bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ubiquitin ligase subunit FBXO9 inhibits V-ATPase assembly and lung cancer metastasis.
Authors: Liu Liang , Chen Xiaodong , Huang Kaizong , Wang Zhenyi , Zheng Yaolin , Zheng Cheng , Zhang Zhenshan , Wei Dongping , Yaping Xu 
Published: July 2024

e20520 Background: The evolutionarily conserved protein FBXO9 acts as a substrate receptor for the SKP1-cullin-1-RBX1 ubiquitin ligase and is implicated in cancer, exhibiting either tumor-suppressive or oncogenic effects depending on the specific tumor type. However, their role in lung cancer metastasis remains unclear. Methods: Lentiviral vectors carrying miRNA-based shRNA sequences for gene-specific knockdown were generated, and Lenti-CRISPR-Cas9 vectors containing gene-specific sgRNA sequences were designed. Gene overexpression was achieved using doxycycline-inducible lentiviral constructs, while gene knockdown or knockout cells were generated using shRNA and CRISPR-Cas9, respectively. Functional assays included migration, clonogenic survival assays, tumor sphere assays, and protein interaction studies using mass spectrometry, immunoprecipitation, and immunoblot analysis. Results: This study identified FBXO9 as a crucial regulator that suppresses lung cancer cell migration, tumor sphere growth and restricts metastasis. We showed that FBXO9 facilitates the ubiquitination of the catalytic subunit A (ATP6V1A) of the Vacuolar-type H+-ATPase (V-ATPase), resulting in its interaction with the cytoplasmic chaperone HSPA8 and subsequent sequestration within the cytoplasm. This process hinders the assembly of functional V-ATPase, resulting in reduced vesicular acidification. In contrast, depletion of FBXO9 reduced ATP6V1A ubiquitination, resulting in increased V-ATPase assembly and vesicular acidification, thus promoting pro-metastatic Wnt signaling and metastasis of lung cancer cells. Furthermore, we demonstrated the effectiveness of inhibitors targeting V-ATPase in inhibiting lung cancer metastasis in a mouse model. Finally, we established a correlation between lower FBXO9 levels and poorer survival outcomes in patients with lung cancer. Conclusions: These findings collectively elucidate the critical role of FBXO9 in regulating V-ATPase assembly and provide a molecular basis for FBXO9's function in inhibiting lung cancer metastasis. This highlights the potential therapeutic opportunities of FBXO9 supplementation.
Implementing personalized lung cancer care with spatial profiling, patient derived organoids, and rationally designed drug testing.
Authors: Pine Sharon R. , Watson Alexander S. , Patil Tejas , Schenk Erin L. , Merrick Daniel , Camidge David Ross , Sabaawy Hatim E. 
Published: July 2024

e20521 Background: Lung cancer (LC) remains the leading cause of cancer-related death in 2024, with most LC diagnoses with non-small cell lung cancer (NSCLC) subtype. Tyrosine kinase inhibitors (TKI) and targeted therapy against oncogenic drivers (KRAS, EGFR, or ALK fusions, others) are effective initial therapies; however, nearly all treated patients eventually develop resistance to therapy. Key reasons are the focus on limited predictive biomarkers and lack of patient derived LC models that reflect the underlying heterogeneity and the various phenotypic cell states among subclones within and between patients. Methods: We report the establishment of a novel platform for personalized LC care by refining the resolution of molecular interrogation of diagnostic and resistance biopsies to the single cell level, and with spatial profiling using single cell spatial multiomic (scSpMO) and coupling these enhanced diagnostic tools with functional validation with rational designed drug screens in patient-derived organoids (PDOs). Results: For deriving LC PDOs in epithelial and tumor microenvironment (TME) conditions to faithfully maintain the histological and genetic features of their respective LC tissues, we developed enrichment conditions for LC PDOs guided by tumor mutation variants and activated pathways. PDOs are maintained under the same treatment condition in the clinic (e.g., Lorlatinib) and drug testing is tailored to identify potentially most effective next lines of therapy. With nine patients enrolled and others in ongoing studies, single cell PDOs (at > 80% establishment rate) were used to determine activated pathways, lineage plasticity and acquired resistance. Functional assays for acquired resistance such as PI3K/AKT signaling, Src kinase, BRAF fusion and MET hyperactivity allow the identification of potentially novel lines of therapy and treatment sequence and/or combinations for each patient, through the compassionate care program and/or trial participation. Conclusions: Our platform when empowered by combining datasets from scRNA-seq and scSpMO signatures, with validated functional drug responses in PDOs, offers the ability to perform high-content assays, predict and/or act on resistance to therapy for each patient, and provides a path for precision medicine-guided impact on patient care.
Using machine learning approach based on gene expression profiling to predict the risk of bone metastasis in lung cancer.
Authors: He Tao 
Published: July 2024

