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Shi-liang Chen,1,* Dan Hu,2,* Tian-zhu Chen,3,* Si-yu Shen,4,* Chen-fei Zhao,1,* Cong Wang,1 Shi-yuan Tong,5 Zhao Liu,6 Shao-hua Lin,1 Li-xia Jin,7 Yi-bo He,1 Zhe-zhong Zhang1 1Department of Clinical Lab, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, People’s Republic of China; 2Department of Clinical Lab, The Cixi Integrated Traditional Chinese and Western Medicine Medical and Health Group Cixi Red Cross Hospital, Cixi, People’s Republic of China; 3Department of Pathology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, People’s Republic of China; 4The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 5The Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, People’s Republic of China; 6Department of General Surgery, Shaoxing Central Hospital, Shaoxing, People’s Republic of China; 7School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhe-zhong Zhang; Yi-bo He, Department of Clinical Lab, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, People’s Republic of China, Email zhangzhezhong2023@163.com; heyb1992@126.comPurpose: Cancer-associated fibroblasts (CAFs) significantly contribute to tumor progression and the development of resistance to therapies across a range of malignancies, notably breast cancer. This study aims to elucidate the specific role and prognostic relevance of CALU across multiple cancer types.Patients and Methods: The association between CALU expression and prognosis, along with clinical characteristics in BRCA, HNSC, KIRP, LGG, and LIHC, was analyzed using data from the TCGA, GTEx, and GEO databases. Transcriptomic analysis of TCGA BRCA project data provided insights into the interaction between CALU and epithelial-mesenchymal transition (EMT) marker genes. Using TIMER and TISCH databases, the correlation between CALU expression and tumor microenvironment infiltration was assessed, alongside an evaluation of CALU expression across various cell types. Furthermore, CALU’s influence on TNBC BRCA cell lines was explored, and its expression in tumor tissues was confirmed through immunohistochemical analysis of clinical samples.Results: This study revealed a consistent upregulation of CALU across several tumor types, including BRCA, KIRP, LIHC, HNSC, and LGG, with elevated CALU expression being associated with unfavorable prognoses. CALU expression was particularly enhanced in clinical contexts linked to poor outcomes. Genomic analysis identified copy number alterations as the principal factor driving CALU overexpression. Additionally, a positive correlation between CALU expression and CAF infiltration was observed, along with its involvement in the EMT process in both CAFs and malignant cells. In vitro experiments demonstrated that CALU is highly expressed in TNBC-BRCA cell lines, and knockdown of CALU effectively reversed EMT progression and inhibited cellular migration. Immunohistochemical analysis of clinical samples corroborated the elevated expression of CALU in tumors, along with alterations in EMT markers.Conclusion: This comprehensive pan-cancer analysis underscores CALU’s critical role in modulating the tumor microenvironment and facilitating cell migration via the EMT pathway, identifying it as a potential therapeutic target.Keywords: CALU, cancer-associated fibroblasts, epithelial-mesenchymal transition, breast cancer, prognosis, pan-cancer analysis

Ching-Hsiung Lin,1– 4,* Shih-Lung Cheng,5,6 Chiung-Zuei Chen,7 Chia-Hung Chen,8 Sheng-Hao Lin,1 Hao-Chien Wang9,* 1Division of Chest Medicine, Changhua Christian Hospital, Changhua, 500, Taiwan; 2Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, 402, Taiwan; 3Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan; 4Department of Recreation and Holistic Wellness, MingDao University, Changhua, Taiwan; 5Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, 220, Taiwan; 6Department of Chemical Engineering and Materials Science, Yuan Ze University, Taoyuan, 320, Taiwan; 7Division of Pulmonary Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 8Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, 404, Taiwan; 9Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan*These authors contributed equally to this workCorrespondence: Hao-Chien Wang, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan, Tel + 886 2 2322-0322, Fax + 886 2 2322-0322, Email haochienwang@gmail.com Ching-Hsiung Lin, Department of Internal Medicine, Division of Chest Medicine, Changhua Christian Hospital, 135 Nanhsiao Street, Changhua, 50006, Taiwan, Tel +886-4-7238595, Fax +886-4-7232942, Email 47822@cch.org.twAbstract: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide, with approximately 70% to 80% of adults with COPD being undiagnosed. Patients with undiagnosed COPD are at increased risk of poor outcomes and a worsened quality of life, making early detection a crucial strategy to mitigate the impact of COPD and reduce the burden on healthcare systems. In the past decade, increased interest has been focused on the development of effective strategies and instrument for COPD early detection. However, identifying undiagnosed cases of COPD is still challenging. Both screening and case-finding approaches have been adopted to identify undiagnosed COPD, with case-finding being recommended by the 2023 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline and the updated United States Preventive Services Task Force (USPTF) recommendation. Nonetheless, the approaches, criteria, and instruments used for early detection of COPD are varied. However, advances in the taxonomy and risk factors of COPD are continuously being investigated. It is important to continuously assess the current state of knowledge on COPD early detection, given the challenges associated with identifying undiagnosed COPD. This review aims to highlight recent advances in early detection of COPD. To discuss the current challenge and opportunity in COPD early detection, providing an overview of existing literature on COPD case-finding strategies, including the approaches, criteria for subjects, and instruments. The review also summarizes the current progress in COPD case-findings and proposes a COPD case-finding flowchart as an efficient method for identifying at risk COPD patients.Keywords: COPD, undiagnosed, at-risk, case-finding, early detection

Chiung-Zuei Chen,1 Chau-Chyun Sheu,2 Shih-Lung Cheng,3,4 Hao-Chien Wang,5 Meng-Chih Lin,6 Wu-Huei Hsu,7 Kang-Yun Lee,8 Diahn-Warng Perng,9 Hen-I Lin,10 Ming-Shian Lin,11 Sheng-Hao Lin,12 Jong-Rung Tsai,13 Chin-Chou Wang,6 Cheng-Yi Wang,10 Tsung-Ming Yang,14 Ching-Lung Liu,15 Tsai-Yu Wang,16 Ching-Hsiung Lin12,17,18 1Division of Pulmonary Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan; 3Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, 220, Taiwan; 4Department of Chemical Engineering and Materials Science, Yuan Ze University, Zhongli, Taoyuan, 320, Taiwan; 5Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan; 6Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, 404, Taiwan; 7Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 8Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, 110, Taiwan; 9Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, 112, Taiwan; 10Department of Internal Medicine, Cardinal Tien Hospital, Fu-Jen Catholic University, Taipei, 242, Taiwan; 11Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, 600, Taiwan; 12Division of Chest Medicine, Changhua Christian Hospital, Changhua, 500, Taiwan; 13Division of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; 14Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Taoyuan City, Taiwan; 15Division of Chest Medicine, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, 104, Taiwan; 16Pulmonary Disease Research Centre, Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, Taipei, Taiwan; 17Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, 402, Taiwan; 18Department of Recreation and Holistic Wellness, MingDao University, Changhua, 523, TaiwanCorrespondence: Ching-Hsiung LinDivision of Chest Medicine, Department of Internal Medicine, Changhua Christian Hospital, 135 Nanhsiao Street, Changhua, 50006, TaiwanTel +886-4-7238595Fax +886-4-7232942Email 47822@cch.org.twBackground and Aim: Chronic obstructive pulmonary disease (COPD) is frequently underdiagnosed because of the unavailability of spirometers, especially in resource-limited outpatient settings. This study provides real-world evidence to identify optimal approaches for COPD case finding in outpatient settings.Methods: This retrospective study enrolled individuals who were at risk of COPD (age ≥ 40 years, ≥ 10 pack-years, and ≥ 1 respiratory symptom). Eligible participants were examined using various COPD case-finding tools, namely the COPD Population Screener (COPD-PS) questionnaire, a COPD prediction (PCOPD) model, and a microspirometer, Spirobank Smart; subsequently, the participants underwent confirmatory spirometry. The definition and confirmation of COPD were based on conventional spirometry. Receiver operating characteristic curve (ROC), area under the curve (AUC), and decision curve analyses were conducted, and a clinical impact curve was constructed.Results: In total, 385 participants took part in the study [284 without COPD (73.77%) and 101 with COPD (26.23%)]. The microspirometer exhibited a higher AUC value than did the COPD-PS questionnaire and the PCOPD model. The AUC for microspirometry was 0.908 (95% confidence interval [CI] = 0.87– 0.95), that for the PCOPD model was 0.788 (95% CI = 0.74– 0.84), and that for the COPD-PS questionnaire was 0.726 (95% CI = 0.67– 0.78). Decision and clinical impact curve analyses revealed that a microspirometry-derived FEV1/FVC ratio of < 74% had superior clinical utility to the other measurement tools.Conclusion: The PCOPD model and COPD-PS questionnaire were useful for identifying symptomatic patients likely to have COPD, but microspirometry was more accurate and had higher clinical utility. This study provides real-world evidence to identify optimal practices for COPD case finding; such practices ensure that physicians have convenient access to up-to-date evidence when they encounter a symptomatic patient likely to have COPD.Keywords: COPD, COPD case-finding, PCOPD model, COPD-PS questionnaire, microspirometry, spirometry

