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Ching-Chun Li,1 Tsung-Kun Chang,1,2 Yen-Cheng Chen,1,3 Hsiang-Lin Tsai,1,2 Ching-Wen Huang,1,2 Wei-Chih Su,1,3 Cheng-Jen Ma,1,3 Tzu-Chieh Yin,1,4,5 Po-Jung Chen,1 Jaw-Yuan Wang1– 3,6– 8 1Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 2Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 3Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 4Division of General and Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 5Department of Surgery, Kaohsiung Municipal Tatung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 6Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan; 7Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan; 8Department of Surgery, Pingtung Hospital, Ministry of Health and Welfare, Pingtung, TaiwanCorrespondence: Jaw-Yuan Wang, Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100 Tzyou 1st Road, Kaohsiung, 807, Taiwan, Tel +886-7-3122805, Email cy614112@ms14.hinet.net; jawyuanwang@gmail.comBackground: The prognosis of metastatic colorectal cancer (mCRC) depends on the metastatic site and systemic therapy regimen. Peritoneal metastases are associated with a relatively unfavorable prognosis among patients with mCRC. In this article, we present the treatment outcomes of patients with peritoneal carcinomatosis (PC)-only, liver metastasis (LiM)-only, and lung metastasis (LuM)-only CRC.Methods: Overall, 206 mCRC patients with single-site metastasis and who had received treatment from January 2014 to December 2018 were recruited. Among 206 patients with mCRC, 15 had PC-only mCRC, 145 had LiM-only mCRC, and 46 had LuM-only mCRC. They attended regular follow-ups until November 2020, and the median follow-up period was 24.7 months (5.1– 41.3 months). Patients’ characteristics, including clinical data, gene mutation profiles, and clinical outcomes, were evaluated. All patients with PC-only CRC were treated with first-line bevacizumab and FOLFIRI, and the irinotecan dose escalation depended on UGT1A1 polymorphism.Results: Of the 206 patients, no statistical difference was observed between the PC-only, LiM-only, and LuM-only groups in terms of age, primary tumor location, RAS mutation status, BRAF mutation status, and epidermal growth factor receptor overexpression (all P > 0.05). Patients with PC-only CRC had a median progression-free survival (mPFS) of 18.0 months and a median overall survival (mOS) of 24.6 months. Patients with LiM-only or LuM-only CRC had mPFS of 18.2 and 26.6 months and mOS of 25.0 and 44.5 months, respectively. No significant differences regarding PFS and OS (both P > 0.05) between the three groups of patients with mCRC were observed.Conclusion: Our study revealed that in patients with PC-only mCRC treatment of first-line bevacizumab and FOLFIRI through irinotecan dose escalation according to UGT1A1 polymorphism could confer such patients with comparable outcomes to that of patients with LiM-only and LuM-only mCRC.Keywords: prognosis, metastatic colorectal cancer, peritoneal carcinomatosis-only, UGT1A1, irinotecan dose escalation

Tsung-Lin Tsai,1,2 Yu-Hsuan Lai,3,4 Helen HW Chen,1,2,4 Wu-Chou Su1,2 1Center of Applied Nanomedicine, National Cheng Kung University, Tainan, 701, Taiwan; 2Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan; 3Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan; 4Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 701, TaiwanCorrespondence: Wu-Chou Su Rm. 6065, 6F., No. 35, Xiaodong Road, North Dist., Tainan, 704, TaiwanTel +886-6-2353535#3120Fax +886-6-2084112Email sunnysu@mail.ncku.edu.twHelen HW Chen No. 138, Sheng Li Road, North Dist., Tainan, 704, TaiwanTel +886-6-2353535#2461Fax +886-6-2359333Email helen@mail.ncku.edu.twBackground: Radiation therapy remains an important treatment modality in cancer therapy, however, resistance is a major problem for treatment failure. Elevated expression of glutathione is known to associate with radiation resistance. We used glutathione overexpressing small cell lung cancer cell lines, SR3A-13 and SR3A-14, established by transfection with γ-glutamylcysteine synthetase (γ-GCS) cDNA, as a model for investigating strategies of overcoming radiation resistance. These radiation-resistant cells exhibit upregulated human copper transporter 1 (hCtr1), which also transports cisplatin. This study was initiated to investigate the effect and the underlying mechanism of iron-platinum nanoparticles (FePt NPs) on radiation sensitization in cancer cells.Materials and Methods: Uptakes of FePt NPs in these cells were studied by plasma optical emission spectrometry and transmission electron microscopy. Effects of the combination of FePt NPs and ionizing radiation were investigated by colony formation assay and animal experiment. Intracellular reactive oxygen species (ROS) were assessed by using fluorescent probes and imaged by a fluorescence-activated-cell-sorting caliber flow cytometer. Oxygen consumption rate (OCR) in mitochondria after FePt NP and IR treatment was investigated by a Seahorse XF24 cell energy metabolism analyzer.Results: These hCtr1-overexpressing cells exhibited elevated resistance to IR and the resistance could be overcome by FePt NPs via enhanced uptake of FePt NPs. Overexpression of hCtr1 was responsible for the increased uptake/transport of FePt NPs as demonstrated by using hCtr1-transfected parental SR3A (SR3A-hCtr1-WT) cells. Increased ROS and drastic mitochondrial damages with substantial reduction of oxygen consumption rate were observed in FePt NPs and IR-treated cells, indicating that structural and functional insults of mitochondria are the lethal mechanism of FePt NPs. Furthermore, FePt NPs also increased the efficacy of radiotherapy in mice bearing SR3A-hCtr1-WT-xenograft tumors.Conclusion: These results suggest that FePt NPs can potentially be a novel strategy to improve radiotherapeutic efficacy in hCtr1-overexpressing cancer cells via enhanced uptake and mitochondria targeting.Keywords: FePt nanoparticles, human copper transporter 1, radiation resistance, reactive oxygen species, mitochondrial targeting

Yu-Jen Chen,1–4 Li-Wen Fang,5 Wen-Chi Su,6,7 Wen-Yi Hsu,1 Kai-Chien Yang,1 Huey-Lan Huang8 1Department of Medical Research, 2Department of Radiation Oncology, Mackay Memorial Hospital, 3Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, 4Institute of Pharmacology, Taipei Medical University, Taipei, 5Department of Nutrition, I-Shou University, Kaohsiung, 6Research Center for Emerging Viruses, China Medical University Hospital, 7Graduate Institute of Clinical Medical Science, China Medical University, Taichung, 8Department of Bioscience Technology, College of Health Science, Chang Jung Christian University, Tainan, Taiwan, Republic of China Abstract: Lapatinib is an oral-form dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR or ErbB/Her) superfamily members with anticancer activity. In this study, we examined the effects and mechanism of action of lapatinib on several human leukemia cells lines, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and acute lymphoblastic leukemia (ALL) cells. We found that lapatinib inhibited the growth of human AML U937, HL-60, NB4, CML KU812, MEG-01, and ALL Jurkat T cells. Among these leukemia cell lines, lapatinib induced apoptosis in HL-60, NB4, and Jurkat cells, but induced nonapoptotic cell death in U937, K562, and MEG-01 cells. Moreover, lapatinib treatment caused autophagic cell death as shown by positive acridine orange staining, the massive formation of vacuoles as seen by electronic microscopy, and the upregulation of LC3-II, ATG5, and ATG7 in AML U937 cells. Furthermore, autophagy inhibitor 3-methyladenine and knockdown of ATG5, ATG7, and Beclin-1 using short hairpin RNA (shRNA) partially rescued lapatinib-induced cell death. In addition, the induction of phagocytosis and ROS production as well as the upregulation of surface markers CD14 and CD68 was detected in lapatinib-treated U937 cells, suggesting the induction of macrophagic differentiation in AML U937 cells by lapatinib. We also noted the synergistic effects of the use of lapatinib and cytotoxic drugs in U937 leukemia cells. These results indicate that lapatinib may have potential for development as a novel antileukemia agent. Keywords: lapatinib, autophagic cell death, leukemia, differentiation, AML