e20522 Background: Bone metastasis (BM) occurs in about 30% of patients with advanced lung cancer, and the prognosis of BM patients is very poor, with a median survival of 6-10 months. Therefore, we attempted to use machine learning methods based on gene expression profiles to construct a model to predict BM. Methods: Gene Expression Omnibus (GEO) database were searched, then these datasets (GSE10096, GSE29367, GSE29391, GSE76194, GSE175601) were included for analysis. Batch effects were removed using the ComBat function from the R package sva (v3.44.0). edgeR was used for differential expression analysis, and genes that had an absolute log2 fold change > 1 and adjusted p-value < 0.05, were selected as differentially expressed genes (DEGs) for modeling. Random forest (RF) modeling was performed using the R package random Forest (v4.7-1.1), and support vector machine (SVM) modeling and SVM Recursive Feature Elimination (SVM-RFE) were performed using the R package e1071 (v1.7-13). Survival curves were generated using the GEPIA2 R packages. Models performance was evaluated using the area under the receiver operating characteristics curve (AUC). Results: A total of 48 qualified cases were subjected to analysis, including 22 BM and 26 non-BM patients. Differential expression analysis revealed that a total of 327 DEGs were identified in the BM group. We divided the sample dataset into a training set and a test set. In the first approach, we attempted to use all 327 DEGs features to train the models. Among the evaluated models, the RF algorithm performed best with an AUC of 0.753, while the SVM algorithm had an AUC of 0.938. The second approach, we applied the SVM-RFE algorithm for feature selection, which ranked the features according to their importance, and the top 10 genes/features (TMC5, S100A4, EEF1A2, CLDN1, RALY, MYH10, MAGEC2, ALDH1A1, PI3, SALL1) were used to build a classification model (in the test set, sensitivity was100%, specificity: 81.8%, AUC:0.909). In addition, TCGA survival analysis of 10 genes was performed and found that the expression levels of five genes, including ALDH1A1, MYH10, RALY, CLDN1 and MAGEC2, were significantly associated with prognosis (p < 0.1). Conclusions: Our study suggests that we have identified ten key genes associated with BM of lung cancer which could be potential therapeutic targets.
The efficacy and safety of furmonertinib in patients with advanced EGFR-mutated NSCLC and leptomeningeal metastases.
Authors: Han Huan , Tang Hong 
Published: July 2024

e20525 Background: Leptomeningeal metastasis (LM) is a common and fatal complication in patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor ( EGFR) mutation. This retrospective study aimed to evaluate the efficacy and safety of furmonertinib in patients with advanced EGFR-mutated ( EGFRm) NSCLC and LM. Methods: Eligible patients with confirmed advanced EGFRm NSCLC and LM were treated with furmonertinib. The primary endpoints were LM response rate and progression-free survival (PFS). Secondary endpoints were overall survival (OS) and adverse events (AEs). Results: This retrospective study analyzed the efficacy and safety of 31 EGFRm advanced NSCLC patients with LM at two hospitals between February 2020 to March 2023. The median age was 56 years (rang: 31-75), 22 (71.0%) were females. 19 (61.3%) patients had ECOG PS≥2 and all 31 patients (100%) had adenocarcinoma histology. For the treatment of LM, 19 (61.3%) patients received furmonertinib as first-line treatment, 8 (25.8%) patients as second-line treatment. 16 (51.6%) patients were treated with 240 mg of furmonertinib and 12 (38.7%) patients with 160 mg of furmonertinib. The median follow-up duration was 16.80 months (95% CI 12.71-20.89 months). LM objective response rate (ORR) was 75.0% and LM disease control rate (DCR) was 95.0% according to RANO-LM radiologic criteria. Overall ORR was 22.6% and DCR was 96.8%. Median LM duration of response (DoR) was 12.00 months (95% CI 7.40-16.60 months) and median overall DoR was 7.20 months (95% CI 3.60-10.80 months). 23 (74.2%) of the 31 patients had progressed or died by data cutoff. The median PFS was 11.70 months (95% CI 9.48-13.92 months) and the median OS was 18.40 months (95% CI 12.49-24.21 months). There was no significant difference in survival (median PFS: 11.70 months vs 10.90 months, p = 0.335; median OS: 18.40 months vs 13.50 months, p = 0.196) between the 19 patients who treated with furmonertinib as first-line therapy and those who treated with furmonertinib as second-line therapy. Although data on cerebrospinal fluid (CSF) clearance were not available, we observed improved neurologic function in 18 (75%) of 24 patients with baseline neurologic abnormalities. Logistic regression analysis showed that the therapeutic dose of furmonertinib was a positive predictor of OS in NSCLC patients harboring EGFR mutation with LM [HR: 2.679 (1.004-7.147), P = 0.049]. The most common AEs were rash, diarrhea and decreased appetite. However, most AEs were grade 1-2. Conclusions: Our study provides real-world clinical evidence that furmonertinib shows an encouraging efficacy and a manageable safety profile in patients with EGFRm NSCLC and LM.
Decision model for durable clinical benefit from front- or late-line immunotherapy alone or with chemotherapy in large population of non-small cell lung cancer.
Authors: Zhao Jie , Wang Lu , Wen Shidi , Zhou Anda , Fang Wenfeng , Zhang Li , Duan Jianchun , Bai Hua , Zhong Jia , Wan Rui , Sun Boyang , Zhuang Wei , Lin Yiwen , He Danming , Wang Zhijie , Wang Jie 
Published: July 2024

