Construction of a Diagnostic Model for Small Cell Lung Cancer Combining Metabolomics and Integrated Machine Learning.

BACKGROUND: To date, no study has systematically explored the potential role of serum metabolites and lipids in the diagnosis of small cell lung cancer (SCLC). Therefore, we aimed to conduct a case-cohort study that included 191 cases of SCLC, 91 patients with lung adenocarcinoma, 82 patients with squamous cell carcinoma, and 97 healthy controls. METHODS: Metabolomics and lipidomics were applied to analyze different metabolites and lipids in the serum of these patients. The SCLC diagnosis model (d-model) was constructed using an integrated machine learning technology and a training cohort (n = 323) and was validated in a testing cohort (n=138). RESULTS: Eight metabolites, including 1-mristoyl-sn-glycero-3-phosphocholine, 16b-hydroxyestradiol, 3-phosphoserine, cholesteryl sulfate, D-lyxose, dioctyl phthalate, DL-lactate and Leu-Phe, were successfully selected to distinguish SCLC from controls. The d-model was constructed based on these 8 metabolites and showed improved diagnostic performance for SCLC, with the area under curve (AUC) of 0.933 in the training cohort and 0.922 in the testing cohort. Importantly, the d-model still had an excellent diagnostic performance after adjusting the stage and related clinical variables and, combined with the progastrin-releasing peptide (ProGRP), showed the best diagnostic performance with 0.975 of AUC for limited-stage patients. CONCLUSION: This study is the first to analyze the difference between metabolomics and lipidomics and to construct a d-model to detect SCLC using integrated machine learning. This study may be of great significance for the screening and early diagnosis of SCLC patients.

Tumor mutational burden adjusted by neutrophil-to-lymphocyte ratio serves as a potential biomarker for atezolizumab-treated patients with extensive stage small cell lung cancer.

BACKGROUND: There is a desperate for the identification of more accurate and efficient biomarkers for ICI responses in patients with SCLC. METHODS: The data of our study was obtained from IMpower133 study. A total of 202 patients with SCLC received the treatment of placebo plus carboplatin plus etoposide (EC) while a total of 201 patients with SCLC received the treatment of atezolizumab plus EC. Overall survival (OS) was compared using Kaplan Meier analyses. Univariate and multivariate Cox regression analysis were used to determine independent prognostic variables affecting OS in patients with SCLC. RESULTS: We have demonstrated that a higher TMB adjusted by a lower neutrophil-to-lymphocyte ratio (NLR) is significantly correlated with improved OS, in patients with SCLC subject to either atezolizumab or placebo (P = 0.001 for atezolizumab and P = 0.034 for placebo). Moreover, Cox model showed that TMB < 10 mut/Mb adjusted by NLR ≥ median was an independent factor of OS for atezolizumab-treated SCLC patients (hazard ratio [HR], 2.82; 95% confidence interval; 1.52-5.24; P = 0.001). Both univariate and multivariate cox regression analysis showed that for patients with SCLC harboring low NLR and high TMB, survival is significantly longer in those treated with atezolizumab than those treated with placebo. Survival benefit is significantly higher in atezolizumab-treated patients with SCLC than those treated with placebo (P = 0.018 for TMB cutoff = 10 mut/Mb, P = 0.034 for TMB cutoff = 16 mut/Mb). CONCLUSION: Our findings provide a promising insight into the utility of NLR-adjusted TMB in the prognosis and immune responses in patients with SCLC.

Boosted Mg-CO2 Batteries by Amine-Mediated CO2 Capture Chemistry and Mg2+ -Conducting Solid-electrolyte Interphases.

Mg-CO2 battery has been considered as an ideal system for energy conversion and CO2 fixation. However, its practical application is significantly limited by the poor reversibility and sluggish kinetics of CO2 cathode and Mg anode. Here, a new amine mediated chemistry strategy is proposed to realize a highly reversible and high-rate Mg-CO2 battery in conventional electrolyte. Judiciously combined experimental characterization and theoretical computation unveiled that the introduced amine could simultaneously modify the reactant state of CO2 and Mg2+ to accelerate CO2 cathodic reactions on the thermodynamic-kinetic levels and facilitate the formation of Mg2+ -conductive solid-electrolyte interphase (SEI) to enable highly reversible Mg anode. As a result, the Mg-CO2 battery exhibits boosted stable cyclability (70 cycles, more than 400 h at 200 mA g-1 ) and high-rate capability (from 100 to 2000 mA g-1 with 1.5 V overpotential) even at -15 °C. This work opens a newly promising avenue for advanced metal-CO2 batteries.