Shih-Lung Cheng,1,2,&ast; Yi-Rong Li,3,&ast; Nicole Huang,4 Chong-Jen Yu,5 Hao-Chien Wang,5 Meng-Chih Lin,6 Kuo-Chin Chiu,7 Wu-Huei Hsu,8 Chiung-Zuei Chen,9 Chau-Chyun Sheu,10,11 Diahn-Warng Perng,12 Sheng-Hao Lin,13 Tsung-Ming Yang,14 Chih-Bin Lin,15 Chew-Teng Kor,16 Ching-Hsiung Lin13,17,18 1Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, 220, Taiwan; 2Department of Chemical Engineering and Materials Science, Yuan Ze University, Zhongli, Taoyuan, 320, Taiwan; 3Changhua Christian Hospital, Thoracic Medicine Research Center, Changhua, 500, Taiwan; 4Institute of Hospital and Health Care Administration, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan; 5Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan; 6Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 7Division of Chest, Department of Internal Medicine, Poh-Ai Hospital, Luodong, 265, Taiwan; 8Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, 404, Taiwan; 9Division of Pulmonary Medicine, Department of Internal Medicine, National Cheng Kung University, College of Medicine and Hospital, Tainan, 701, Taiwan; 10Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan; 11Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; 12Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, 112, Taiwan; 13Department of Internal Medicine, Division of Chest Medicine, Changhua Christian Hospital, Changhua, 500, Taiwan; 14Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, 613, Taiwan; 15Department of Internal Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, 970, Taiwan; 16Big Data Center, Changhua Christian Hospital, Changhua, Changhua Christian Hospital, Changhua, 500, Taiwan; 17Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, 402, Taiwan; 18Department of Recreation and Holistic Wellness, MingDao University, Changhua, 523, Taiwan&ast;These authors contributed equally to this workCorrespondence: Ching-Hsiung LinDepartment of Internal Medicine, Division of Chest Medicine, Changhua Christian Hospital, 135 Nanhsiao Street, Changhua, 50006, TaiwanTel +886-4-7238595Fax +886-4-7232942Email 47822@cch.org.twBackground: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. It has also imposed a substantial economic and social burden on the health care system. In Taiwan, a nationwide COPD pay-for-performance (P4P) program was designed to improve the quality of COPD-related care by introducing financial incentives for health care providers and employing a multidisciplinary team to deliver guideline-based, integrated care for patients with COPD, reducing adverse outcomes, especially COPD exacerbation. However, the results of a survey of the effectiveness of the pay-for-performance program in COPD management were inconclusive. To address this knowledge gap, this study evaluated the effectiveness of the COPD P4P program in Taiwan.Methods: This retrospective cohort study used data from Taiwan’s National Health Insurance claims database and nationwide COPD P4P enrollment program records from June 2016 to December 2018. Patients with COPD were classified into P4P and non-P4P groups. Patients in the P4P group were matched at a ratio of 1:1 based on age, gender, region, accreditation level, Charlson Comorbidity Index (CCI), and inhaled medication prescription type to create the non-P4P group. A difference-in-difference analysis was used to evaluate the influence of the P4P program on the likelihood of COPD exacerbation, namely COPD-related emergency department (ED) visit, intensive care unit (ICU) admission, or hospitalization.Results: The final sample of 14,288 patients comprised 7144 in each of the P4P and non-P4P groups. The prevalence of COPD-related ED visits, ICU admissions, and hospitalizations was higher in the P4P group than in the non-P4P group 1 year before enrollment. After enrollment, the P4P group exhibited a greater decrease in the prevalence of COPD-related ED visits and hospitalizations than the non-P4P group (ED visit: − 2.98%, p< 0.05, 95% confidence interval [CI]: − 0.277 to − 0.086; hospitalization: − 1.62%, p< 0.05, 95% CI: − 0.232 to − 0.020), whereas no significant difference was observed between the groups in terms of the changes in the prevalence of COPD-related ICU admissions.Conclusion: The COPD P4P program exerted a positive net effect on reducing the likelihood of COPD exacerbation, namely COPD-related ED visits and hospitalizations. Future studies should examine the long-term cost-effectiveness of the COPD P4P program.Keywords: COPD, pay-for-performance program, guideline-based, comprehensive care, exacerbation, financial incentive

Brian De,1,* Sweet Ping Ng,1,2,* Amy Y Liu,1 Santiago Avila,1 Randa Tao,3 Emma B Holliday,1 Zachary Brownlee,4 Ahmed Kaseb,5 Sunyoung Lee,3 Kanwal Raghav,5 Jean-Nicolas Vauthey,6 Bruce D Minsky,1 Joseph M Herman,1 Prajnan Das,1 Grace L Smith,1 Cullen M Taniguchi,1 Sunil Krishnan,7 Christopher H Crane,8 Clemens Grassberger,9 Theodore S Hong,9 Steven H Lin,1 Albert C Koong,1 Radhe Mohan,1 Eugene J Koay1 1Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Radiation Oncology, Austin Health, Melbourne, Victoria, Australia; 3Department of Radiation Oncology, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA; 4Department of Radiation Oncology, Tufts Medical Center, Boston, MA, USA; 5Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 6Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 7Department of Radiation Oncology, Mayo Clinic Jacksonville, Jacksonville, FL, USA; 8Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 9Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA*These authors contributed equally to this workCorrespondence: Eugene J KoayMD Anderson Cancer Center, Department of Radiation Oncology, 1400 Pressler St. Unit 1422, Houston, TX, 77030, USATel + 1 713-563-2381Fax +1 713-563-2331Email EKoay@mdanderson.orgBackground: The immune system plays a crucial role in cancer surveillance. Previous studies have shown that lymphopenia associated with radiotherapy (RT) portends a poor prognosis. We sought to differentiate the effects of proton and photon RT on changes in absolute lymphocyte count (ALC) for patients with hepatocellular carcinoma (HCC).Patients and Methods: Patients with HCC treated with definitive RT from 2006 to 2016 were studied. Serial ALCs were graded according to CTCAE v4.0. Overall survival (OS), disease-free survival, and distant metastasis-free survival were analyzed using the Kaplan–Meier method. Univariable and multivariable Cox-proportional hazards analyses were used to identify predictors of OS. A cohort analysis matched for treatment volume was performed to investigate differences in ALC dynamics between photon and proton therapy.Results: Of 143 patients identified, the median age was 66 (range, 19– 90) years. The treatment modality was photon in 103 (72%) and proton in 40 (28%). Median follow-up was 17 months (95% confidence interval, 13– 25 months). The median time to ALC nadir after initiation of RT was 17 days with a median relative decrease of 67%. Those who received proton RT had a higher median ALC nadir (0.41 vs 0.32 k/μL, p=0.002) and longer median OS (33 vs 13 months, p=0.002) than those who received photon RT. Matched cohort analyses revealed a larger low-dose liver volume in the photon group, which correlated with lower ALC. On multivariable Cox analysis, Grade 3 or higher lymphopenia prior to or after RT, portal venous tumor thrombus, larger planning target volumes, Child-Pugh (CP) Class B, and increased CP score after RT were associated with a higher risk of death, whereas the use of proton therapy was associated with lower risk.Conclusion: Grade 3 or higher lymphopenia may be associated with poorer outcomes in patients receiving RT for HCC. Protons may mitigate lymphopenia compared with photons, potentially due to reduced dose exposure of sites of lymphopoiesis.Keywords: lymphocyte count, circulating lymphocytes, splenic dose, liver dose, overall survival