Wen-Ching Su,1 Chin-Kai Lin,1 Shih-Chung Chang2,3 1Program of Early Intervention, Department of Early Childhood Education, National Taichung University of Education, Taichung, Taiwan; 2Department of Physical Medicine and Rehabilitation, Chung Shan Medical University Hospital, Taichung, Taiwan; 3School of Medicine, Chung Shan Medical University, Taichung, Taiwan Abstract: The objectives of this study were to determine a safe rotatory vestibular ­stimulation input for preschool children and to study the effects of grade level and sex of preschool children during active, passive, clockwise, and counterclockwise rotation vestibular input. This study adopted purposive sampling with 120 children from three kindergarten levels (K1, K2, and K3) in Taiwan. The subjects ranged in age from 46 to 79 months of age (mean: 62.1 months; standard deviation =9.60). This study included testing with four types of vestibular rotations. The number, duration, and speed of rotations were recorded. The study found that the mean number of active rotations was 10.28; the mean duration of rotation was 24.17 seconds; and the mean speed was 2.29 seconds per rotation. The mean number of passive rotations was 23.04. The differences in number of rotations in clockwise, counterclockwise, active, and passive rotations were not statistically significant. Sex and grade level were not important related factors in the speed and time of active rotation. Different sexes, rotation methods (active, passive), and grades made significant differences in the number of rotations. The safety and tolerability of rotatory vestibular stimulation input data obtained in this study can provide useful reference data for therapists using sensory integration therapy. Keywords: sensory integration, rotatory vestibular stimulation, tolerable input for rotatory vestibular stimulation

Chia-Cheng Hou,1,6 Tsung-Lin Tsai,1,6 Wen-Pin Su,6 Hsing-Pang Hsieh,7 Chen-Sheng Yeh,4,5 Dar-Bin Shieh,1–4 Wu-Chou Su1,6 1Institute of Basic Medical Sciences, 2Institute of Oral Medicine and Department of Stomatology, 3Advanced Optoelectronic Technology Center, 4Center for Micro/Nano Science and Technology, 5Department of Chemistry, 6Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 7Division of Biotechnology and Pharmaceutical Research, NHRI, Miaoli, Taiwan Background: LY294002 (LY) is a potent inhibitor of phosphatidylinositol 3-kinases (PI3Ks); however, biological applications of LY are limited by its poor solubility and pharmacokinetic profile. This study aimed at developing LY-loaded surfactant-free poly(lactic-co-glycolic acid) (PLGA) nanoparticles (SF-LY NPs) to improve the therapeutic efficacy of LY. Materials and methods: Cellular viability was measured by MTT assay. The subcellular distribution of NPs was studied using an ultraviolet-visible spectrophotometer and confocal microscope. The expression of cell-death-associated proteins was determined using Western blotting and the in vivo activity of SF-LY NPs was tested in a xenograft animal model. Results: SF-LY NPs enhanced the intracellular level of LY, induced sustained suppression of AKT, and induced marked cancer cell death. In addition, SF-LY NPs tended to accumulate in the endoplasmic reticulum (ER) and induce pronounced ER stress. Finally, SF-LY NPs exhibited a prominent antitumor effect in vivo. Conclusion: The surfactant-free formulation of PLGA is critical to the promising anticancer activity of SF-LY NPs. Keywords: LY294002, AKT, surfactant-free poly(lactic-co-glycolic acid), endoplasmic reticulum stress

Tsung-Lin Tsai,1,5 Chia-Cheng Hou,1,5 Hao-Chen Wang,1,5 Zih-Syuan Yang,2 Chen-Sheng Yeh,4 Dar-Bin Shieh,2,3 Wu-Chou Su1,51Institute of Basic Medical Sciences, 2Institute of Oral Medicine and Department of Stomatology, 3Center for Micro/Nano Science and Technology, 4Department of Chemistry, National Cheng Kung University, Tainan, Taiwan; 5Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, TaiwanAbstract: Gold nanoparticles modified with the nuclear localization signal from simian virus 40 large T antigen (GNP-PEG/SV40) accumulate on the cytoplasmic side of the nuclear membrane in HeLa cells. Accumulation of GNP-PEG/SV40 around the nucleus blocks nucleocytoplasmic transport and prevents RNA export and nuclear shuttling of signaling proteins. This long-term blockage of nucleocytoplasmic transport results in cell death. This cell death is not caused by apoptosis or necrosis because caspases 3 and 9 are not activated, and the expression of annexin V/propidium iodide is not enhanced in HeLa cells after treatment. Using transmission electron microscopy, autophagosomes and autolysosomes were seen to appear after 72 hours of treatment with GNP-PEG/SV40. Increasing levels of enhanced green fluorescent protein-microtubule-associated protein 1 light chain 3 (EGFP-LC3)-positive punctate and LC3-II confirmed GNP-PEG/SV40-induced autophagy. In SiHa cells, treatment did not induce accumulation of GNP-PEG/SV40 around the nucleus and autophagy. Treating cells with wheat germ agglutinin, a nuclear pore complex inhibitor, induced autophagy in both HeLa and SiHa cells. GNP-PEG/SV40-induced autophagy plays a role in cell death, not survival, and virus-mediated small hairpin RNA silencing of Beclin-1 attenuates cell death. Taken together, the results indicate that long-term blockade of nucleocytoplasmic transport results in autophagic cell death.Keywords: gold nanoparticles, nucleocytoplasmic transport blockage, autophagy, wheat germ agglutinin

Wen-Pin Su,1,2 Fong-Yu Cheng,3 Dar-Bin Shieh,3–6 Chen-Sheng Yeh,5–7 Wu-Chou Su1,2,81Graduate Institute of Clinical Medicine, College of Medicine, National Cheng Kung University; 2Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University; 3Institute of Oral Medicine, College of Medicine, National Cheng Kung University; 4Department of Stomatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University; 5Advanced Optoelectronic Technology Center; 6Center for Frontier Materials and Micro/Nano Science and Technology, and 7Department of Chemistry, National Cheng Kung University; 8Cancer Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.Abstract: Background: Effective cancer chemotherapy remains an important issue in cancer treatment, and signal transducer and activator of transcription-3 (Stat3) activation leads to cellular resistance of anticancer agents. Polymers are ideal vectors to carry both chemotherapeutics and small interfering ribonucleic acid (siRNA) to enhance antitumor efficacy. In this paper, poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with paclitaxel and Stat3 siRNA were successfully synthesized, and their applications in cancer cells were investigated.Methods: Firstly, paclitaxel was enclosed by PLGA nanoparticles through solvent evaporation. They were then coated with cationic polyethylenimine polymer (PLGA-PEI-TAX), enabling it to carry Stat3 siRNA on its surface through electrostatic interactions (PLGA-PEI-TAX-S3SI). The size, zeta potential, deliver efficacy, and release profile of the PLGA nanocomplexes were characterized in vitro. The cellular uptake, intracellular nanoparticle trajectory, and subsequent cellular events were evaluated after treatment with various PLGA nanocomplexes in human lung cancer A549 cells and A549-derived paclitaxel-resistant A549/T12 cell lines with α-tubulin mutation.Results: A549 and A549/T12 cells contain constitutively activated Stat3, and silencing Stat3 by siRNA made both cancer cells more sensitive to paclitaxel. Therefore, PLGA-PEI-TAX-S3SI was synthesized to test its therapeutic role in A549 and A549/T12 cells. Transmission electron microscopy showed the size of PLGA-PEI-TAX-S3SI to be around 250 nm. PLGA-PEI nanoparticles were nontoxic. PLGA-PEI-TAX was taken up by A549 and A549/T12 cells more than free paclitaxel, and they induced more condensed microtubule bundles and had higher cytotoxicity in these cancer cells. Moreover, the yellowish fluorescence observed in the cytoplasm of the cancer cells indicates that the PLGA-PEI nanoparticles were still simultaneously delivering Oregon Green paclitaxel and cyanine-5-labeled Stat3 siRNA 3 hours after treatment. Furthermore, after the cancer cells were incubated with the synthesized PLGA nanocomplexes, PLGA-PEI-TAX-S3SI suppressed Stat3 expression and induced more cellular apoptosis in A549 and A549/T12 cells compared with PLGA-PEI-TAX.Conclusion: The PLGA-PEI-TAX-S3SI complex provides a new therapeutic strategy to control cancer cell growth.Keywords: PLGA, nanoparticle, paclitaxel, siRNA, simultaneous drug delivery

Background: PEP02, also known as MM-398, is a novel nanoliposomal irinotecan that has improved pharmacokinetics and tumour bio-distribution of the free drug. This phase 2 study evaluated PEP02 monotherapy as second-line treatment for pancreatic cancer. Met

The IL6-GP130-STAT3 pathway facilitates lung cancer progression and resistance to tyrosine kinase inhibitors. Although glycosylation alters the stability of GP130, its effect on the ligand IL6 remains unclear. We herein find that N-glycosylated IL6, especially at Asn73, primarily stimulates JAK-STAT3 signaling and prolongs STAT3 phosphorylation, whereas N-glycosylation-defective IL6 (deNG-IL6) induces shortened STAT3 activation and alters the downstream signaling preference for the SRC-YAP-SOX2 axis. This signaling shift induces epithelial-mesenchymal transition (EMT) and migration in vitro and metastasis in vivo, which are suppressed by targeted inhibitors and shRNAs against SRC, YAP, and SOX2. Osimertinib-resistant lung cancer cells secrete a large amount of deNG-IL6 through reduced N-glycosyltransferase gene expression, leading to clear SRC-YAP activation. deNG-IL6 contributes to drug resistance, as confirmed by in silico analysis of cellular and clinical transcriptomes and signal expression in patient specimens. Therefore, the N-glycosylation status of IL6 not only affects cell behaviors but also shows promise in monitoring the dynamics of lung cancer evolution., (© 2024. The Author(s).)