e20533 Background: Predictive biomarkers and models of immune checkpoint inhibitors (ICI) have been extensively studied in NSCLC. However, evidence for many biomarkers remains inconclusive, and the opaqueness of machine learning models hinders their practicality. We aimed to provide compelling evidence for biomarkers and develop a transparent decision-tree model. Methods: We consolidated data from ICI-treated patients with NSCLC (n = 3,288) across real-world multicentre studies, public cohorts, and the Choice-01 trial (NCT03607539). Over 50 features were gathered to examine the predictive capacity of durable clinical benefits (DCB) from mono-ICIs and ICIs plus chemotherapy. Noteworthy biomarkers were identified to establish a decision tree model. We also explored the tumour microenvironment and peripheral PD-1+ CD8+ T-cell receptor profiles. Results: Multivariate logistic regression analysis identified tumour histology, PD-L1 expression, tumour mutational burden, line, and regimen of ICI treatment as significant factors. Mutation subtypes of EGFR, KRAS, KEAP1, STK11, and disruptive TP53 mutations demonstrated significant association with DCB. The decision-tree (DT10) model, using the aforementioned five clinicopathological markers and five genomic mutations, predicted DCB with superior performance in the training set (N = 286, AUC = 0.82), and consistently outperformed the logistic regression, random forest, and support vector machine models, as well as FDA-approved biomarkers of PD-L1 and TMB in the internal and three external test sets (Table). We visualized the decision routes for DCB from ICI-based treatment based on the DT10 model, which was interpretable for clinical use. Furthermore, DT10 predicted-DCB patients manifested significantly longer progression-free survival and overall survival than -NDB patients across the train and test tests (HR < 1, p < 0.05). Additionally, the DT10 predicted-DCB group presented an enriched inflamed tumour immune phenotype (67%) and higher peripheral TCR diversity, whereas the -NDB group showed an enriched desert immune phenotype (86%) and higher peripheral TCR clonality. Conclusions: Based on the large population, we provided persuasive evidence for the predictive reliability of biomarkers in NSCLC. The development of the DT10 model introducing an easily interpretable, visually engaging, and clinically relevant model, which assisted the decision making in varied clinical scenarios. [Table: see text]
First-line treatment of EGFR mutation adenosquamous carcinoma of the lung with aumolertinib: A multicenter, single-arm, prospective study (ARISE Study).
Authors: Lin Gen , Huang Long , Chu Qian , Huang Dingzhi , Liu Zhe , Yu Yongfeng 
Published: July 2024