Shu-Hui Lin,1,2,* Hsin-Kai Wang,3,4,* Kun-Tu Yeh,1,5 Hui-Chun Tai,1,6 Hui-Yi Wang,1 Lan-Ru Huang,2 Chun-Wen Chiu,7 Chia-Min Chung,8,9 Bharath Kumar Velmurugan101Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan; 2Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan; 3Public Health Bureau, Tainan City Government, Tainan, Taiwan; 4Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan; 5School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 6Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; 7Department of Emergency Medicine, Changhua Christian Hospital, Changhua, Taiwan; 8Graduate Institute of BioMedical Sciences, China Medical University, Taichung, Taiwan; 9Environment-Omics-Diseases Research Center, China Medical University Hospital, Taichung, Taiwan; 10Toxicology and Biomedicine Research Group, Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam*These authors contributed equally to this work Purpose: c-MYC has been noted in many tumor types, but its functional significance and clinical utility in oral squamous cell carcinoma (OSCC) are not well known. Here we studied the expression of c-MYC in correlation to clinical outcome in patients with oral squamous cell carcinoma.Methods: The current study, using immunohistochemical staining, first examined c-MYC expression in OSCC patients and further correlated its expression with clinicopathological parameters.Results: c-MYC was expressed in the majority of OSCC patients (n=133). The c-MYC expression is associated with histological grade (P=0.0205) of patients with oral squamous cell carcinoma. Multivariate Cox regression analysis revealed that TN stage (P0.05). Multiplicative-scale interaction between T stage (III/IV) and low c-MYC expression on mortality risk was identified (P=0.0233). Kaplan–Meier survival analysis demonstrated that oral cancer patients (T III/IV stage) with high c-MYC expression had better survival than those with low and medium c-MYC expression (P=0.0270).Conclusion: Our data indicate that c-MYC is a potential biomarker that can be used as a therapeutic target for treating OSCC patients with T stage (III/IV).Keywords: T stage, c-MYC, OSCC, biomarker, survival

Bharath Kumar Velmurugan,1 Hsin-Kai Wang,2,3 Chia-Min Chung,4,5 Chien-Hsun Lee,6 Lan-Ru Huang,7 Kun-Tu Yeh,6,7* Shu-Hui Lin6,8*1Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam; 2Public Health Bureau, Tainan City Government, Tainan City, Taiwan; 3Jenteh Junior College of Medicine, Nursing and Management, Taiwan; 4Graduate Institute of BioMedical Sciences, China Medical University, Taichung, Taiwan; 5Environment-Omics-Diseases Research Center, China Medical University Hospital, Taichung, Taiwan; 6Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan; 7School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 8Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan *These authors contributed equally to this workIntroduction: Oral cancer is a prevalent form of cancer worldwide, particularly in Taiwan, and mechanisms involved in oral squamous cell carcinoma (OSCC) progression remain relatively unknown. Cancerous inhibitor of protein phosphatase 2A (CIP2A), an oncoprotein, is aberrantly expressed in many human malignant tumors including oral cancer. However, the expression and role played by CIP2A in oral cancer pathogenesis remain obscure.Methods: In this study, immunohistochemistry was used to analyze CIP2A expression between OSCC tissues and their adjacent noncancerous tissues. Furthermore, associations between CIP2A expression and histopathological parameters were investigated.Results: In this study, we showed that CIP2A was overexpressed in most of the OSCC tissues. High CIP2A expression was significantly associated with moderate/poor tumor differentiation (P=0.02). No significant association was found between CIP2A expression and other clinical parameters. Kaplan–Meier analysis revealed that high CIP2A expression showed poorer survival rates than those with low CIP2A expression (P=0.047). Multivariate Cox regression analysis indicated that CIP2A expression, N stage, American Joint Committee on Cancer stage and clinical therapy were independent prognostic factors for survival.Conclusion: Thus, our study suggests that CIP2A is an independent prognostic marker for OSCC and a novel target for OSCC treatment.Keywords: CIP2A, OSCC: prognosis, survival, Taiwan

Cho-I Lin,1 Yu-Ching Lin,1–3 Wei-Chih Lien,1 Pei-Chun Hsieh,1 Sheng-Han Lin,1 Ta-Shen Kuan1,2 1Department of Physical Medicine and Rehabilitation, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Department of Physical Medicine and Rehabilitation, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 3Medical Device Innovation Center, National Cheng Kung University, Tainan, Taiwan Introduction: Punding is a complex stereotyped behavior, characterized by excessiveness, non-goal orientation, and repetitiveness. It is mostly associated with Parkinson’s disease, and very few cases in non-Parkinson’s disease have been reported. We report a case of punding associated with supratentorial ischemic stroke.Case presentation: We present a 70-year-old man with left posterior cerebral artery infarction with quetiapine-induced punding manifesting as repetitive unidirectional body turning. Remission of punding behavior ensued after cessation of quetiapine and administration of clonazepam.Conclusion: This case describes the clinical course of quetiapine-induced punding in a patient with left posterior cerebral artery infarction. It suggests clonazepam may serve as a treatment option for poststroke punding. Keywords: punding, stereotyped behavior, stroke, quetiapine, clonazepam

Sheng-Hao Lin,1,2 Diahn-Warng Perng,3,4 Ching-Pei Chen,5,6 Woei-Horng Chai,1 Chin-Shui Yeh,1 Chew-Teng Kor,7 Shih-Lung Cheng,8,9 Jeremy JW Chen,2,* Ching-Hsiung Lin1,10,11,* 1Department of Internal Medicine, Division of Chest Medicine, Changhua Christian Hospital, Changhua, 2Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 3Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, 4School of Medicine, National Yang-Ming University, Taipei, 5Department of Internal Medicine, Division of Cardiology, Changhua Christian Hospital, 6Department of Beauty Science and Graduate Institute of Beauty Science Technology, Chien-Kuo Technology University, 7Department of Internal Medicine, Internal Medicine Research Center, Changhua Christian Hospital, Changhua, 8Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, 9Department of Chemical Engineering and Materials Science, Yuan Ze University, Zhongli City, Taoyuan, 10Department of Respiratory Care, College of Health Sciences, Chang Jung Christian University, Tainan, 11School of Medicine, Chung Shan Medical University, Taichung, Taiwan *These authors contributed equally to this work Background and objective: COPD patients with community-acquired pneumonia (CAP) have worse clinical outcomes, as compared to those without COPD. Cardiovascular disease (CVD) is a common comorbidity for COPD patients. Whether COPD with comorbid CVD will increase the risk of CAP is not well investigated. The incidence and factors associated with CAP in COPD patients with and without CVD were analyzed. Methods: The medical records of patients with newly diagnosed COPD between 2007 and 2010 were reviewed. The patients’ characteristics, medical history of CVD, occurrence of CAP, and type of medication were recorded. Kaplan–Meier curves were used to assess the differences in cumulative incidence of CAP. Cox’s proportional hazards regression model was used to determine the adjusted hazard ratios with 95% confidence intervals in relation to factors associated with CAP in COPD patients with and without CVD. Results: Among 2,440 patients, 475 patients (19.5%) developed CAP during the follow-up period. COPD patients who developed CAP were significantly older, had lower forced expiratory volume in 1 second, frequent severe exacerbation and comorbid CVD, as well as received inhaled corticosteroid (ICS)-containing therapy than those without CAP. The cumulative incidence of CAP was higher in COPD patients with CVD compared to those without CVD. Patients who received ICS-containing therapy had significantly increased risk of developing CAP compared to those who did not. Conclusion: For patients with COPD, comorbid CVD is an independent risk factor for developing CAP. ICS-containing therapy may increase the risk of CAP among COPD patients. Keywords: chronic obstructive pulmonary disease, COPD, community-acquired pneumonia, cardiovascular disease, inhaled corticosteroids, CAP, CVD

Shao-Hui Lin,1 Wei Cui,2 Gui-Ling Wang,1 Shuai Meng,1 Ying-Chun Liu,3 Hong-Wei Jin,4 Liang-Ren Zhang,4 Ying Xie1,4 1Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, 2School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Beijing, 3Soft Matter Research Center, Department of Chemistry, Zhejiang University, Hangzhou, 4State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, People’s Republic of China Abstract: Albumin-based nanoparticles (NPs) are a promising technology for developing drug-carrier systems, with improved deposition and retention profiles in lungs. Improved understanding of these drug–carrier interactions could lead to better drug-delivery systems. The present study combines computational and experimental methods to gain insights into the mechanism of binding of albuterol sulfate (AS) to bovine serum albumin (BSA) on the molecular level. Molecular dynamics simulation and surface plasmon resonance spectroscopy were used to determine that there are two binding sites on BSA for AS: the first of which is a high-affinity site corresponding to AS1 and the second of which appears to represent the integrated functions of several low-affinity sites corresponding to AS2, AS3, and AS8. AS1 was the strongest binding site, established via electrostatic interaction with Glu243 and Asp255 residues in a hydrophobic pocket. Hydrogen bonds and salt bridges played a main role in the critical binding of AS1 to BSA, and water bridges served a supporting role. Based upon the interaction mechanism, BSA NPs loaded with AS were prepared, and their drug-loading efficiency, morphology, and -release profiles were evaluated. Successful clinical development of AS-BSA-NPs may improve therapy and prevention of bronchospasm in patients with reversible obstructive airway disease, and thus provide a solid basis for expanding the role of NPs in the design of new drug-delivery systems. Keywords: molecular dynamics, surface plasmon resonance, interaction mechanism, BSA nanoparticles, drug delivery systems