SARS-CoV-2 causes COVID-19, with symptoms ranging from mild to severe, including pneumonia and death. This beta coronavirus has a 30-kilobase RNA genome and shares about 80 % of its nucleotide sequence with SARS-CoV-1. The replication/transcription complex, essential for viral RNA synthesis, includes RNA-dependent RNA polymerase (RdRp, nsp12) enhanced by nsp7 and nsp8. Antivirals like molnupiravir and remdesivir, which are RdRp inhibitors, treat severe COVID-19 but have limitations, highlighting the need for new therapies. This study assessed (-)-cytisine, methylcytisine, and thermopsine derivatives against SARS-CoV-1 and SARS-CoV-2 in vitro, focusing on their RdRp inhibition. Selected compounds from a previous study were evaluated using a SARS-CoV-2 RNA polymerase assay kit to investigate their structure-activity relationships. Compound 17 (1,3-dimethyluracil conjugate with (-)-cytisine and thermopsine) emerged as a potent inhibitor of SARS-CoV-1 and SARS-CoV-2 RdRp, with an IC50 value of 7.8 μM against SARS-CoV-2 RdRp. It showed a dose-dependent reduction in cytopathic effects in cells infected with SARS-CoV-1 and SARS-CoV-2 replicon-based single-round infectious particles (SRIPs) and significantly inhibited SARS-CoV N protein expression, with EC50 values of 0.12 µM for SARS-CoV-1 and 1.47 µM for SARS-CoV-2 SRIPs. Additionally, compound 17 reduced viral subgenomic RNA levels in a concentration-dependent manner in SRIP-infected cells. The structure-activity relationships of compound 17 with SARS-CoV-1 and SARS-CoV-2 RdRp were also investigated, highlighting it as a promising lead for developing antiviral agents against SARS and COVID-19., 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 Ltd. All rights reserved.)

The ascomycete filamentous fungus Neurospora intermedia is commonly used in the food industry and considered nonpathogenic to humans. This study characterizes four N. intermedia isolates recovered from three patients. The first patient had a mediastinal germ cell tumor with multiple metastases. N. intermedia was recovered from his endotracheal aspirate and from the endobronchial mass obtained by bronchoscopic forceps biopsy. Histopathology of the biopsy tissue revealed necrotic tissue mixed with septate fungal hyphae with right-angle branching. An endobronchial mass caused by N. intermedia was thus diagnosed. Another two N. intermedia isolates were recovered from the endotracheal aspirates of two critically ill patients. In vitro, N. intermedia grows rapidly and forms orange, conidiating colonies composed of septate hyphae. Two isolates from the first patient belong to mating type a; the other two isolates belong to mating type A. Coculture of isolates of opposite mating types yielded dark ascomata containing ascospores, supporting that N. intermedia is a heterothallic fungus. N. intermedia isolates cross-reacted with the Aspergillus galactomannan antigen assay and were susceptible to amphotericin B and voriconazole. In conclusion, this report describes the first human infection (endobronchial mass) caused by N. intermedia, highlighting its potential to invade the human respiratory tract., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The surge in RNA therapeutics has revolutionized treatments for infectious diseases like COVID-19 and shows the potential to expand into other therapeutic areas. However, the typical requirement for ultra-cold storage of mRNA-LNP formulations poses significant logistical challenges for global distribution. Lyophilization serves as a potential strategy to extend mRNA-LNP stability while eliminating the need for ultra-cold supply chain logistics. Although recent advancements have demonstrated the promise of lyophilization, the choice of lyoprotectant is predominately focused on sucrose, and there remains a gap in comprehensive evaluation and comparison of lyoprotectants and buffers. Here, we aim to systematically investigate the impact of a diverse range of excipients including oligosaccharides, polymers, amino acids, and various buffers, on the quality and performance of lyophilized mRNA-LNPs. From the screening of 45 mRNA-LNP formulations under various lyoprotectant and buffer conditions for lyophilization, we identified previously unexplored formulation compositions, e.g., polyvinylpyrrolidone (PVP) in Tris or acetate buffers, as promising alternatives to the commonly used oligosaccharides to maintain the physicochemical stability of lyophilized mRNA-LNPs. Further, we delved into how physicochemical and structural properties influence the functionality of lyophilized mRNA-LNPs. Leveraging high-throughput small-angle X-ray scattering (SAXS) and cryogenic transmission electron microscopy (cryo-TEM), we showed that there is complex interplay between mRNA-LNP structural features and cellular translation efficacy. We also assessed innate immune responses of the screened mRNA-LNPs in human peripheral blood mononuclear cells (PBMCs), and showed minimal alterations of cytokine secretion profiles induced by lyophilized formulations. Our results provide valuable insights into the structure-activity relationship of lyophilized formulations of mRNA-LNP therapeutics, paving the way for rational design of these formulations. This work creates a foundation for a comprehensive understanding of mRNA-LNP properties and in vitro performance change resulting from lyophilization., Competing Interests: Declaration of competing interest Yuchen Fan, Diamanda Rigas, Nanzhi Zang, Kristina McKee, Christopher C. Kemball, Wan-Chih Su, Pierce Jessen, Tao Chen, Stefan G. Koenig, Karthik Nagapudi, Dennis Leung, and Chun-Wan Yen are employees of Genentech, Inc. Feng-Peng Chang, Zhixin Yu, and Pascal Winkler are former employees of Genentech, Inc. Lee Joon Kim and Greg L. Hura are employees of Lawrence Berkeley National Lab., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: Phenotyping is a core task in observational health research utilizing electronic health records (EHRs). Developing an accurate algorithm demands substantial input from domain experts, involving extensive literature review and evidence synthesis. This burdensome process limits scalability and delays knowledge discovery. We investigate the potential for leveraging large language models (LLMs) to enhance the efficiency of EHR phenotyping by generating high-quality algorithm drafts., Materials and Methods: We prompted four LLMs-GPT-4 and GPT-3.5 of ChatGPT, Claude 2, and Bard-in October 2023, asking them to generate executable phenotyping algorithms in the form of SQL queries adhering to a common data model (CDM) for three phenotypes (ie, type 2 diabetes mellitus, dementia, and hypothyroidism). Three phenotyping experts evaluated the returned algorithms across several critical metrics. We further implemented the top-rated algorithms and compared them against clinician-validated phenotyping algorithms from the Electronic Medical Records and Genomics (eMERGE) network., Results: GPT-4 and GPT-3.5 exhibited significantly higher overall expert evaluation scores in instruction following, algorithmic logic, and SQL executability, when compared to Claude 2 and Bard. Although GPT-4 and GPT-3.5 effectively identified relevant clinical concepts, they exhibited immature capability in organizing phenotyping criteria with the proper logic, leading to phenotyping algorithms that were either excessively restrictive (with low recall) or overly broad (with low positive predictive values)., Conclusion: GPT versions 3.5 and 4 are capable of drafting phenotyping algorithms by identifying relevant clinical criteria aligned with a CDM. However, expertise in informatics and clinical experience is still required to assess and further refine generated algorithms., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: FGFR genomic aberrations occur in approximately 5-10% of human cancers. Erdafitinib has previously demonstrated efficacy and safety in FGFR-altered advanced solid tumors, such as gliomas, thoracic, gastrointestinal, gynecological, and other rare cancers. However, its efficacy and safety in Asian patients remain largely unknown. We conducted a multicenter, open-label, single-arm phase IIa study of erdafitinib to evaluate its efficacy in Asian patients with FGFR-altered advanced cholangiocarcinoma, non-small cell lung cancer (NSCLC), and esophageal cancer., Methods: Patients with pathologically/cytologically confirmed, advanced, or refractory tumors who met molecular and study eligibility criteria received oral erdafitinib 8 mg once daily with an option for pharmacodynamically guided up-titration to 9 mg on a 28-day cycle, except for four NSCLC patients who received erdafitinib 10 mg (7 days on/7 days off) as they were recruited before the protocol amendment. The primary endpoint was investigator-assessed objective response rate per RECIST v1.1. Secondary endpoints included progression-free survival, duration of response, disease control rate, overall survival, safety, and pharmacokinetics., Results: Thirty-five patients (cholangiocarcinoma: 22; NSCLC: 12; esophageal cancer: 1) were enrolled. At data cutoff (November 19, 2021), the objective response rate for patients with cholangiocarcinoma was 40.9% (95% CI, 20.7-63.6); the median progression-free survival was 5.6 months (95% CI, 3.6-12.7) and median overall survival was 40.2 months (95% CI, 12.4-not estimable). No patient with RET/FGFR-altered NSCLC achieved objective response and the disease control rate was 25.0% (95% CI, 5.5-57.2%), with three patients with stable disease. The single patient with esophageal cancer achieved partial response. All patients experienced treatment-emergent adverse events, and grade ≥ 3 treatment-emergent adverse events were reported in 22 (62.9%) patients. Hyperphosphatemia was the most frequently reported treatment-emergent adverse event (all-grade, 85.7%)., Conclusions: Erdafitinib demonstrated efficacy in a population of Asian patients in selected advanced solid tumors, particularly in those with advanced FGFR-altered cholangiocarcinoma. Treatment was tolerable with no new safety signals., Trial Registration: This trial is registered with ClinicalTrials.gov (NCT02699606); study registration (first posted): 04/03/2016., (© 2024. The Author(s).)