Molecular subtyping of small-cell lung cancer based on mutational signatures with different genomic features and therapeutic strategies.

Small-cell lung cancer (SCLC) is an exceptionally lethal malignancy characterized by extremely high alteration rates and tumor heterogeneity, which limits therapeutic options. In contrast to non-small-cell lung cancer that develops rapidly with precision oncology, SCLC still remains outside the realm of precision medicine. No recurrent and actionable mutations have been detected. Additionally, a paucity of substantive tumor specimens has made it even more difficult to classify SCLC subtypes based on genetic background. We therefore carried out whole-exome sequencing (WES) on the largest available Chinese SCLC cohort. For the first time, we partitioned SCLC patients into three clusters with different genomic alteration profiles and clinical features based on their mutational signatures. We showed that these clusters presented differences in intratumor heterogeneity and genome instability. Moreover, a wide existence of mutually exclusive gene alterations, typically within similar biological functions, was detected and suggested a high SCLC intertumoral heterogeneity. Particularly, Cluster 1 presented the greatest potential to benefit from immunotherapy, and Cluster 3 constituted recalcitrant SCLC, warranting biomarker-directed drug development and targeted therapies in clinical trials. Our study would provide an in-depth insight into the genome characteristics of the Chinese SCLC cohort, defining distinct molecular subtypes as well as subtype-specific therapies and biomarkers. We propose tailoring differentiated therapies for distinct molecular subgroups, centering on a personalized precision chemotherapy strategy combined with immunization or targeted therapy for patients with SCLC.

Orchestrating smart therapeutics to achieve optimal treatment in small cell lung cancer: recent progress and future directions.

Small cell lung cancer (SCLC) is a recalcitrant malignancy with elusive mechanism of pathogenesis and dismal prognosis. Over the past decades, platinum-based chemotherapy has been the backbone treatment for SCLC. However, subsequent chemoresistance after initial effectiveness urges researchers to explore novel therapeutic targets of SCLC. Recent years have witnessed significant improvements in targeted therapy in SCLC. New molecular candidates such as Ataxia telangiectasia and RAD3-related protein (ATR), WEE1, checkpoint kinase 1 (CHK1) and poly-ADP-ribose polymerase (PARP) have shown promising therapeutic utility in SCLC. While immune checkpoint inhibitor (ICI) has emerged as an indispensable treatment modality for SCLC, approaches to boost efficacy and reduce toxicity as well as selection of reliable biomarkers for ICI in SCLC have remained elusive and warrants our further investigation. Given the increasing importance of precision medicine in SCLC, optimal subtyping of SCLC using multi-omics have gradually applied into clinical practice, which may identify more drug targets and better tailor treatment strategies to each individual patient. The present review summarizes recent progress and future directions in SCLC. In addition to the emerging new therapeutics, we also focus on the establishment of predictive model for early detection of SCLC. More importantly, we also propose a multi-dimensional model in the prognosis of SCLC to ultimately attain the goal of accurate treatment of SCLC.

Expression pattern of miR-16-2-3p and its prognostic values on pediatric acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is a debilitating illness that easily occurs in adolescents. microRNAs (miRNAs) are potential biomarkers for multiple diseases. This paper was to elaborate on the expression of miR-16-2-3p in childhood ALL and its clinical values on ALL diagnosis and prognosis. First, serum miR-16-2-3p expression in ALL children and healthy volunteers was measured using RT-qPCR. Next, diagnostic potential and prognostic values of miR-16-2-3p on ALL were analyzed through receiver operating characteristic (ROC) curve, Kaplan-Meier survival curve, and multivariate Cox regression analysis, respectively. No significant difference was observed in the clinical baseline data between ALL patients and healthy children. ALL patients showed downregulated serum miR-16-2-3p (0.65 ± 0.27) (p < .01), whose area under the ROC curve was 0.837 with a cut-off value of 0.745 (67.92% sensitivity, 96.94% specificity). ALL patients with higher miR-16-2-3p expression had higher survival rates than those with lower miR-16-2-3p expression. Low miR-16-2-3p expression predicted poor prognosis of ALL patients. After adjusting LDH and lymphomyelocyte proportion (p = 0.003, HR = 0.003, 95%CI = 0.000-0.145), miR-16-2-3p was recognized as an independent prognostic factor for ALL patient survival. Briefly, low serum miR-16-2-3p expression in ALL children could aid ALL diagnosis and predict poor prognosis.