Shih-Hung Lin,1 Kao-Jean Huang,1,2 Ching-Feng Weng,1 David Shiuan1 1Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, Republic of China; 2Development Center of Biotechnology, Taipei, Taiwan, Republic of China Abstract: Cholesterol plays an important role in living cells. However, a very high level of cholesterol may lead to atherosclerosis. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase is the key enzyme in the cholesterol biosynthesis pathway, and the statin-like drugs are inhibitors of human HMG-CoA reductase (hHMGR). The present study aimed to virtually screen for potential hHMGR inhibitors from natural product to discover hypolipidemic drug candidates with fewer side effects and lesser toxicities. We used the 3D structure 1HWK from the PDB (Protein Data Bank) database of hHMGR as the target to screen for the strongly bound compounds from the traditional Chinese medicine database. Many interesting molecules including polyphenolic compounds, polisubstituted heterocyclics, and linear lipophilic alcohols were identified and their ADMET (absorption, disrtibution, metabolism, excretion, toxicity) properties were predicted. Finally, four compounds were obtained for the in vitro validation experiments. The results indicated that curcumin and salvianolic acid C can effectively inhibit hHMGR, with IC50 (half maximal inhibitory concentration) values of 4.3 µM and 8 µM, respectively. The present study also demonstrated the feasibility of discovering new drug candidates through structure-based virtual screening. Keywords: HMG-CoA reductase, virtual screening, curcumin, salvianolic acid C

Shu-Her Chiao,1* Siou-Hong Lin,1* Ching-I Shen,2* Jiunn-Wang Liao,3 I-Jiuan Bau,1 Jiun-Chiou Wei,4 Li-Ping Tseng,1 Shan-hui Hsu,4 Ping-Shan Lai,2 Shinn-Zong Lin,5–7 Jiang-Jen Lin,4 Hong-Lin Su,1,8 1Department of Life Sciences, Agricultural Biotechnology Center, National Chung Hsing University, 2Department of Chemistry, Agricultural Biotechnology Center, National Chung Hsing University, 3Graduate Institute of Veterinary Pathobiology, Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan; 4Institute of Polymer Science and Engineering, National Taiwan University, Taipei, Taiwan; 5Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Taiwan; 6Department of Neurosurgery, China Medical University Beigan Hospital, Yunlin, Taiwan; 7Graduate Institute of Immunology, China Medical University, Taichung, Taiwan; 8Department of Physical Therapy, China Medical University, Taichung, Taiwan*These three authors contributed equallyAbstract: Developing effective and safe drugs is imperative for replacing antibiotics and controlling multidrug-resistant microbes. Nanoscale silicate platelet (NSP) and its nanohybrid, silver nanoparticle/NSP (AgNP/NSP), have been developed, and the nanohybrids show a strong and general antibacterial activity in vitro. Here, their efficacy for protecting Salmonella-infected chicks from fatality and septicemia was evaluated. Both orally administrated NSP and AgNP/NSP, but not AgNPs alone, effectively reduced the systemic Salmonella infection and mortality. In addition, quantitative Ag analyses demonstrated that Ag deposition from AgNP/NSP in the intestines was less than that from conventional AgNPs, indicating that the presence of NSP for immobilizing AgNPs reduced Ag accumulation in tissue and improved the safety of AgNPs. These in vivo results illustrated that both NSP and AgNP/NSP nanohybrid represent potential agents for controlling enteric bacterial infections.Keywords: silver, nanoparticle, biocompatibility, infection, cytotoxicity

Abstract Low temperatures are a key factor affecting the growth, development, and geographical distribution of prickly ash. This study investigated the impact of ecological and geographical factors on the freezing tolerance of prickly ash germplasm. Thirty-seven germplasm samples from 18 different origins were collected, and their freezing tolerance was comprehensively evaluated. The correlation between freezing tolerance and the ecological and geographical factors of their origins was also analyzed. Significant differences in freezing tolerance were observed among germplasm from different origins. The semi-lethal temperature of the germplasm ranged from − 12.37 to 1.08 °C. As temperatures decreased, the relative conductivity (REC) and catalase (CAT) activity of the germplasm gradually increased, while soluble sugar (SS), soluble protein (SP), free proline (Pro), and Peroxidase (POD) activities decreased and then increased. Superoxide dismutase (SOD) activity initially increased and then decreased. A comprehensive evaluation of freezing tolerance was conducted using a logistic equation, membership function, and cluster analysis. Germplasm from Tongchuan and Hancheng (Shaanxi Province, China), Asakura (Japan), and Yuncheng (Shanxi Province, China) exhibited the highest freezing tolerance, whereas those from Rongchang (Chongqing Municipality, China), Qujing (Yunnan Province, China), and Honghe (Yunnan Province, China) had the lowest. The correlation analysis revealed a significant positive correlation between freezing tolerance and latitude, and a significant negative correlation with the temperature of origin. Germplasm from higher latitudes showed higher SS content, SOD and CAT activities, stronger antioxidant enzyme activity, and better freezing tolerance compared to those from lower latitudes. REC was lower in germplasm originating from low-temperature areas than in those from high-temperature areas. Additionally, SP, Pro content, SOD, and POD activities were higher, indicating effective scavenging of active oxygen free radicals. No significant correlation was found between altitude and longitude of origin and freezing tolerance. However, at similar latitudes, prickly ash from higher altitudes displayed higher antioxidant enzyme activity and stronger freezing tolerance compared to those from lower altitudes. These findings provide a scientific basis for breeding prickly ash cultivars suited to different ecological regions.

Objective To compare the clinical efficacy and safety of levetiracetam and oxcarbazepine in the treatment of focal epilepsy. Methods A total of 476 patients with focal epilepsy treated at Fujian Provincial Hospital from October 2020 to October 2022 were selected. Based on their medication, they were divided into the levetiracetam group (n = 275) and the oxcarbazepine group (n = 201). Both groups underwent continuous treatment for 12 months. The overall effective rate and incidence of adverse reactions in both groups and different subgroups were analyzed. Results The overall effective rate in the levetiracetam group was 57.82% (159/275), and in the oxcarbazepine group was 46.77% (94/201). The overall effective rate in the levetiracetam group was higher than that in the oxcarbazepine group (χ2 = 5.696, P = 0.017). Efficacy analysis of levetiracetam monotherapy across different age subgroups showed statistically significant differences (χ2 = 6.785, P = 0.034), with the overall effective rate in younger patients being higher than that in minors (χ2 = 3.898, P = 0.048) and middle-aged/older patients (χ2 = 4.946, P = 0.026). Levetiracetam was more effective in patients with initially normal imaging compared to those with abnormal imaging (χ2 = 5.349, P = 0.021). In the oxcarbazepine monotherapy subgroup analysis, oxcarbazepine was also more effective in patients with initially normal imaging (χ2 = 10.036, P = 0.002). Efficacy analysis of the same subgroup with different medications indicated that for younger patients with focal epilepsy, levetiracetam was superior to oxcarbazepine (χ2 = 6.591, P = 0.010). In the levetiracetam group, 13 cases (4.73%) experienced adverse reactions, while the oxcarbazepine group had 19 cases (9.45%). The incidence of adverse reactions in the oxcarbazepine group was higher than that in the levetiracetam group (χ2 = 4.135, P = 0.042). Conclusions Compared to oxcarbazepine monotherapy, levetiracetam monotherapy demonstrated better clinical efficacy in treating focal epilepsy, particularly in younger patients. The incidence of adverse reactions in levetiracetam was lower. Both medications were more effective in patients with initially normal imaging compared to those with abnormal imaging.