In recent years, the use of lipid nanoparticles (LNPs) for delivery of messenger RNA (mRNA)-based therapies has gained substantial attention in the field of drug development. In such an application, multiple LNP attributes have to be carefully characterized to ensure product safety and quality, whereas accurate and efficient characterization of these complex mRNA-LNP formulations remains a challenging endeavor. Here, we present the development and application of an online separation and characterization platform designed for the isolation and in-depth analysis of mRNAs and mRNA-loaded LNPs. Our asymmetrical flow field-flow fractionation with a multi-detector (MD-AF4) method has demonstrated exceptional resolution between mRNA-LNPs and mRNAs, delivering excellent recoveries (over 70%) for both analytes and exceptional repeatability. Notably, this platform allows for comprehensive and multi-attribute LNP characterization, including online particle sizing, morphology characterization, and determination of encapsulation efficiency, all within a single injection. Furthermore, real-time online sizing by synchronizing multi-angle light scattering (MALS) and dynamic light scattering (DLS) presented higher resolution over traditional batch-mode DLS, particularly in differentiating heterogeneous samples with a low abundance of large-sized particles. Additionally, our method proves to be a valuable tool for monitoring LNP stability under varying stress conditions. Our work introduces a robust and versatile analytical platform using MD-AF4 that not only efficiently provides multi-attribute characterizations of mRNA-LNPs but also holds promise in advancing studies related to formulation screening, quality control, and stability assessment in the evolving field of nanoparticle delivery systems for mRNAs., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Purpose: Children with Autism Spectrum Disorder (ASD) have motor, social communication, and behavioral challenges. During the pandemic, children lost access to face-to-face (F2F) services and had to revert to telehealth (TH) options. We compared the efficacy, fidelity, acceptability, and feasibility of a general motor (GM) intervention using an F2F or telehealth (TH) format., Methods: Fifteen children with ASD participated in an 8-week program involving gross motor games to promote motor and social communication skills. Differences across TH and F2F formats for motor and socially directed verbalization as well as stakeholder feedback on formats were collected., Results: Gross motor and socially directed verbalization did not differ between the F2F and TH subgroups, and parents and trainers were satisfied with either format. However, TH interventions were longer, had more technological challenges, and required more parental effort., Conclusions: The findings of this study support the use of TH as a comparable and viable substitute for F2F interactions for children with ASD., Competing Interests: The authors declare no financial or other conflicts of interest., (Copyright © 2024 Academy of Pediatric Physical Therapy of the American Physical Therapy Association.)

Background: The combination of the checkpoint inhibitor (CPI) pembrolizumab and platinum-based chemotherapy is effective frontline therapy for advanced non-small cell lung cancer (NSCLC) lacking targetable mutations. Indoleamine 2,3- dioxygenase 1 (IDO1), an enzyme involved in kynurenine production, inhibits immune responses. Inhibition of IDO1 may restore antitumor immunity and augment CPI activity. This trial evaluated addition of epacadostat, a potent and highly selective IDO1 inhibitor, to pembrolizumab and chemotherapy for metastatic NSCLC., Methods: ECHO-306/KEYNOTE-715 was a partial double-blind, randomized phase II study of adults with treatment-naïve stage IV NSCLC not indicated for EGFR-, ALK-, or ROS1-directed therapy. Patients were randomized to one of three treatment arms: epacadostat-pembrolizumab-chemotherapy (E + P + C; blinded), epacadostat-pembrolizumab (E + P; open-label) or placebo-pembrolizumab-chemotherapy (PBO + P + C; blinded). Stratification was by PD-L1 tumor proportion score (< 50% vs. ≥ 50%) and tumor histology (non-squamous vs. squamous). A protocol amendment closed enrollment in the open-label E + P group, excluding it from efficacy analyses. Intravenous pembrolizumab (200 mg) was administered every 21 days and epacadostat 100 mg or matching placebo (oral) twice daily (BID) for ≤ 35 3-week cycles. The primary objective was objective response rate (ORR) for E + P + C vs. PBO + P + C., Results: 178 patients were randomized to E + P + C (n = 91) or PBO + P + C (n = 87); 55 were enrolled in the E + P group. The E + P + C group had a lower confirmed ORR (26.4%; 95% CI 17.7-36.7) than the PBO + P + C group (44.8%; 95% CI 34.1-55.9), with a difference of - 18.5% (95% CI - 32.0 - (- 4.3); one-sided P = 0.9948). The E + P + C group had a numerically higher percentage of confirmed responders with extended response ≥ 6 months (29.2% vs. 15.4%). Circulating kynurenine levels at C1D1 were similar to those at C2D1 in all treatment groups and were not reduced to normal levels with epacadostat 100 mg BID plus P + C. The safety profile of E + P + C was consistent with that for PBO + P + C., Conclusions: Addition of epacadostat 100 mg BID to pembrolizumab and platinum-based chemotherapy was generally well tolerated but did not improve ORR in patients with treatment-naïve metastatic NSCLC. Evaluating epacadostat doses that normalize circulating kynurenine in combination with CPIs may help determine the clinical potential of this combination., Trial Registration: NCT03322566. Registered October 26, 2017., (© 2023. The Author(s).)

We still do not have comprehensive knowledge of which framework of patient-centered care (PCC) is appropriate for diabetes care, which elements of PCC are evidence-based, and the mechanism by which PCC elements are associated with outcomes through mediators. In this review, we elaborate on these issues. We found that for diabetes care, PCC elements such as autonomy support (patient individuality), cooperation and collaboration (system-level approach), com-munication and education (behavior change techniques), emotional support (biopsychosocial approach), and family/other involvement and support are critically important. All of these factors are directly associated with different patient outcomes and indirectly associated with outcomes through patient activation. We present the practical implications of these PCC elements., Competing Interests: Conflict-of-interest statement: We have no financial relationships to disclose., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