Untargeted metabolomics and lipidomics identified four subtypes of small cell lung cancer.

INTRODUCTION: Small cell lung cancer (SCLC) is a heterogeneous malignancy with dismal prognosis. However, few studies have conducted on the metabolic heterogeneity in SCLC. OBJECTIVE: We therefore identify SCLC classifications using untargeted metabolomics and lipidomics. We also compared their survival and the immunotherapy responses. METHODS: Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS) analysis was performed in 191 SCLC serum samples. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was conducted to identify metabolic pathways. The Kaplan-Meier and log-rank test were used to analyze the survival curves. The univariate and multivariate Cox proportional hazards regression models were used to evaluate prognostic factors for OS in patients with SCLC. RESULTS: Distinct subtypes of SCLC were identified by consensus clustering algorithm using partioning around medoids (pam) based on untargeted metabolomics and lipidomics. Four distinct subtypes of SCLC were identified, with distinct metabolic pathways. Subgroup 2 had the longest survival whereas Subgroup 1 had the shortest. Subtype 2 benefited most from immunotherapy in OS, as in contrast to Subtype 3 with shortest survival. CONCLUSION: Our study revealed the metabolic heterogeneity in SCLC and identified four subtypes with distinct metabolic features. It indicates promising therapeutic and prognostic value that may guide treatment for SCLC. The subtype-specific clinical trials may be designed and would be instructive for drug development.

Non-small-cell lung cancer patients harboring TP53/KRAS co-mutation could benefit from a PD-L1 inhibitor.

Aim: To explore the association between TP53 mutation and atezolizumab in non-small-cell lung cancer (NSCLC) patients. Materials & methods: Patients with NSCLC from the POPLAR and OAK studies were included. Kaplan-Meier analysis was performed to detect progression-free survival (PFS) and overall survival (OS). PFS and OS were compared using multivariate Cox regression analysis. Results: OS was significantly longer with atezolizumab compared with docetaxel among TP53/KRAS co-mutant NSCLC patients (hazard ratio [HR]: 0.014; 95% CI: 0.000-0.721). There is no significant OS difference between atezolizumab versus docetaxel for TP53-mutant NSCLC patients (HR: 0.831; 95% CI: 0.473-1.458). There is no significant OS difference between atezolizumab versus docetaxel for KRAS-mutant NSCLC patients (HR: 1.354; 95% CI: 0.528-3.472). Conclusion: PD-L1 inhibitors may bring OS benefits for patients with NSCLC harbored TP53/KRAS co-mutation.

Mutations in TP53 have been reported to be the most frequent oncogenic mutations in non-small-cell lung cancer (NSCLC), but there are no favorable targeted therapies. The association between TP53 mutation and atezolizumab in NSCLC patients was explored in this study. Patients with NSCLC from the POPLAR and OAK studies were included. Longer overall survival (OS) was found in TP53-wildtype NSCLC patients treated with atezolizumab compared with those treated with docetaxel. OS benefit of atezolizumab over docetaxel was detected for NSCLC patients only with co-occurrence of TP53 and KRAS mutations. For patients with NSCLC harboring TP53 mutation detected by fluid biopsy, this study provides insights and perspectives into anti-PD-L1 treatment.

Characteristic changes of ozone and its precursors in London during COVID-19 lockdown and the ozone surge reason analysis.

The London COVID-19 lockdown reduced emissions from anthropogenic sources, providing unique conditions for air contamination research. This research uses tropospheric ozone (O3), volatile organic compounds (VOCs) and NOx (NO+NO2) hourly monitoring data at the London Marylebone Road station from 2001 to 2020 to investigate the effects of lockdown on (O3) and its precursors. Both NOx and VOCs pollution showed a decreasing trend between 2001 and 2021, with a gradual increase in O3 in contrast. During the COVID-19 lockdown period (from 23rd March to July 4, 2020), there was a surge in O3 concentration, accompanied by a sharp reduction in NOx concentrations. Because all the monitoring VOCs/NOx results were less than eight during the lockdown, indicating that O3 formation in urban London was in the VOC-limited regime. The rapid increase in O3 concentrations caused by the lockdown was closely related to the rapid decrease in NOx emissions.

A Moisture-Assisted Rechargeable Mg-CO2 Battery.