Objective To investigate short-term clinical efficacy of autologous leukocyte-poor platelet-rich plasma(LP-PRP) treatment of knee osteoarthritis(KOA). Methods 85 cases of patients with Keligren Lawrence grade Ⅰ-Ⅲ knee osteoarthritis in Peking University First Hospital Taiyuan Hospital (Taiyuan Central Hospital) from 2022 to 2023 were collected for autologous LP-PRP collection and quality assessment using a blood component separator, and all patients were treated with autologous LP-PRP. The degree and function of knee pain were assessed by visual analog scale(VAS) and knee arthritis index scale(WOMAC) at 1, 3 and 6 months after injection. Knee MRI was performed after 6 months of treatment, and the MRI imaging changes before and after treatment were compared. Different influencing factors in the treatment results were grouped and analyzed, mainly including platelet concentration in LP-PRP and K-L grading of knee joint. According to the platelet concentration in LP-PRP, it was divided into three grades, which are low concentration[(1 000)×109/L]; According to the K-L grade of the knee joint, the severity of knee osteoarthritis was divided into three grades: Ⅰ、Ⅱ、Ⅲ. Results The VAS and WOMAC scores at 1, 3 and 6 months after LP-PRP treatment were significantly lower than those before treatment, and the difference was statistically significant (P

Abstract Synaptojanin 2 (SYNJ2) has crucial role in various tumors, but its role in papillary thyroid carcinoma (PTC) remains unexplored. This study first detected SYNJ2 protein expression in PTC using immunohistochemistry method and further assessed SYNJ2 mRNA expression through mRNA chip and RNA sequencing data and its association with clinical characteristics. Additionally, KEGG, GSVA, and GSEA analyses were conducted to investigate potential biological functions, while single‐cell RNA sequencing data were used to explore SYNJ2's underlying mechanisms in PTC. Meanwhile, immune infiltration status in different SYNJ2 expression groups were analyzed. Besides, we investigated the immune checkpoint gene expression and implemented drug sensitivity analysis. Results indicated that SYNJ2 is highly expressed in PTC (SMD = 0.66 [95% CI: 0.17–1.15]) and could distinguish between PTC and non‐PTC tissues (AUC = 0.74 [0.70–0.78]). Furthermore, the study identified 134 intersecting genes of DEGs and CEGs, mainly enriched in the angiogenesis and epithelial‐mesenchymal transition (EMT) pathways. Subsequent analysis showed the above pathways were activated in PTC epithelial cells. PTC patients with high SYNJ2 expression showed higher sensitivity to the six common drugs. Summarily, SYNJ2 may promote PTC progression through angiogenesis and EMT pathways. High SYNJ2 expression is associated with better response to immunotherapy and chemotherapy.

Abstract. Background:. While some studies have reported the impact of COVID-19 vaccines on immune recovery and human immunodeficiency virus (HIV) reservoirs in persons living with HIV (PLWH), their findings remain inconsistent. Furthermore, limited data exist on the safety of multiple COVID-19 vaccines among PLWH. This study aimed to investigate the safety of heterological COVID-19 vaccine administration in PLWH receiving antiretroviral treatment (ART) and its effects on HIV reservoirs and immune recovery. Such an investigation can help provide a basis for vaccinations against COVID-19 in PLWH. Methods:. In this cross-sectional study, PLWH receiving ART were recruited from the outpatient clinic of the Department of Infectious Diseases at the Fifth Medical Center of the Chinese PLA General Hospital from September 1, 2021 to December 31, 2021. Fifty-three PLWH receiving ART were vaccinated against COVID-19, with 35 receiving an inactivated vaccine (IN group) and 18 receiving a recombinant protein (CHO cells) vaccine (CHO group) as the third dose. We assessed the changes in liver and kidney functions, blood lipids, and other laboratory parameters at 0, 1, 2, 4, 7, 8, 10, and 13 months after the first vaccination dose. We also monitored CD4+ and CD8+ T cell counts using flow cytometry at 0, 1, 2, 4, 7, 8, 10, and 13 months after the first vaccination dose, as well as levels of cell-associated HIV DNA (CA HIV DNA) and cell-associated HIV RNA (CA HIV RNA) in peripheral blood using the corresponding quantitative detection kits at 0, 2, and 8 months after the first vaccination dose. Results:. No severe adverse events related to either type of COVID-19 vaccine were observed in HIV patients, irrespective of their CD4+ T cell levels. Both the IN and CHO groups showed significant increases in CD4+ T cell counts during follow-up, CD4+ T cells increased from 438 ± 45 cells/μL to 557 ± 48 cells/μL in the CHO group, while in the IN group, it increased from 448 ± 34 cells/μL to 572 ± 39 cells/μL (both P < 0.001). CA HIV DNA initially decreased and then increased in both groups. CA HIV RNA levels showed significantly decreased in both group after three doses of vaccination (P < 0.01 in CHO group and P < 0.001 in IN group). CD8+ T cells increased from 608 ± 77 cells/μL to 812 ± 116 cells/μL in the CHO group (P < 0.01), while in the IN group, it increased from 702 ± 71 cells/μL to 852 ± 68 cells/μL(P < 0.001) from baseline to the 13 month of following up. Conclusion:. Our data suggest that the SARS-CoV-2 booster vaccine is safe for PLWH on ART, although it may affect HIV reservoirs and CD8+ T cell counts.

Abstract Biocatalysis is an attractive approach for the synthesis of chiral pharmaceuticals and fine chemicals, but assessing and/or improving the enantioselectivity of biocatalyst towards target substrates is often time and resource intensive. Although machine learning has been used to reveal the underlying relationship between protein sequences and biocatalytic enantioselectivity, the establishment of substrate fitness space is usually disregarded by chemists and is still a challenge. Using 240 datasets collected in our previous works, we adopt chemistry and geometry descriptors and build random forest classification models for predicting the enantioselectivity of amidase towards new substrates. We further propose a heuristic strategy based on these models, by which the rational protein engineering can be efficiently performed to synthesize chiral compounds with higher ee values, and the optimized variant results in a 53-fold higher E-value comparing to the wild-type amidase. This data-driven methodology is expected to broaden the application of machine learning in biocatalysis research.

Abstract The pathophysiology of immune checkpoint inhibitor-related pneumonitis remains incompletely understood. We conducted single-cell and T-cell receptor transcriptomic sequencing on the bronchoalveolar lavage fluid from five patients with grade ≥2 immune checkpoint inhibitor-related pneumonitis. Our analyses revealed a prominent enrichment of T cells in the bronchoalveolar lavage fluid of patients with immune checkpoint inhibitor-related pneumonitis. Within the CD4 + T cell subset, Tfh-like T cells were highly enriched and exhibited signatures associated with inflammation and clonal expansion. Regulatory T cells were also enriched and displayed enhanced inhibitory functions. Within the CD8 + T-cell subset, effector memory/tissue-resident memory T cells with an elevated cytotoxic phenotype were highly infiltrated. Among myeloid cells, alveolar macrophages were depleted, while pro-inflammatory intermediate monocytes were elevated. Dendritic cells demonstrated enhanced antigen presentation capabilities. Cytokines CXCR4, CXCL13, TNF-α, IFN-α, IFN-γ, and TWEAK were elevated. Through a comprehensive single-cell analysis, we depicted the landscape of immune checkpoint inhibitor-related pneumonitis.

Abstract Most advanced lung adenocarcinoma (LUAD) patient deaths are attributed to metastasis. However, the complete understanding of the metastatic mechanism in LUAD remains elusive. Single-cell RNA-seq (scRNA-seq), spatial RNA-seq (stRNA-seq) and bulk RNA-seq of primary LUAD were integrated to investigate metastatic driver genes, cell–cell interactions, and spatial colocalization of cells and ligand-receptor pairs. A lung adenocarcinoma metastasis risk scoring model (LMRS) was established to estimate the risk of metastasis in LUAD. Forty-two metastasis driver genes were identified and tumor epithelial cells were classified into two subtypes. Epithelial cell subclass characterized by susceptibility to metastasis are referred to as Epithelial_LM, and the remaining as Epithelial_LL. Epithelial_LM subtype has intimate ligand-receptor interactions with inflammatory endothelial cells (iendo), inflammatory cancer-associated fibroblasts (iCAF), and NKT cells. Epithelial_LM cells have a spatial colocalization relationship with these three types of cells. The LMRS was established and its efficacy was verified in bulk RNA-seq. We identified a subclass of epithelial cells prone to metastasis and demonstrated the contribution of inflammatory stromal cells and NKT cells in facilitating tumor metastasis. Graphical Abstract

Abstract Metabolic reprogramming, a key mechanism regulating the growth and recurrence of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), still lacks effective clinical strategies for its integration into the precise screening of primary liver cancer. This study utilized ultra-high-performance liquid chromatography with quadrupole time-of-flight mass spectrometry to conduct a comprehensive, non-targeted metabolomics analysis, revealing significant upregulation of lipid metabolites such as phosphatidylcholine and lysophosphatidylcholine in patients with HCC and CCA, particularly within the glycerophospholipid metabolic pathway. Hematoxylin and eosin and immunohistochemical staining demonstrated marked upregulation of phospholipase A2 in tumor tissues, further emphasizing the potential of lipid metabolism as a therapeutic target and its important part in the course of cancer. This work provides a new viewpoint for addressing the clinical challenges associated with HCC and CCA, laying the groundwork for the broad application of early diagnosis and personalized treatment strategies, and ultimately aiming to provide tailored and precise therapeutic options for patients.