e20541 Background: Adenosquamous carcinoma of the lung (ASC), which composed of squamous cell carcinoma and adenocarcinoma, is a rare lung cancer. In Asian population, the mutation rate of epidermal growth factor receptor (EGFR) in ASC is approximately 15.4% to 44%. There were no large prospective clinical studies using EGFR tyrosine kinase inhibitors (TKI) to treat ASC. Methods: We conducted a prospective, multicenter, single-arm clinical trial, designed to evaluate the efficacy and safety of Aumolertinib for ASC patients with EGFR mutations without prior systemic therapy (originally designed as a randomized controlled study versus chemotherapy; the protocol was revised to single-arm study due to insufficient enrollment; Clinical Trial Registry No. NCT04354961). Eligible participants of stage IIIB/IV ASC with EGFR mutations from six Chinese medical centers received Aumolertinib 110mg orally once daily. Follow-up were performed every 6 weeks conducted by independent central review (ICR), based on the RECIST 1.1 criteria. Primary endpoints was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety. Results: Of the 18 patients recruited, 12 were evaluated for efficacy and safety. The median follow-up was 13.3 months, with 17 (range 4-26) doses of Aumolertinib treatment. The median PFS was 6.2 months (95% CI 5.0-8.2), while the median OS has not been reached. Of the 12 patients, 7 (58.3%) achieved PR, 3 (25.0%) achieved SD, and 2 (16.7%) were PD. The ICR-confirmed ORR and DCR were 58.3% (95% CI: 62.6%-74.6%) and 83.3% (95% CI: 89.6%-96.2%), respectively. A total of 9 patients (75%) experienced at least one treatment-related adverse events (TRAEs). the most common TRAEs were anemia (27.3%) and elevated aminotransferase (18.2%). three patients (25%) experienced grade 3-4 TRAEs in the form of paralysis, neutropenia and hypokalemia. No treatment-related deaths occurred. Conclusions: This is the first prospective clinical study showing that Aumolertinib is an effective and well-tolerated third-generation EGFR TKI for ASC with EGFR mutations, with favorable ORR and general PFS. In future, head-to-head comparisons of EGFR TKI with chemotherapy and combination therapy would be needed to be explored. Clinical trial information: NCT04354961 .
Efficacy and safety of time-of-day infusion of pemetrexed plus platinum and paclitaxel plus platinum for patients with advanced non-small cell lung cancer: A retrospective study.
Authors: Sun Li-Yue , Xu Quan-An , Xu Xian , Xian Ke-Xin , Zeng Xin-Xin , Li Hua-Gen , Zhang Xu-Hui 
Published: July 2024

e20557 Background: Retrospective studies suggest that administering chemotherapy infusions in the morning can enhance treatment efficacy and mitigate side effects in non-small cell lung cancer (NSCLC) patients. However, the effectiveness of chronotherapy using pemetrexed plus platinum (AP) and paclitaxel plus platinum (TP) in advanced NSCLC chemotherapy remains unexplored. This study aims to evaluate the impact of AP and TP chrono-chemotherapy (CCT) on treatment response and adverse events in advanced NSCLC patients. Methods: We retrospectively analyzed 78 advanced NSCLC patients treated with AP (AP cohort) and 50 advanced NSCLC patients treated with TP (TP cohort) at Guangdong Second Provincial General Hospital from 2018 to 2021. Based on previous research, we classified patients who received chemotherapy infusions more than twice after 2:00 PM as the afternoon (PM) group, while the rest were categorized as the morning (AM) group. Treatment response was evaluated using the Response Evaluation Criteria in Solid Tumors Criteria V.1.1. The primary endpoint was progression-free survival (PFS). All adverse events were identified and graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 5.0. Results: In the AP cohort, the AM group exhibited a longer PFS compared to the PM group (AM vs. PM, n = 26 vs. n = 52, 43.0 vs. 13.0 months, p = 0.001). However, no significant difference was observed in PFS in the TP cohort (AM vs. PM, n = 23 vs. n = 27, 11.0 vs. 22.0 months, p = 0.501). Subsequent subgroup analysis in the AP cohort favored the AM group across all major subgroups for PFS treatment effect. In contrast, the TP cohort subgroups showed a PFS benefit only in the smoking patients of the PM group. Furthermore, the analysis of adverse reactions revealed similar incidences of any treatment emergent adverse events (TEAE) in both AP and TP cohorts (AM vs. PM, 92.3% vs. 86.5% in AP cohort and 95.7% vs. 100.0% in TP cohort), and grade 3 TEAEs (AM vs. PM, 34.6% vs. 21.2% in AP cohort and 39.1% vs. 29.63% in TP cohort). The most common adverse events were anemia (73.1%), leukopenia (57.7%), and elevated ALT (46.2%) in AP cohort and anemia (100%), leukopenia (65.2%), and hypoalbuminemia (47.8%) in TP cohort. Univariate and multivariate analyses indicated that afternoon infusion of AP chemotherapy (p = 0.009) was an independent prognostic factor for NSCLC. Conclusions: AP treatment administered in the morning may enhance PFS in advanced NSCLC, while TP remains unaffected. This suggests that CCT could potentially enhance the efficacy of individualized chemotherapy in advanced NSCLC.
5-hydroxymethylcytosine in cell-free DNA as liquid biomarker for immune checkpoint inhibitor therapy in non–small cell lung cancer.
Authors: Ajmal Zainub , Shao Jianming , Olsen Randall , Kasparian Saro , He Chuan , Bernicker Eric , Li Zejuan , Zhang Jun 
Published: July 2024