New sustainable energy conversion and storage technologies are required to address the energy crisis and CO2 emission. Among various metal-CO2 batteries that utilize CO2 and offer high energy density, rechargeable Mg-CO2 batteries based on earth-abundant and safe magnesium (Mg) metal have been limited due to the lack of a compatible electrolyte, operation atmosphere, and unambiguous reaction process. Herein, the first rechargeable nonaqueous Mg-CO2 batteries have been proposed with moisture assistance in a CO2 atmosphere. These display more than 250 h cycle life and maintain the discharge voltage over 1 V at 200 mA g-1 . Combining with the experimental observations and theoretical calculations, the reaction in the moisture-assisted Mg-CO2 battery is revealed to be 2 Mg+3 CO2 +6 H2 O↔2 MgCO3 ⋅3 H2 O+C. It is anticipated that the moisture-assisted rechargeable Mg-CO2 batteries would stimulate the development of multivalent metal-CO2 batteries and extend CO2 fixation and utilization for carbon neutrality.

CD44, a marker of cancer stem cells, is positively correlated with PD-L1 expression and immune cells infiltration in lung adenocarcinoma.

BACKGROUND: PD-L1 inhibitors is widely applied in lung adenocarcinoma patients. Tumor cells with high PD-L1 expression could trigger immune evasion. Cancer stem cells (CSCs) can evade from immunesurveillance due to their immunomodulating effects. However, the correlation between CSC and PD-L1 and some immune-related markers is seldom reported in patients with lung adenocarcinoma. Therefore, we aimed to ascertain their association in lung adenocarcinoma patients. METHODS: We assessed CD44 expression and its association with PD-L1 in lung adenocarcinoma, using Tumor Immune Estimation Resource (TIMER), which was further validated in our patient cohort. The immune cells infiltration was depicted by CIBERSORT using GEO database. The correlation between CD44 and immune cells was also analyzed. We further evaluated the prognostic role of CD44 in patients with lung adenocarcinoma both using Kaplan-Meier plotter and validated in our patient cohort. RESULTS: Positive association between CD44 and PD-L1 were found in lung adenocarcinoma patients. T cells CD4 memory resting cells and mast cells resting cells varied significantly between patients with CD44 high and those with CD44 low. Furthermore, positive association could be found between CD44 expression and immune cells. Arm-level depletion of CD44 was linked with B cell, CD4+ T cell, neutrophil and dendritic cell infiltration. Patients with higher CD44 levels had worsened overall survival (OS). CONCLUSIONS: In summary, these results demonstrate that CD44 was associated with PD-L1 and infiltration of immune cells, and was a negative prognostic factor for predicting worsened OS in lung adenocarcinoma.

Bioactive Diterpenoids from the Stems of Euphorbia royleana.

Two ingenane- (1 and 2), two ent-atisane- (3 and 4), two ent-kaurane- (5 and 6), two ent-abietane- (7 and 8), and one ent-isopimarane-type (9) diterpenoid and 12 known analogues have been isolated from the methanolic extract of the stems of Euphorbia royleana. Their structures, including absolute configurations, were determined by extensive spectroscopic methods and ECD data analysis. The nitric oxide inhibitory activities of those diterpenoids were examined biologically in lipopolysaccharide-stimulated BV-2 cells, with compounds 1, 2, 5-7, 10, and 12 having IC50 values lower than 40 µM. Molecular docking was used to investigated the possible mechanism of compounds 1, 2, 5-7, 10, and 12.

Nitric oxide inhibitory limonoids as potential anti-neuroinflammatory agents from Swietenia mahagoni.

Recent studies have revealed that there is a close relationship between neuroinflammation and Alzheimer's disease (AD) and compounds with anti-neuroinflammatory effects are potentially useful for the treatment of AD. A phytochemical investigation to obtain new neuroinflammatory inhibitors resulted in the isolation of four new and three known limonoids from Swietenia mahagoni. The structures of these limonoids were established by NMR, MS, and electronic circular dichroism (ECD) data analysis. Compounds 1-3 feature complicated polycyclic caged structures of limonoid orthoester and represent new examples of phragmalin-type limonoids. All of the isolates showed anti-neuroinflammatory activities by inhibiting nitric oxide (NO) release in LPS-induced murine microglial BV-2 cells with compounds 1 and 3-6 having IC50 values of 26.8, 26.1, 26.0, 37.1, and 16.5 µM, respectively. The possible mechanism of NO inhibition of some bioactive compounds was also investigated using molecular docking, which revealed the interactions of bioactive compounds with the inducible nitric oxide synthase (iNOS) protein.

Carbonic anhydrase 2 inhibits epithelial-mesenchymal transition and metastasis in hepatocellular carcinoma.

