive next-generation sequencing, preferably with DNA and RNA interrogation for fusions. Targeted therapies for RET -dependent cancers have evolved from older multikinase inhibitors to selective inhibitors of RET such as selpercatinib and pralsetinib. Prospective basket trials and retrospective reports have demonstrated the activity of these drugs in a wide variety of RET -altered cancers, notably those with RET fusions. This paved the way for the first tumor-agnostic selective RET inhibitor US FDA approval in 2022. Acquired resistance to RET kinase inhibitors can take the form of acquired resistance mutations (e.g., RET G810X) or bypass alterations.