COVID-19 pandemic is predominantly caused by SARS-CoV-2, with its main protease, Mpro, playing a pivotal role in viral replication and serving as a potential target for inhibiting different variants. In this study, potent Mpro inhibitors were identified from glycyrrhizic acid (GL) derivatives with amino acid methyl/ethyl esters. Out of the 17 derivatives semisynthesized, Compounds 2, 6, 9, and 15, with methionine methyl esters, D-tyrosine methyl esters, glutamic acid methyl esters, and methionines in the carbohydrate moiety, respectively, significantly inhibited wild-type SARS-CoV-2 Mpro-mediated proteolysis, with IC50 values ranging from 0.06 μM to 0.84 μM. They also demonstrated efficacy in inhibiting trans-cleavage by mutant Mpro variants (Mpro&#95;P132H, Mpro&#95;E166V, Mpro&#95;P168A, Mpro&#95;Q189I), with IC50 values ranging from 0.05 to 0.92 μM, surpassing nirmatrelvir (IC50: 1.17-152.9 μM). Molecular modeling revealed stronger interactions with Valine166 in the structural complex of Mpro&#95;E166V with the compounds compared to nirmatrelvir. Moreover, these compounds efficiently inhibited the post-entry viral processes of wild-type SARS-CoV-2 single-round infectious particles (SRIPs), mitigating viral cytopathic effects and reducing replicon-driven GFP reporter signals, as well as in vitro infectivity of wild-type, Mpro&#95;E166V, and Mpro&#95;Q189I SRIPs, with EC50 values ranging from 0.02 to 0.53 μM. However, nirmatrelvir showed a significant decrease in inhibiting the replication of mutant SARS-CoV-2 SRIPs carrying Mpro&#95;E166V (EC50: >20 μM) and Mpro&#95;Q189I (EC50: 13.2 μM) compared to wild-type SRIPs (EC50: 0.06 μM). Overall, this study identifies four GL derivatives as promising lead compounds for developing treatments against various SARS-CoV-2 strains, including Omicron, and nirmatrelvir-resistant variants., Competing Interests: Declaration of competing interest Please find attached our Research Article “Glycyrrhizic acid conjugates with amino acid methyl esters target the main protease, exhibiting antiviral activity against wild-type and nirmatrelvir-resistant SARS-CoV-2 variants”, which we wish to submit for publication in Antiviral Research. All of the authors (Uyen Nguyen Phuong Le, Yu-Jen Chang, Chih-Hao Lu, Yeh Chen, Wen-Chi Su, Shao-Ting Chao, Lia A. Baltina, Svetlana F. Petrova, Sin-Rong Li, Mien-Chie Hung, Michael M. C. Lai, Lidia A. Baltina, Cheng-Wen Lin) declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Sodium taurocholate co-transporting polypeptide (NTCP), a bile acid transporter, plays a crucial role in regulating bile acid levels and influencing the risk of HBV infection. Genetic variations in the SLC10A1 gene, which encodes NTCP, affect these functions. However, the impact of SLC10A1 gene variants on the metabolic and biochemical traits remained unclear. We aimed to investigate the association of SLC10A1 gene variants with the clinical and biochemical parameters, and the risk of different HBV infection statuses and gallstone disease in the Taiwanese population. Genotyping data from 117,679 Taiwan Biobank participants were analyzed using the Axiom genome-wide CHB arrays. Regional-plot association analysis demonstrated genome-wide significant association between the SLC10A1 rs2296651 genotypes and lipid profile, gamma glutamyl transferase (γGT) level and anti-HBc-positivity. Genotype-phenotype association analyses revealed significantly lower total cholesterol, low-density lipoprotein (LDL) cholesterol and uric acid levels, a higher γGT level and a higher gallstone incidence in rare rs2296651-A allele carrier. Participants with the rs2296651 AA-genotype exhibited significantly lower rates of anti-HBc-positivity and HBsAg-positivity. Compared to those with the GG-genotype, individuals with non-GG-genotypes had reduced risks for various HBV infection statuses: the AA-genotype showed substantially lower risks, while the GA-genotype demonstrated modestly lower risks. Predictive tools also suggested that the rs2296651 variant potentially induced protein damage and pathogenic effects. In conclusion, our data revealed pleiotropic effects of the SLC10A1 rs2296651 genotypes on the levels of biochemical traits and the risk of HBV infection and gallstone disease. This confirms SLC10A1's versatility and implicates its genotypes in predicting both biochemical traits and disease susceptibility., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Observational studies examining outcomes among opioid-exposed infants are limited by phenotype algorithms that may under identify opioid-exposed infants without neonatal opioid withdrawal syndrome (NOWS). We developed and validated the performance of different phenotype algorithms to identify opioid-exposed infants using electronic health record data., Methods: We developed phenotype algorithms for the identification of opioid-exposed infants among a population of birthing person-infant dyads from an academic health care system (2010-2022). We derived phenotype algorithms from combinations of 6 unique indicators of in utero opioid exposure, including those from the infant record (NOWS or opioid-exposure diagnosis, positive toxicology) and birthing person record (opioid use disorder diagnosis, opioid drug exposure record, opioid listed on medication reconciliation, positive toxicology). We determined the positive predictive value (PPV) and 95% confidence interval for each phenotype algorithm using medical record review as the gold standard., Results: Among 41 047 dyads meeting exclusion criteria, we identified 1558 infants (3.80%) with evidence of at least 1 indicator for opioid exposure and 32 (0.08%) meeting all 6 indicators of the phenotype algorithm. Among the sample of dyads randomly selected for review (n = 600), the PPV for the phenotype requiring only a single indicator was 95.4% (confidence interval: 93.3-96.8) with varying PPVs for the other phenotype algorithms derived from a combination of infant and birthing person indicators (PPV range: 95.4-100.0)., Conclusions: Opioid-exposed infants can be accurately identified using electronic health record data. Our publicly available phenotype algorithms can be used to conduct research examining outcomes among opioid-exposed infants with and without NOWS., (Copyright © 2024 by the American Academy of Pediatrics.)

This study aimed to investigate the physicochemical properties of modified starch prepared through the simultaneous heat-moisture and phosphorylation treatment (HMPT) and osmotic pressure treatment (OPT) for water caltrop starch (WCS), mung bean starch (MBS), and amylose-rich corn starch (CS) for different time periods. Furthermore, variations in starch content [amylose and resistant starch (RS)], swelling powder (SP), water solubility index (WSI), crystallinity, thermal properties, gelatinization enthalpy (ΔH), and glycemic index (GI) were examined. This study demonstrates that neither HMPT nor OPT resulted in a significant increase in the resistant starch (RS) content, whereas all samples succeeded in heat-treating at 105 °C for another 10 min exhibited a significant increase in RS content compared to their native counterparts. Moreover, the gelatinization temperatures of the three starches increased (T o , T p , and T c ), whereas their gelatinization enthalpy (ΔH) and pasting viscosity decreased. In particular, the GI of all three modified starches subjected to HMPT or OPT showed a decreasing trend with modification time, with OPT exhibiting the best effect. Therefore, appropriate modification through HMPT or OPT is a viable approach to develop MBS, WCS, and CS as processed foods with low GI requirements, which exceptionally may be suitable for canned foods, noodles, and bakery products., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

IL-33 is a danger signal that binds to its receptor ST2L to promote tumor progression. This study identifies the IL-33/ST2L positive-feedback loop and the trafficking of ST2L membrane presentation in macrophages that contribute to lung tumor progression. Mechanistically, IL-33 induces ST2L upregulation by activating NF-κB, which binds to the promoter region of the ST2L gene. Moreover, Rab37, a small GTPase involved in membrane trafficking, mediates ST2L trafficking to the plasma membrane of M2 macrophages. This IL-33/NF-κB/ST2L/Rab37 axis promotes positive-feedback loops that enhance ST2L expression and membrane trafficking in M2 macrophages. Notably, neutralizing antibodies against IL-33 or ST2L block NF-κB activity, suppress M2 macrophage polarization, and synergistically inhibit tumor growth when combined with cisplatin treatment in vitro/vivo. Clinically, Rab37 + /ST2L + /CD206 + tumor-infiltrating M2 macrophages correlate with advanced-stage lung cancer patients with poor response to chemotherapy. These findings unveil a positive-feedback mechanism and provide a basis for IL-33/ST2L-targeting therapy for cancer., (© 2024. The Author(s).)