Abstract Although histological and molecular classifications have been extensively studied for gastric cancer (GC), targeted therapies for GC remain limited. CDH1 mutations (MT) are characteristic of genomically stable GC and are associated with poor prognosis, but lack effective or targeted therapies. Here, we showed the overall mutation frequency of CDH1 was 9.7% (155 of 1596). CDH1-MT GC showed significantly lower rates of PD-L1 positivity (CPS score ≥1) than CDH1-wildtype (WT) GC (56.7% vs. 73.3%, p

Abstract The ecological compensation mechanism is a tool for managing regional development and promoting the green economy. This paper proposes a revised model for carbon emissions and absorption based on IPCC, then analyses the spatial and temporal variations of carbon emissions, absorption, and deficit in 31 provinces of China from 2001 to 2019. A model was developed to redistribute carbon deficits and compensate for ecological imbalances, with the aim of eliminating background differences between regions. The concept of ecological compensation sensitivity was proposed, and a redundancy analysis (RDA) was conducted to detect possible influencing factors. Results indicate that: (1) The carbon deficits were relatively substantial in the centre and developed coastal regions, which were the subject regions of China’s ecological compensation. Meanwhile, the northwest and southwest regions were the object regions of ecological compensation, and the compensated object regions tended to extend towards the southeast. The majority of compensated subject areas are generally less sensitive than compensated object regions. (2) The graph of carbon deficit volume over time shows that China’s two carbon targets are closely aligned. The distribution of China’s ecological compensation amounts follows the pattern of provincial economic development levels, with higher compensation amounts concentrated in the central and coastal regions. There is a positive correlation between GDP, year, and population size with carbon emission and carbon deficit. Additionally, there is a positive correlation between year, region, and carbon absorption. (3) This compensation model can strongly incentivise the compensation subject area to proactively adjust its economic development model to cope with the significant compensation pressure. Additionally, it can fully encourage the compensation recipient area to continue adhering to the green economic development model. The conclusions of the study hold significant reference value for promoting the development of a green, low-carbon economy.

The fibroblast growth factor receptor (FGFR) is a crucial receptor tyrosine kinase involved in essential biological processes, including growth, development, and tissue repair. However, FGFR gene mutations, including amplification, fusion, and mutation, can disrupt epigenetics, transcriptional regulation, and tumor microenvironment interactions, leading to cancer development. Targeting these kinase mutations with small molecule drugs or antibodies has shown clinical benefits. For example, erdafitinib is approved for treating locally advanced or metastatic urothelial cancer patients with FGFR2/FGFR3 mutations, and pemigatinib is approved for treating cholangiocarcinoma with FGFR2 fusion/rearrangement. Effective screening of FGFR variant patients is crucial for the clinical application of FGFR inhibitors. Various detection methods, such as polymerase chain reaction, next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry, are available, and their selection should be based on diagnostic and treatment decision-making needs. Our developed expert consensus aims to standardize the diagnosis and treatment process for FGFR gene mutations and facilitate the practical application of FGFR inhibitors in clinical practice.

Abstract This study aimed to reveal the diversity and variation in panicle traits of the Chinese prickly ash and clarify their influence on the its systematic classification to provide a theoretical basis and technical support for the efficient utilization of Chinese prickly ash germplasm resources and breeding. Sixteen panicle traits were identified from 35 Chinese prickly ash germplasm resources from 2021 to 2022. The diversity of these panicle traits and their role in the plant’s systematic classification were studied using variance, correlation, cluster, and principal component analyses. Cluster analysis showed that the 35 Chinese prickly ash germplasm resources could be divided into two groups with Euclidean distances of 25. Further analysis showed that yield traits such as panicle length, panicle width, primary branching, grain number per panicle, and grain weight per panicle were significantly positively correlated with grain chlorophyll content, while grain anthocyanin content was negatively correlated with both panicle (panicle length, panicle width, panicle length to width ratio, primary branching, grain number per panicle, and grain weight per panicle) and grain characteristics (single grain weight, thousand-grain weight, grain length, grain width and fruit shape index). In conclusion, Chinese prickly ash germplasms have diverse panicle traits. Z. armatum has dark green grains, long and wide panicles, a long conical shape, many primary branches, high grain weight, and high grain number per panicle. In contrast, Z. bungeanum has bright red seeds, a panicle width larger than its length, short and conical panicles, a small number of primary branches, and low grain weight per panicle and number of grains per panicle. Overall, Z. armatum had a significant yield advantage over Z. bungeanum.

Abstract The sole use of single modality data often fails to capture the complex heterogeneity among patients, including the variability in resistance to anti-HER2 therapy and outcomes of combined treatment regimens, for the treatment of HER2-positive gastric cancer (GC). This modality deficit has not been fully considered in many studies. Furthermore, the application of artificial intelligence in predicting the treatment response, particularly in complex diseases such as GC, is still in its infancy. Therefore, this study aimed to use a comprehensive analytic approach to accurately predict treatment responses to anti-HER2 therapy or anti-HER2 combined immunotherapy in patients with HER2-positive GC. We collected multi-modal data, comprising radiology, pathology, and clinical information from a cohort of 429 patients: 310 treated with anti-HER2 therapy and 119 treated with a combination of anti-HER2 and anti-PD-1/PD-L1 inhibitors immunotherapy. We introduced a deep learning model, called the Multi-Modal model (MuMo), that integrates these data to make precise treatment response predictions. MuMo achieved an area under the curve score of 0.821 for anti-HER2 therapy and 0.914 for combined immunotherapy. Moreover, patients classified as low-risk by MuMo exhibited significantly prolonged progression-free survival and overall survival (log-rank test, P

Abstract Background Chronic kidney disease (CKD) is the third most common cause of death after cancer and heart disease. The continuous treatment of children with CKD was greatly challenged during the COVID-19 pandemic, which significantly impacted the CKD children’s prognosis and the caregivers’ psychological status. However, the influence mechanism of socioeconomic status, medical delay duration, traffic pressure, and online consultation duration on caregivers’ hope and psychological resilience still lacks relevant evidence. Methods This study investigated the general social information, hope, and psychological resilience of 247 caregivers with CKD in 13 provinces of China in March 2020. Factor analysis and an exploratory Structural Equation Model ( SEM ) were used to find the best-fit model, and Bootstrapping was used to calculate the 95% CI of indirect effects. Results The factor analysis obtained four common factors, namely, socioeconomic status (annual family income, education, and career stability), medical accessibility (online consultation duration, medical delay duration, and traffic pressure), hope (positive attitude, positive action, and intimate relationship) and psychological resilience (optimism, tenacity, and strength), with the cumulative contribution rate of 65.34%. Bootstrapping obtains the socioeconomic status β = 0.30 (95% CI [0.14, 0.47], P = 0.002), medical accessibility β = 0.31 (95% CI [0.12, 0.47], P = 0.002), and hope β = 0.40 (95% CI [0.27, 0.52], P = 0.002) has a direct impact on psychological resilience of CKD children caregivers, followed by medical accessibility β = 0.20 (95% CI [0.10, 0.38], P = 0.001) and hope β = 0.23 (95% CI [0.16, 0.32], P = 0.001) plays a mediating role between socioeconomic status and psychological resilience. The indirect impact effect β = 0.35 (95% CI [0.25, 0.50], P = 0.001) is greater than the direct impact effect β = 0.30 (95% CI [0.14, 0.47], P = 0.002). Conclusions Sufficient attention should still be given to children with immunodeficiency after the COVID-19 pandemic, such as CKD, to avoid infection of deadly. Secondly, the government should vigorously develop Primary medical institutions to ensure efficient treatment of severe patients in tertiary hospitals; Finally, the professional literacy of medical workers in remote diagnosis and treatment should be improved to enhance the country’s emergency response capacity for similar major public events and the requirements for normalised epidemic prevention and control.

Abstract In the KEYNOTE-811 study, anti-HER2 and immunotherapy treatments resulted in longer survival in HER2-positive gastric cancer patients with CPS ≥ 1, whereas CPS

Abstract The ceiling structure in a long-narrow space has a significant impact on the thickness of the fire smoke layer. This paper mainly studies the influence of the height of the ceiling structure on the thickness of the smoke layer before the ceiling structure. Firstly, a theoretical analysis is conducted on the relationship between the critical thickness that affects the smoke flow state and the smoke layer thickness directly below the ceiling structure, and a formula for calculating the smoke layer thickness under gradient flow conditions is derived. Then a small-scale experimental platform was built to study the deviation of actual fire smoke relative to theoretical calculations. Experimental results show that due to the smoke cannot maintain gradient flow when crossing the ceiling structure, there is difference with theoretical calculations in the smoke layer thickness directly below the ceiling structure and some distance before the ceiling structure (which may be of greater concern for personnel evacuation). The gradient flow coefficient and thickness coefficient are defined to represent the above differences. After analysis, it was found that the gradient flow coefficient and thickness coefficient showed different linear variation patterns when the height of the ceiling structure was longer than 35 cm or shorter than 30 cm. Through numerical analysis, this study suggests that the main reason for the change in this linear pattern is whether the potential energy conversed from kinetic energy of the thin layer close to the ceiling structure can directly make the smoke to cross the ceiling structure. The research conclusions of this paper can assist in the engineering design of building smoke control and personnel evacuation.