e20563 Background: Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1), and its ligand (PD-L1) are the mainstay of treatment for metastatic non-small cell lung cancer (NSCLC) in patients lacking targetable driver mutations. However, optimal predictive biomarkers are lacking. We used a plasma cell-free DNA (cfDNA) 5-hydroxymethylcytosine (5hmC) signature-based predictive model to assess treatment response and potentially select patients eligible for ICI monotherapy. Methods: 40 plasma samples were collected from adult patients with stage III or IV lung cancer at Houston Methodist Hospital between 2019 and 2022. These were divided into a training (n = 24) and validation (n = 16) set. By identifying genes associated with progression free survival (PFS), a 16-gene signature was used to develop a 5hmC predictive model. A weighted predictive score (wp-score) based on the model was calculated for each patient and grouped into low and high wp-scores. Results: Low wp-scores were associated with higher objective response rate(ORR) in both training and validation set and better correlated with response rates compared to PD-L1. In the training set, PFS was longer in low wp-scores compared to high wp-scores (median 12.3 versus 3.0 months; p = 3.5x10-6; hazard ratio (HR) 4.6x10-10). This was also seen in the validation set (median 7.6 versus 1.8 months p = .0012; HR 0.12). Contrarily, high ( > 1%) or low ( < 1%) PD-L1 was not associated with PFS (median 6.8 versus 6.0 months; p = .40; HR 0.70; 95% CI, 0.30–1.60) or overall survival (OS) (median 10.1 versus 12.0 months; p = .38; HR 0.56; 95% CI, 0.15–2.10). 15 out of the 40 total patients received ICI monotherapy. Among these, low wp-scores (n = 8) were significantly associated with longer PFS compared to high wp-scores (n = 7), (median 19.6 versus 2.8 months; p = .00073; HR: 0.059). OS although longer, was not significant among the two groups (median 38.1 versus 10.5 months; p = .12). Conclusions: Our study provides a proof of concept that cfDNA 5hmC signature can be used to predict response to ICI therapy and select patients appropriate for monotherapy. It is a more sensitive and specific biomarker to PD-L1. Larger studies are underway to further validate cfDNA 5hmC based-signature predictive model. [Table: see text]
Stage IV non-small cell lung cancer in Veterans undergoing lung cancer screening who were not prescribed statins despite U.S. Preventative Services Task Force recommendations.
Authors: Elfessi Zane , Dell Catherine , Rubinstein Israel 
Published: July 2024

e20583 Background: It is well established that Veterans eligible for lung cancer screening (LCS) are also at risk of atherosclerotic cardiovascular disease (ASCVD) due to smoking. Current concepts suggest that statins could play a role in lung cancer prevention and treatment. Accordingly, the purpose of this retrospective, quality improvement project was to determine whether newly diagnosed stage IV non-small cell lung cancer (NCSLC) rate is higher in Veterans undergoing LCS who were not prescribed statins despite U.S. Preventative Services Task Force (USPSTF) recommendations. Methods: Electronic health records of Veterans undergoing LCS and subsequently diagnosed with NSCLC at the Jesse Brown VA Medical Center, Chicago, Illinois between 2021 and 2023 were reviewed. In each case, pertinent demographic, clinical, pathological, and pharmacy data were retrieved. The American College of Cardiology’s ASCVD Risk Estimator was used to assess the Veteran’s 10-year risk for a first ASCVD event. Data are presented as means ± SD. Statistical analysis was performed using Student’s t- and chi-squared tests as indicated. P < 0.05 was considered statistically significant. Results: Out of 57 Veterans diagnosed NSCLC, 33 (all males; 71±6 years; 28 African Americans) were prescribed and 24 (21 males, 3 females; 70±7 years; 18 African Americans) were not prescribed statins. Body mass index was similar in both groups (26.6±6.0 and 26.0±6.0 kg/m2, respectively; p = 0.73). Twenty one out of 24 Veterans (88%) not prescribed statins were eligible according to USPSTF recommendations (10-year calculated risk, 15.23%±6.9%). Stage IV NSCLC was diagnosed in 7/33 (21%) Veterans prescribed statins and in 10/21 (48%) USPSTF-eligible Veterans not prescribed statins (p < 0.05). Conclusions: Clinicians should assess the needfor a statin for primary prevention of ASCVD in each Veteran undergoing LCS. Stage IV NSCLC is more prevalent in Veterans with ASCVD risk who were not prescribed statins despite USPSTF recommendations. A larger, multi-site study is warranted to support or refute these initial observations.