We delve into the distinctive color gamut characteristics resulting from color dispersion of surface relief grating (SRG) and wavelength degeneracy of volume holographic optical element (VHOE) in a diffractive light guide. While a laser-like spectrum achieves an impressive 194% sRGB color gamut for both cases, it proves unsuitable for VHOE light guides due to limitations in breaking the field of view (FOV) of the display. Conversely, a broad-band light source, such as LEDs, offers continuous FOV but reduces the common color gamut to 50% sRGB. We then present a newly designed VHOE light guide capable of achieving the common color gamut of 130% sRGB using two multiplexed holograms of each color, closely matching the 133% sRGB achieved by an SRG light guide. This article presents the first theoretical methodology to elucidate color performance of diffractive light guides utilizing VHOEs with holographic multiplexing, affirming their suitability for crafting high-quality near-eye display., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Background: Patient-centered care (PCC) is a crucial objective for enhancing healthcare in the 21st century. PCC has demonstrated effectiveness in caring for patients with chronic conditions. However, the process from PCC to patient outcomes has not been thoroughly studied, particularly for patients with chronic hepatitis., Objective: To investigate the relationship between PCC and the outcomes of hepatitis patients and determine the key mediator in the connection between PCC and outcomes., Methods: A cross-sectional study was conducted from October to December 2016 in four hospitals in northern Taiwan. Patients with chronic viral hepatitis were assessed for five PCC factors: autonomy support, goal setting, coordination of care, information/education/communication, and emotional support. Trust in the physician, patient adherence, and patient activation (PA) were selected as mediators, with health-related quality of life (HRQoL) as the patient outcome. Pathway analysis was applied to examine the correlation., Results: In total, 496 chronic hepatitis patients were included in the study. The pathway analysis revealed that autonomy support (β = 0.007, p = 0.011), information/education/communication (β = 0.009, p = 0.017), and emotional support (β = 0.001, p = 0.011) correlated with better HRQoL. The effects of PCC factors are fully mediated by trust in physicians, patient adherence, and PA. Among them, PA is the key factor in the process of PCC., Conclusion: For chronic viral hepatitis care, PCC should be introduced into clinical practice for better HRQoL, and PA is a key mediator., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Although quality improvement is crucial for ERCP, a low practice volume can pose challenges to achieving high-quality bile duct cannulation. Transpancreatic precut sphincterotomy (TPS) has been proven effective for advanced cannulation. However, existing data mainly come from skilled endoscopists in large medical centers. The impact of TPS on ERCP quality in a lower-volume setting deserves investigation., Methods: Our hospital performs approximately 200 ERCPs annually, with 1 expert endoscopist performing approximately half of them and 3 nonexpert endoscopists sharing the remaining cases. TPS was started and became our predominant advanced cannulation technique in April 2016. We retrospectively reviewed ERCP cases 3 years before and after the introduction of TPS. The primary endpoints of the study were the differences in 2 ERCP quality indicators, the bile duct cannulation rate and the incidence of post-ERCP pancreatitis (PEP)., Results: A total of 701 ERCP cases with naïve papilla were analyzed, with 350 patients treated before the introduction of TPS and 351 patients treated afterward. The successful cannulation rate was significantly improved (before, 87.4%; after, 92.3%, P = .032), whereas the incidence of PEP decreased, but not significantly (before, 4.0%; after, 2.8%; P = .402). All endoscopists benefited from using TPS, with nonexperts demonstrating a significantly higher improvement in the cannulation rate (before, 85.5%; after, 93.1%; P = .019)., Conclusions: TPS can effectively enhance the quality of ERCP irrespective of practice volume., Competing Interests: Disclosure All authors disclosed no financial relationships., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background: Human epidermal growth factor receptor 3 (HER3) is broadly expressed in non-small-cell lung cancer (NSCLC) and is the target of patritumab deruxtecan (HER3-DXd), an antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. U31402-A-U102 is an ongoing phase I study of HER3-DXd in patients with advanced NSCLC. Patients with epidermal growth factor receptor (EGFR)-mutated NSCLC that progressed after EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy (PBC) who received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks had a confirmed objective response rate (cORR) of 39%. We present median overall survival (OS) with extended follow-up in a larger population of patients with EGFR-mutated NSCLC and an exploratory analysis in those with acquired genomic alterations potentially associated with resistance to HER3-DXd., Patients and Methods: Safety was assessed in patients with EGFR-mutated NSCLC previously treated with EGFR TKI who received HER3-DXd 5.6 mg/kg; efficacy was assessed in those who also had prior PBC., Results: In the safety population (N = 102), median treatment duration was 5.5 (range 0.7-27.5) months. Grade ≥3 adverse events occurred in 76.5% of patients; the overall safety profile was consistent with previous reports. In 78/102 patients who had prior third-generation EGFR TKI and PBC, cORR by blinded independent central review (as per RECIST v1.1) was 41.0% [95% confidence interval (CI) 30.0% to 52.7%], median progression-free survival was 6.4 (95% CI 4.4-10.8) months, and median OS was 16.2 (95% CI 11.2-21.9) months. Patients had diverse mechanisms of EGFR TKI resistance at baseline. At tumor progression, acquired mutations in ERBB3 and TOP1 that might confer resistance to HER3-DXd were identified., Conclusions: In patients with EGFR-mutated NSCLC after EGFR TKI and PBC, HER3-DXd treatment was associated with a clinically meaningful OS. The tumor biomarker characterization comprised the first description of potential mechanisms of resistance to HER3-DXd therapy., Competing Interests: Disclosure HAY has received consulting fees from AstraZeneca, Daiichi Sankyo, Cullinan, Blueprint Medicines, Janssen, Black Diamond, and Takeda. CB has received consulting fees from AstraZeneca, Blueprint Medicines, Daiichi Sankyo, Takeda, Turning Point Therapeutics, Guardant Health, Regeneron, and Silverback Therapeutics; institutional research funding grants/contracts from Loxo, AstraZeneca, Pfizer, Spectrum Pharmaceuticals, Blueprint Medicines, Daiichi Sankyo, Rain Therapeutics, AbbVie, Turning Point Therapeutics, Lilly, and Janssen. D-WK has received institutional research funding grants/contracts from Alpha Biopharma, AstraZeneca, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, Turning Point Therapeutics, Xcovery, Yuhan, Boehringer Ingelheim, Amgen, Daiichi Sankyo, Chong Kun Dang Pharmaceutical, BridgeBio Pharma, GSK, and Merck. MLJ has received consulting fees from Genentech/Roche, AstraZeneca, Calithera Biosciences, Merck, Sanofi, Mirati Therapeutics, Ribon Therapeutics, AbbVie, GSK, Gritstone Bio, Janssen Oncology, Lilly, Amgen, Daiichi Sankyo, Eisai, Axelia Oncology, Black Diamond Therapeutics, CytomX Therapeutics, EcoR1 Capital, Editas Medicine, Genmab, IDEAYA Biosciences, ITeos Therapeutics, Oncorus, Regeneron, Turning Point Therapeutics, Astellas Pharma, Checkpoint Therapeutics, Genocea Biosciences, Molecular Axiom, Novartis, Revolution Medicines, Takeda, and VBL Therapeutics; payment/honoraria from AbbVie, AstraZeneca, Genentech, Incyte, Merck, Pfizer, and Sanofi; research funding/grants from EMD Serono, Kadmon, Janssen, Mirati Therapeutics, Genmab, Pfizer, AstraZeneca, Stemcentrx, Novartis, Array BioPharma, Regeneron, Merck, Hengrui Pharmaceutical, Lycera, BeiGene, Tarveda Therapeutics, Loxo, AbbVie, Boehringer Ingelheim, Guardant Health, Daiichi Sankyo, Sanofi, CytomX Therapeutics, Dynavax Technologies, Corvus Pharmaceuticals, Incyte, Genocea Biosciences, Gritstone Bio, Amen, Genentech/Roche, Adaptimmune, Syndax, Neovia Oncology, Takeda, Shattuck Labs, GSK, Apexigen, Atreca, OncoMed, Lilly, Immunocore, University of Michigan, TCR2 Therapeutics, Arcus Biosciences, Ribon Therapeutics, BerGenBio, Calithera Biosciences, Tmunity Therapeutics, Seven and Eight Biopharmaceuticals, Rubius Therapeutics, Curis, Silicon Therapeutics, Dracen, PMV Pharma, Artios, BioAtla, Elicio Therapeutics, Erasca, Harpoon, Helsinn Healthcare, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Memorial Sloan Kettering Cancer Center, NeoImmune Tech, Numab, RasCal Therapeutics, Relay Therapeutics, Revolution Medicines, Tempest Therapeutics, Tizona Therapeutics, Turning Point Therapeutics, Vyriad, Y-mAbs Therapeutics, Exelixis, Fate Therapeutics, Merus, Black Diamond Therapeutics, Kartos Therapeutics, Carisma Therapeutics, Rain Therapeutics, Nuvalent, Palleon Pharmaceuticals, IMPAC Medical Systems, and EQRx. HH has received grants/contracts from AstraZeneca K.K., Astellas Pharma, MSD K.K., Ono Pharmaceutical, Nippon Boehringer Ingelheim, Novartis Pharma K.K., Pfizer Japan, Bristol Myers Squibb, Eli Lilly Japan K.K., Chugai Pharmaceutical, Daiichi Sankyo, Merck Serono, Merck Biopharma, Takeda, Taiho Pharmaceutical, SymBio Pharmaceuticals, AbbVie, inVentiv Health Japan, ICON Japan K.K., Gritstone Bio, Parexel International, Kissei Pharmaceutical, EPS Corporation, Syneos Health, Pfizer R&D Japan G.K., A2 Healthcare, Quintiles/IQVIA Services Japan K.K., EP-CRSU CO, Linical, Eisai, CMIC Shift Zero K.K., Kyowa Hakko Kirin, Bayer Yakuhin, EPS International, and Otsuka Pharmaceutical; payment/honoraria from Amgen K.K, AstraZeneca K.K., Boehringer Ingelheim Japan, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan K.K., Guardant Health, Kyorin Pharmaceutical, Merck Biopharma, MSD K.K., Novartis Pharma K.K., Ono Pharmaceutical, Shanghai Haihe Biopharma, Taiho Pharmaceutical, Pfizer, and Takeda outside the submitted work. MN has received payment/honoraria from Pfizer, Bristol Myers Squibb Japan, Ono Pharmaceutical, Chugai Pharma, Taiho Pharmaceutical, AstraZeneca, Boehringer Ingelheim, MSD, Novartis, Lilly, Nippon Kayaku, Takeda, Merck, Janssen, and Amgen; institutional research funding grants/contracts from Bristol Myers Squibb, Taiho Pharmaceutical, Pfizer, AstraZeneca, Lilly, MSD, Merck, Takeda, Amgen, and Janssen. JC-HY has received grants, personal fees, and advising/consulting institutional fees from AstraZeneca; personal fees and advising/consulting institutional fees from Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Merck KGaA, MSD, Novartis, Roche/Genentech, Takeda, and Yuhan Pharmaceuticals; advising/consulting institutional fees from Eli Lilly and Johnson & Johnson; advising/consulting fees from Ono Pharmaceutical, Pfizer, Puma Technology, Gilead, and GSK. W-CS has received advising/consulting fees from Bayer Schering Pharma, MSD Oncology, Lilly, and Merck. KAG has received advising/consulting fees from Takeda, AstraZeneca, Rakuten Medical, Regeneron; research funding grants/contracts from Pharmacyclics, AstraZeneca, AbbVie, BerGenBio, and Pfizer. MK has received payment/honoraria from AstraZeneca and Celgene. EFS has received personal fees from AstraZeneca, Daiichi Sankyo, Merck KGaA, and Boehringer Ingelheim; advising/consulting and research funding grants/contracts and institutional fees from Lilly, AstraZeneca, Boehringer Ingelheim, Roche/Genentech, Bristol Myers Squibb, Merck KGaA, MSD Oncology, Takeda, Bayer, Novartis, Daiichi Sankyo, and Seattle Genetics. CES has received personal fees and advising/consulting from AbbVie, BerGenBio, ARMO BioSciences, Lilly, Mirati Therapeutics, Sanofi/Regeneron, Caris Life Sciences, and Merck; research funding grants/contracts from Vaccinex, Seattle Genetics, Daiichi Sankyo, and Infinity Pharmaceuticals. EF has received institutional research funding grants/contracts from Grant for Oncology Innovation, Merck Healthcare KGaA, and Fundación Merck Salud; consulting fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, GSK, Ipsen, Janssen, Merck Serono, MSD, Novartis, Peptomyc, Pfizer, Sanofi, Takeda, and Turning Point; payment/honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Janssen, Medical Trends, Medscape, Merck Serono, MSD, PeerVoice, Pfizer, Sanofi, Takeda, and Touch Oncology; other financial aid from Grifols as an independent member of the board. HM has received grants, personal fees, and advising/consulting institutional fees from Chugai Pharma, GAIA BioMedicine, Taiho Pharmaceutical, AstraZeneca, Lilly Japan, Ono Pharmaceutical, Bristol Myers Squibb Japan, MSD, Takeda, Novartis, Daiicho Sankyo, Eisai, Nippon Kayaku, Pfizer, Boehringer Ingelheim, and AbbVie; institutional research funding grants/contracts from AstraZeneca, AbbVie, Takeda, Daiichi Sankyo, IQVIA, and Chugai Pharma. XS, SS, P-DF, MF, YT, PP, DWS, and DS are employees of and have stock ownership in Daiichi Sankyo. PAJ has received royalties for licenses from Labcorp; consulting fees from AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Chugai Pharmaceutical, Eli Lilly, SFJ Pharmaceuticals, VORONOI, Daiichi Sankyo, Biocartis, Novartis, Sanofi, Takeda, Mirati Therapeutics, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Eisai, Allorion Therapeutics, Accutar Biotech, and AbbVie; had stock ownership in Gatekeeper Pharmaceuticals. S-WK has declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Although PM 2.5 (fine particulate matter with an aerodynamic diameter less than 2.5 µm) is an air pollutant of great concern in Texas, limited regulatory monitors pose a significant challenge for decision-making and environmental studies., Objective: This study aimed to predict PM 2.5 concentrations at a fine spatial scale on a daily basis by using novel machine learning approaches and incorporating satellite-derived Aerosol Optical Depth (AOD) and a variety of weather and land use variables., Methods: We compiled a comprehensive dataset in Texas from 2013 to 2017, including ground-level PM 2.5 concentrations from regulatory monitors; AOD values at 1-km resolution based on images retrieved from the MODIS satellite; and weather, land-use, population density, among others. We built predictive models for each year separately to estimate PM 2.5 concentrations using two machine learning approaches called gradient boosted trees and random forest. We evaluated the model prediction performance using in-sample and out-of-sample validations., Results: Our predictive models demonstrate excellent in-sample model performance, as indicated by high R 2 values generated from the gradient boosting models (0.94-0.97) and random forest models (0.81-0.90). However, the out-of-sample R 2 values fall within a range of 0.52-0.75 for gradient boosting models and 0.44-0.69 for random forest models. Model performance varies slightly across years. A generally decreasing trend in predicted PM 2.5 concentrations over time is observed in Eastern Texas., Impact Statement: We utilized machine learning approaches to predict PM 2.5 levels in Texas. Both gradient boosting and random forest models perform well. Gradient boosting models perform slightly better than random forest models. Our models showed excellent in-sample prediction performance (R 2  > 0.9)., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Smoking is the most important risk factor for chronic obstructive pulmonary disease (COPD), however evidence from large-scale studies on whether secondhand smoke (SHS) increases the risk of COPD is still lacking. We conducted this large longitudinal study to investigate the association between SHS and the development of COPD. This is a longitudinal study. Data on 6519 subjects who were never-smokers, had no history of COPD, and had complete lung function records were extracted from the Taiwan Biobank. They were divided into two groups according to SHS exposure: no exposure and exposure groups. Data were collected when participants enrolled in the study and during regular follow-up. Cox proportional hazards regression models were used to estimate the relative risk (RR) and 95% confidence interval (CI) for the association between SHS and the risk of developing COPD. At 48 months of follow-up, 260 (4%) participants in the no exposure group and 34 (7%) participants in the exposure group developed COPD. The RR of incident COPD development was significantly higher in the exposure group than that in the no exposure group after adjusting for confounders (RR = 1.49; 95% CI 1.04 to 2.14; P value = 0.031). There is a dose-response relationship between the duration of exposure to SHS and the risk of incident COPD, which demonstrates that an additional hour of exposure to SHS per week was associated with a 1.03-fold increased likelihood of developing COPD after adjusting for confounders (RR = 1.03; 95% CI 1.00 to 1.05; P value = 0.027). SHS exposure contributes to the development of COPD. This finding can help raise awareness of the harms of SHS and provide a reference for formulating anti-smoking policies., (© 2024. The Author(s).)