Abstract Background Despite recent advances the prognosis of pulmonary hypertension remains poor and warrants novel therapeutic options. Extensive studies, including ours, have revealed that hypoxia-induced pulmonary hypertension is associated with high oxidative stress. Cerium oxide nanozyme or nanoparticles (CeNPs) have displayed catalytic activity mimicking both catalase and superoxide dismutase functions and have been widely used as an anti-oxidative stress approach. However, whether CeNPs can attenuate hypoxia-induced pulmonary vascular oxidative stress and pulmonary hypertension is unknown. Results In this study, we designed a new ceria nanozyme or nanoparticle (AuCeNPs) exhibiting enhanced enzyme activity. The AuCeNPs significantly blunted the increase of reactive oxygen species and intracellular calcium concentration while limiting proliferation of pulmonary artery smooth muscle cells and pulmonary vasoconstriction in a model of hypoxia-induced pulmonary hypertension. In addition, the inhalation of nebulized AuCeNPs, but not CeNPs, not only prevented but also blunted hypoxia-induced pulmonary hypertension in rats. The benefits of AuCeNPs were associated with limited increase of intracellular calcium concentration as well as enhancement of extracellular calcium-sensing receptor (CaSR) activity and expression in rat pulmonary artery smooth muscle cells. Nebulised AuCeNPs showed a favorable safety profile, systemic arterial pressure, liver and kidney function, plasma Ca2+ level, and blood biochemical parameters were not affected. Conclusion We conclude that AuCeNPs is an improved reactive oxygen species scavenger that effectively prevents and treats hypoxia-induced pulmonary hypertension. Graphical Abstract

Abstract 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.

Abstract Purpose of review Atherosclerosis, a highly pathogenic and lethal disease, is difficult to locate accurately via conventional imaging because of its scattered and deep lesions. However, second near-infrared (NIR-II) nanomaterials show great application potential in the tracing of atherosclerotic plaques due to their excellent penetration and angiographic capabilities. Recent findings With the development of nanotechnology, among many nanomaterials available for the visual diagnosis and treatment of cardiovascular diseases, optical nanomaterials provide strong support for various biomedical applications because of their advantages, such as noninvasive, nondestructive and molecular component imaging. Among optical nanomaterials of different wavelengths, NIR-II-range (900 ~ 1700 nm) nanomaterials have been gradually applied in the visual diagnosis and treatment of atherosclerosis and other vascular diseases because of their deep biological tissue penetration and limited background interference. Summary This review explored in detail the prospects and challenges of the biological imaging and clinical application of NIR-II nanomaterials in treating atherosclerosis. Graphical abstract

Abstract Eleocharis dulcis (Burm. f.) Trin. ex Hensch., commonly known as Chinese water chestnut, is a traditional aquatic vegetable in China, and now is widely cultivated throughout the world because of its high nutritional value and unique tastes. Here, we report the assembly of a 493.24 Mb telomere-to-telomere (T2T) genome of E. dulcis accomplished by integrating ONT ultra-long reads, PacBio long reads and Hi-C data. The reference genome was anchored onto 111 gap-free chromosomes, containing 48.31% repeat elements and 33,493 predicted protein-coding genes. Whole genome duplication (WGD) and inter-genomic synteny analyses indicated that chromosome breakage and genome duplication in E. dulcis possibly occurred multiple times during genome evolution after its divergence from a common ancestor with Rhynchospora breviuscula at ca. 35.6 Mya. A comparative time-course transcriptome analysis of corm development revealed different patterns of gene expression between cultivated and wild accessions with the highest number of differentially expressed genes (DEGs, 15,870) at the middle swelling stage and some of the DEGs were significantly enriched for starch metabolic process.

Abstract Major strike-slip faults that develop between strong and weaker regions are thought to focus along narrow shear zones at the rheological boundary. Here we present the InSAR-derived velocity field spanning almost the entire length of one such fault, the 1600 km-long Altyn Tagh Fault (ATF), and analyse the strain distribution. We find that localisation of strain is actually variable, in contrast to other major strike-slip faults that show little variation, with strain concentrated at the fault for some sections and distributed over broad (>100 km) shear zones for others. Slip rate along the ATF is also variable, decreasing along the fault from 11.6 ± 1.6 mm/yr in the west to 7.2 ± 1.4 mm/yr in the central portion, before increasing again to 11.7 ± 0.9 mm/yr over the eastern portion. We show that the variable shear zone width may be linked to geological variability and the influence of heat flow, and the results imply that sub-parallel faults play an important role in the overall deformation field. This demonstrates the significance of accurately characterising strain rates over a broad region when assessing seismic hazard.

Abstract The past few decades have witnessed the rise of immunotherapy for Gastrointestinal (GI) tract cancers. The role of immune checkpoint inhibitors (ICIs), particularly programmed death protein 1 (PD-1) and PD ligand-1 antibodies, has become increasingly pivotal in the treatment of advanced and perioperative GI tract cancers. Currently, anti-PD-1 plus chemotherapy is considered as first-line regimen for unselected advanced gastric/gastroesophageal junction adenocarcinoma (G/GEJC), mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC), and advanced esophageal cancer (EC). In addition, the encouraging performance of claudin18.2-redirected chimeric antigen receptor T-cell (CAR-T) therapy in later-line GI tract cancers brings new hope for cell therapy in solid tumour treatment. Nevertheless, immunotherapy for GI tumour remains yet precise, and researchers are dedicated to further maximising and optimising the efficacy. This review summarises the important research, latest progress, and future directions of immunotherapy for GI tract cancers including EC, G/GEJC, and CRC.

Objective: This study evaluated the safety and efficacy of an anti-epidermal growth factor receptor (EGFR) antibody (SCT200) and an anti-programmed cell death 1 (PD-1) antibody (SCT-I10A) as third-line or subsequent therapies in patients with rat sarcoma viral oncogene (RAS)/v-raf murine sarcoma viral oncogene homolog B (BRAF) wild-type (wt) metastatic colorectal cancer (mCRC). Methods: We conducted a multicenter, open-label, phase Ib clinical trial. Patients with histologically confirmed RAS/BRAF wt mCRC with more than two lines of treatment were enrolled and treated with SCT-I10A and SCT200. The primary endpoints were the objective response rate (ORR) and safety. The secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results: Twenty-one patients were enrolled in the study through January 28, 2023. The ORR was 28.57% and the DCR was 85.71% (18/21). The median PFS and OS were 4.14 and 12.84 months, respectively. The treatment-related adverse events (TRAEs) were tolerable. Moreover, compared with the monotherapy cohort from our previous phase I study evaluating SCT200 for RAS/BRAF wt mCRC in a third-line setting, no significant improvements in PFS and OS were observed in the combination group. Conclusions: SCT200 combined with SCT-I10A demonstrated promising efficacy in previously treated RAS/BRAF wt mCRC patients with an acceptable safety profile. Further head-to-head studies with larger sample sizes are needed to validate whether the efficacy and safety of combined anti-EGFR and anti-PD-1 therapy are superior to anti-EGFR monotherapy in the third-line setting. (Registration No. NCT04229537).

Abstract Immunoinflammation is associated with the development of post-stroke cognitive impairment (PSCI), however, peripheral immunity has not been fully explored. We aimed to investigate the association between PSCI and peripheral immune indicators, including neutrophil, lymphocyte, and mononuclear percentages and counts; the systemic immune inflammation index; platelet-to-lymphocyte ratio; neutrophil-to-lymphocyte ratio (NLR); and lymphocyte-to-monocyte ratio. A total of 224 patients with acute minor ischemic stroke or transient ischemic attack with 6–12 months of follow-up were included. PSCI was defined as a Montreal Cognitive Assessment score

The World Health Organization (WHO) 2017 classifications for neuroendocrine neoplasms (NENs) subdivided grade 3 pancreatic neuroendocrine neoplasms (pNENs) into G3 well-differentiated pancreatic neuroendocrine tumors (G3 pNETs) and poorly differentiated pancreatic neuroendocrine carcinomas (pNECs), according to the mitotic count, Ki-67 index, and cell differentiation. As a new category, G3 pNETs remain a challenging group of tumors to manage by lacking large randomized trials and consensus to support its clinical practice. Therefore, the Chinese Pancreatic Surgery Association, Chinese Society of Surgery, Chinese Medical Association gathered experts in this field to formulate this consensus for the diagnosis and treatment of G3 pNETs.