Aims: We compared the efficacy, fidelity, acceptability, and feasibility of a creative movement (CM) intervention for children with autism spectrum disorder (ASD), delivered face-to-face (F2F) or through telehealth (TH)., Methods: Fifteen children with ASD received the CM intervention F2F or through TH. Motor assessments were used to evaluate effects of F2F and TH interventions on children's motor skills, while video coding was used to assess affect, socially directed verbalization, interpersonal synchrony, and motor coordination during training. Stakeholder feedback and training fidelity data on the intervention were also collected., Results: Children in both subgroups showed similar baseline performance and training-related improvements in motor skills, positive/interested affect, socially directed verbalization, interpersonal synchrony, and dual/multilimb coordination. Parents in the TH subgroup considered the intervention feasible and acceptable; however, they reported greater effort to supervise and redirect their child's attention compared to the F2F subgroup. Trainers for the TH subgroup reported more communication difficulties, technological issues, and longer session lengths, but found greater parental involvement compared to the F2F subgroup., Conclusions: CM interventions are consistent, acceptable, feasible, and effective in improving social, behavioral-affective, and motor skills of children with ASD, regardless of the method of delivery. Clinicians should make efforts to reduce communication/technological issues and parental burden when delivering CM interventions through TH. ClinicalTrials.Gov Study ID-NCT04258254., Competing Interests: No competing financial interests exist., (© Wan-Chun Su et al., 2024; Published by Mary Ann Liebert, Inc.)

Ultrafine particles (UFPs) in urban air environments have been an essential public health concern. The inhalation of UFPs can introduce transition metals contained in the UFP into the human airways, leading to adverse health effects. Therefore, it is crucial to investigate urban air UFP exposure and health risks induced by transition metals. This research carried out a series of field measurements to study urban air UFP exposure in the Greater Houston Area. Three sampling sites in the Greater Houston Area representing varying levels of UFP exposures were selected. The newly developed Mobile Aerosol Lung Deposition Apparatus (MALDA) which consists of a complete set of human airway replicas and a pair of UFP particle sizers was deployed in the sampling sites during three sampling timeframes (morning rush hours, noon, and afternoon rush hours) to obtain on-site UFP respiratory deposition data. UFP samples were collected at the sampling sites for metal composition analysis. The acquired UFP respiratory deposition data and UFP composition data were then used to calculate the respiratory deposited mass of transition metals and estimate the associated health risks for individuals living near sampling sites. Our results showed that transition metal-induced non-cancer risks caused by exposure to urban UFPs were within acceptable limits. The estimated lifetime excess cancer risks were generally <10 -6 , indicating an overall acceptable level of transition metal-induced cancer risk., 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 © 2023. Published by Elsevier B.V.)

Background: Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor expressed on the surface of T cells. High expression of PD-1 leads to T-cell dysfunction in the tumor microenvironment (TME). However, the mechanism of intracellular trafficking and plasma membrane presentation of PD-1 remains unclear., Methods: Multiple databases of lung cancer patients were integratively analyzed to screen Rab proteins and potential immune-related signaling pathways. Imaging and various biochemical assays were performed in Jurkat T cells, splenocytes, and human peripheral blood mononuclear cells (PBMCs). Rab37 knockout mice and specimens of lung cancer patients were used to validate the concept., Results: Here, we identify novel mechanisms of intracellular trafficking and plasma membrane presentation of PD-1 mediated by Rab37 small GTPase to sustain T cell exhaustion, thereby leading to poor patient outcome. PD-1 colocalized with Rab37-specific vesicles of T cells in a GTP-dependent manner whereby Rab37 mediated dynamic trafficking and membrane presentation of PD-1. However, glycosylation mutant PD-1 delayed cargo recruitment to the Rab37 vesicles, thus stalling membrane presentation. Notably, T cell proliferation and activity were upregulated in tumor-infiltrating T cells from the tumor-bearing Rab37 knockout mice compared to those from wild type. Clinically, the multiplex immunofluorescence-immunohistochemical assay indicated that patients with high Rab37 + /PD-1 + /TIM3 + /CD8 + tumor infiltrating T cell profile correlated with advanced tumor stages and poor overall survival. Moreover, human PBMCs from patients demonstrated high expression of Rab37, which positively correlated with elevated levels of PD-1 + and TIM3 + in CD8 + T cells exhibiting reduced tumoricidal activity., Conclusions: Our results provide the first evidence that Rab37 small GTPase mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion, and the tumor promoting function of Rab37/PD-1 axis in T cells of TME in lung cancer. The expression profile of Rab37 high /PD-1 high /TIM3 high in tumor-infiltrating CD8 + T cells is a biomarker for poor prognosis in lung cancer patients., (© 2024. The Author(s).)

Background: In Taiwan, lung cancers occur predominantly in never-smokers, of whom nearly 60% have stage IV disease at diagnosis. We aimed to assess the efficacy of low-dose CT (LDCT) screening among never-smokers, who had other risk factors for lung cancer., Methods: The Taiwan Lung Cancer Screening in Never-Smoker Trial (TALENT) was a nationwide, multicentre, prospective cohort study done at 17 tertiary medical centres in Taiwan. Eligible individuals had negative chest radiography, were aged 55-75 years, had never smoked or had smoked fewer than 10 pack-years and stopped smoking for more than 15 years (self-report), and had one of the following risk factors: a family history of lung cancer; passive smoke exposure; a history of pulmonary tuberculosis or chronic obstructive pulmonary disorders; a cooking index of 110 or higher; or cooking without using ventilation. Eligible participants underwent LDCT at baseline, then annually for 2 years, and then every 2 years up to 6 years thereafter, with follow-up assessments at each LDCT scan (ie, total follow-up of 8 years). A positive scan was defined as a solid or part-solid nodule larger than 6 mm in mean diameter or a pure ground-glass nodule larger than 5 mm in mean diameter. Lung cancer was diagnosed through invasive procedures, such as image-guided aspiration or biopsy or surgery. Here, we report the results of 1-year follow-up after LDCT screening at baseline. The primary outcome was lung cancer detection rate. The p value for detection rates was estimated by the χ 2 test. Univariate and multivariable logistic regression analyses were used to assess the association between lung cancer incidence and each risk factor. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of LDCT screening were also assessed. This study is registered with ClinicalTrials.gov, NCT02611570, and is ongoing., Findings: Between Dec 1, 2015, and July 31, 2019, 12 011 participants (8868 females) were enrolled, of whom 6009 had a family history of lung cancer. Among 12 011 LDCT scans done at baseline, 2094 (17·4%) were positive. Lung cancer was diagnosed in 318 (2·6%) of 12 011 participants (257 [2·1%] participants had invasive lung cancer and 61 [0·5%] had adenocarcinomas in situ). 317 of 318 participants had adenocarcinoma and 246 (77·4%) of 318 had stage I disease. The prevalence of invasive lung cancer was higher among participants with a family history of lung cancer (161 [2·7%] of 6009 participants) than in those without (96 [1·6%] of 6002 participants). In participants with a family history of lung cancer, the detection rate of invasive lung cancer increased significantly with age, whereas the detection rate of adenocarcinoma in situ remained stable. In multivariable analysis, female sex, a family history of lung cancer, and age older than 60 years were associated with an increased risk of lung cancer and invasive lung cancer; passive smoke exposure, cumulative exposure to cooking, cooking without ventilation, and a previous history of chronic lung diseases were not associated with lung cancer, even after stratification by family history of lung cancer. In participants with a family history of lung cancer, the higher the number of first-degree relatives affected, the higher the risk of lung cancer; participants whose mother or sibling had lung cancer were also at an increased risk. A positive LDCT scan had 92·1% sensitivity, 84·6% specificity, a PPV of 14·0%, and a NPV of 99·7% for lung cancer diagnosis., Interpretation: TALENT had a high invasive lung cancer detection rate at 1 year after baseline LDCT scan. Overdiagnosis could have occurred, especially in participants diagnosed with adenocarcinoma in situ. In individuals who do not smoke, our findings suggest that a family history of lung cancer among first-degree relatives significantly increases the risk of lung cancer as well as the rate of invasive lung cancer with increasing age. Further research on risk factors for lung cancer in this population is needed, particularly for those without a family history of lung cancer., Funding: Ministry of Health and Welfare of Taiwan., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background and Objective: While impact of heat exposure on human health is well-documented, limited research exists on its effect on kidney disease hospital admissions especially in Texas, a state with diverse demographics and a high heat-related death rate. We aimed to explore the link between high temperatures and emergency kidney disease hospital admissions across 12 Texas Metropolitan Statistical Areas (MSAs) from 2004 to 2013, considering causes, age groups, and ethnic populations., Methods: To investigate the correlation between high temperatures and emergency hospital admissions, we utilized MSA-level hospital admission and weather data. We employed a Generalized Additive Model to calculate the association specific to each MSA, and then performed a random effects meta-analysis to estimate the overall correlation. Analyses were stratified by age groups, admission causes, and racial/ethnic disparities. Sensitivity analysis involved lag modifications and ozone inclusion in the model., Results: Our analysis found that each 1 °C increase in temperature was associated with a 1.73 % (95 % CI [1.43, 2.03]) increase in hospital admissions related to all types of kidney diseases. Besides, the effect estimates varied across different age groups and specific types of kidney diseases. We observed statistically significant associations between high temperatures and emergency hospital admissions for Acute Kidney Injury (AKI) (3.34 % (95 % CI [2.86, 3.82])), Kidney Stone (1.76 % (95 % CI [0.94, 2.60])), and Urinary Tract Infections (UTI) (1.06 % (95 % CI [0.61, 1.51])). Our research findings indicate disparities in certain Metropolitan Statistical Areas (MSAs). In Austin, Houston, San Antonio, and Dallas metropolitan areas, the estimated effects are more pronounced for African Americans when compared to the White population. Additionally, in Dallas, Houston, El Paso, and San Antonio, the estimated effects are greater for the Hispanic group compared to the Non-Hispanic group., Conclusions: This study finds a strong link between higher temperatures and kidney disease-related hospital admissions in Texas, especially for AKI. Public health actions are necessary to address these temperature-related health risks, including targeted kidney health initiatives. More research is needed to understand the mechanisms and address health disparities among racial/ethnic groups., 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 © 2023 Elsevier B.V. All rights reserved.)

A variety of cellular processes use liquid-liquid phase separation (LLPS) to create functional levels of organization, but the kinetic pathways by which it proceeds remain incompletely understood. Here in real time, we monitor the dynamics of LLPS of mixtures of segregatively phase-separating polymers inside all-synthetic, giant unilamellar vesicles. After dynamically triggering phase separation, we find that the ensuing relaxation-en route to the new equilibrium-is non-trivially modulated by a dynamic interplay between the coarsening of the evolving droplet phase and the interactive membrane boundary. The membrane boundary is preferentially wetted by one of the incipient phases, dynamically arresting the progression of coarsening and deforming the membrane. When the vesicles are composed of phase-separating mixtures of common lipids, LLPS within the vesicular interior becomes coupled to the membrane's compositional degrees of freedom, producing microphase-separated membrane textures. This coupling of bulk and surface phase-separation processes suggests a physical principle by which LLPS inside living cells might be dynamically regulated and communicated to the cellular boundaries., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)