Abstract Radiation‐induced heart disease (RIHD) is a heterogeneous, delayed, and potentially fatal adverse reaction to radiation that can damage all structures of the heart, including the pericardium, myocardium, coronary arteries, valves, and conduction system, leading to a series of diseases. Acute and chronic disease processes play a role in the development of RIHD, the onset times of which range from months to decades. However, the clinical manifestations of RIHD are usually insidious, overlap with several other diseases, and lack specificity. Cardiovascular imaging is essential for early diagnosis, follow‐up, and outcome assessment in patients with RIHD. This review first describes the pathogenesis and clinical manifestations of RIHD before providing an overview of the practical approaches and research advances in multimodal cardiovascular imaging in patients with RIHD, including echocardiography, cardiac magnetic resonance (CMR) and nuclear medicine, and cardiac computed tomography (CT). Then, the value of new cardiac imaging assessments for the early diagnosis of RIHD is described, particularly with relation to speckle‐tracking echocardiography, extracellular volume fraction assessment as a quantitative CMR technique, CMR myocardial strain assessment, positron emission tomography‐CT myocardial perfusion imaging, CT‐ECV, and CT strain assessment, amongst others. In addition, the advantages and disadvantages of each screening technique are compared with the aim of better guiding the follow‐up and diagnosis of subclinical RIHD and preventing cardiovascular events.

Abstract Purpose The objective of this study was to provide a comprehensive review of the existing literature regarding the treatment of osteochondral lesions of the talus (OLT) using autologous matrix-induced chondrogenesis (AMIC), while also discussing the mid-long term functional outcomes, complications, and surgical failure rate. Methods We searched Embase, PubMed, and Web of Science for studies on OLT treated with AMIC with an average follow-up of at least 2 years. Publication information, patient data, functional scores, surgical failure rate, and complications were extracted. Results A total of 15 studies were screened and included, with 12 case series selected for meta-analysis and 3 non-randomized controlled studies chosen for descriptive analysis. The improvements in the Visual Analog Scale (VAS), the American Orthopaedic Foot & Ankle Society (AOFAS) ankle-hindfoot, and Tegner scores at the last follow-up were (SMD = − 2.825, 95% CI − 3.343 to − 2.306, P

Abstract Background Mediterranean diet rich in polyphenolic compounds holds great promise to prevent and alleviate multiple sclerosis (MS), a central nervous system autoimmune disease associated with gut microbiome dysbiosis. Health-promoting effects of natural polyphenols with low bioavailability could be attributed to gut microbiota reconstruction. However, its underlying mechanism of action remains elusive, resulting in rare therapies have proposed for polyphenol-targeted modulation of gut microbiota for the treatment of MS. Results We found that oral ellagic acid (EA), a natural polyphenol rich in the Mediterranean diet, effectively halted the progression of experimental autoimmune encephalomyelitis (EAE), the animal model of MS, via regulating a microbiota-metabolites-immunity axis. EA remodeled the gut microbiome composition and particularly increased the relative abundances of short-chain fatty acids -producing bacteria like Alloprevotella. Propionate (C3) was most significantly up-regulated by EA, and integrative modeling revealed a strong negative correlation between Alloprevotella or C3 and the pathological symptoms of EAE. Gut microbiota depletion negated the alleviating effects of EA on EAE, whereas oral administration of Alloprevotella rava mimicked the beneficial effects of EA on EAE. Moreover, EA directly promoted Alloprevotella rava (DSM 22548) growth and C3 production in vitro. The cell-free supernatants of Alloprevotella rava co-culture with EA suppressed Th17 differentiation by modulating acetylation in cell models. C3 can alleviate EAE development, and the mechanism may be through inhibiting HDAC activity and up-regulating acetylation thereby reducing inflammatory cytokines secreted by pathogenic Th17 cells. Conclusions Our study identifies EA as a novel and potentially effective prebiotic for improving MS and other autoimmune diseases via the microbiota-metabolites-immunity axis. Video Abstract

Abstract Epidermal growth factor receptor (EGFR) is reportedly overexpressed in most esophageal squamous cell carcinoma (ESCC) patients, but anti-EGFR treatments offer limited survival benefits. Our preclinical data showed the promising antitumor activity of afatinib in EGFR-overexpressing ESCC. This proof-of-concept, phase II trial assessed the efficacy and safety of afatinib in pretreated metastatic ESCC patients (n = 41) with EGFR overexpression (NCT03940976). The study met its primary endpoint, with a confirmed objective response rate (ORR) of 39% in 38 efficacy-evaluable patients and a median overall survival of 7.8 months, with a manageable toxicity profile. Transcriptome analysis of pretreatment tumors revealed that neurotrophic receptor tyrosine kinase 2 (NTRK2) was negatively associated with afatinib sensitivity and might serve as a predictive biomarker, irrespective of EGFR expression. Notably, knocking down or inhibiting NTRK2 sensitized ESCC cells to afatinib treatment. Our study provides novel findings on the molecular factors underlying afatinib resistance and indicates that afatinib has the potential to become an important treatment for metastatic ESCC patients.

Abstract CD8+ T cell immune responses are regulated by multi-layer networks, while the post-translational regulation remains largely unknown. Transmembrane ectodomain shedding is an important post-translational process orchestrating receptor expression and signal transduction through proteolytic cleavage of membrane proteins. Here, by targeting the sheddase A Disintegrin and Metalloprotease (ADAM)17, we defined a post-translational regulatory mechanism mediated by the ectodomain shedding in CD8+ T cells. Transcriptomic and proteomic analysis revealed the involvement of post-translational regulation in CD8+ T cells. T cell-specific deletion of ADAM17 led to a dramatic increase in effector CD8+ T cell differentiation and enhanced cytolytic effects to eliminate pathogens and tumors. Mechanistically, ADAM17 regulated CD8+ T cells through cleavage of membrane CD122. ADAM17 inhibition led to elevated CD122 expression and enhanced response to IL-2 and IL-15 stimulation in both mouse and human CD8+ T cells. Intriguingly, inhibition of ADAM17 in CD8+ T cells improved the efficacy of chimeric antigen receptor (CAR) T cells in solid tumors. Our findings reveal a critical post-translational regulation in CD8+ T cells, providing a potential therapeutic strategy of targeting ADAM17 for effective anti-tumor immunity.

Gastric cancer is among the most frequently occurring cancers and a leading cause of cancer-related deaths globally. Because gastric cancer is highly heterogenous and comprised of different subtypes with distinct molecular and clinical characteristics, the management of gastric cancer calls for better-defined, biomarker-guided, molecular-based treatment strategies. MET is a receptor tyrosine kinase mediating important physiologic processes, such as embryogenesis, tissue regeneration, and wound healing. However, mounting evidence suggests that aberrant MET pathway activation contributes to tumour proliferation and metastasis in multiple cancer types, including gastric cancer, and is associated with poor patient outcomes. As such, MET-targeting therapies are being actively developed and promising progress has been demonstrated, especially with MET tyrosine kinase inhibitors. This review aims to briefly introduce the role of MET alterations in gastric cancer and summarize in detail the current progress of MET tyrosine kinase inhibitors in this disease area with a focus on savolitinib, tepotinib, capmatinib, and crizotinib. Building on current knowledge, this review further discusses existing challenges in MET alterations testing, possible resistance mechanisms to MET inhibitors, and future directions of MET-targeting therapies.

Abstract A method has been developed to increase computational efficiency in Monte Carlo simulations of electron transport and interactions in matter. The method serves as the computational engine for the open-source code AMCSET (Aggie Monte Carlo Simulations of Electron and Ion Transport). The key is to combine n consecutive neighboring free flying distances into groups. Within each group, both flying distance and Mott scattering angles are obtained using Monte Carlo sampling under an equal energy approximation. This reduces the number of integrations of the tabulated differential Mott scattering cross-section in scattering angle selection, i.e., from 1000 to 1 if n = 1000. The method increases efficiency by more than 100 times. At the same time, the calculation still guarantees accuracy in calculating electron trajectory, excitation/ionization energy deposition, elastic scattering energy deposition, and displacement creation. For demonstration, 10 MeV electron bombardments of pure Fe with n up to 1000 are used as examples. The method, due to the availability of tabulated scattering cross-sections, is applicable for targets of the entire elemental table up to Z = 118, and for electron energies up to 900 MeV.