Carbonic anhydrase 2 (CA2) plays vital role in the regulation of ion transport and pH balance and is involved in many biological processes; however, its role in cancer remains obscure. In this study, we identified a novel function of CA2 in facilitating hepatocellular carcinoma (HCC) metastasis. CA2 expression was elevated in Na+-K+-ATPase α1 (ATP1A1)-downregulated HCC cells and was inversely correlated with that of ATP1A1 in HCC. ATP1A1 acted as an oncoprotein whereas CA2 overexpression inhibited cell migration and invasion by reversing epithelial-mesenchymal transition (EMT) in HCC. CA2 downregulation promoted HCC metastasis and invasion whereas ATP1A1 downregulation inhibited HCC metastasis. Because of the opposing effects of CA2 and ATP1A1 in HCC, we examined the role of their correlation in HCC metastasis. CA2 attenuated ATP1A1-triggered tumor growth in vivo and ATP1A1-induced metastasis in vitro. Taken together, the present results suggest that CA2 serves as a suppressor of HCC metastasis and EMT and is correlated with favorable overall survival (OS) in HCC patients.

Circular RNA Hsa_Circ_0091579 Serves as a Diagnostic and Prognostic Marker for Hepatocellular Carcinoma.

BACKGROUND/AIMS: An increasing number of studies have suggested that circular RNAs (circRNAs) have vital roles in carcinogenesis and tumor progression. However, the function of circRNAs in hepatocellular carcinoma (HCC) remains poorly characterized. METHODS: We investigated the levels of circRNAs in patients with HCC to identify potential diagnostic biomarkers. We examined circRNA expression profiles in liver tumors and paired non-cancerous liver tissues from three HCC patients with cancer thrombus using a circRNA microarray. Bioinformatics analysis was performed to find circRNAs with significantly altered expression levels between tumors and their paired non-tumor tissues. We confirmed our initial findings by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Receiver operating characteristic (ROC) curves were also applied to identify a candidate circRNA with the optimal specificity and sensitivity. Finally, X-tile software was adopted to calculate the most efficient cut-off value for hsa_circ_0091579 expression. RESULTS: Microarray analysis identified 20 unique circRNAs that were differentially expressed between tumor and non-tumor tissues (P < 0.05). The expression of these 20 circRNAs was verified by qRT-PCR. The expression of hsa_circ_16245-1 and hsa_circ_0091579 mRNA was consistent with their levels as tested by the microarray. The ROC curves showed that both hsa_circ_16245-1 and hsa_circ_0091579 had favorable specificity and sensitivity. We further confirmed that hsa_circ_0091579 was significantly upregulated in HCC and its high expression was intimately associated with a worse overall survival in patients with HCC. CONCLUSION: Hsa_circ_0091579 may play a critical role in HCC progression and serve as a potential biomarker for the prognosis of patients with HCC.

Postmastectomy radiation therapy for breast cancer patients with one to three positive lymph nodes: a propensity score matching analysis.

AIM: Conducting postmastectomy radiation therapy (PMRT) for breast cancer patients with one to three positive lymph nodes is still controversial. METHODS: Propensity score matching analysis was applied to balance the clinical baseline characteristics of patients. Cox proportional hazard analysis was used to analyze the survival prognosis factors and perform subgroup analysis. RESULTS: There was no statistical difference in overall survival and cancer-specific survival rates (all, p > 0.05) between the PMRT and non-PMRT groups. However, for subgroup patients with tumor size ≥5 cm and the number of positive lymph nodes = 3, PMRT showed a significant survival benefit. CONCLUSION: PMRT can improve overall survival and cancer-specific survival only in breast cancer patients whose tumor size is larger than 5 cm and with three positive lymph nodes.

Acupuncture for cancer-related fatigue in lung cancer patients: a randomized, double blind, placebo-controlled pilot trial.

BACKGROUND: Cancer-related fatigue (CRF) is a distressing symptom that is the most common unpleasant side effect experienced by lung cancer patients and is challenging for clinical care workers to manage. METHODS: We performed a randomized, double-blind, placebo-controlled pilot trial to evaluate the clinical effect of acupuncture on CRF in lung cancer patients. Twenty-eight patients presenting with CRF were randomly assigned to active acupuncture or placebo acupuncture groups to receive acupoint stimulation (LI-4, Ren-6, St-36, KI-3, and Sp-6) twice per week for 4 weeks, followed by 2 weeks of follow-up. The primary outcome was the change in intensity of CFR based on the Chinese version of the Brief Fatigue Inventory (BFI-C). As the secondary endpoint, the Functional Assessment of Cancer Therapy-Lung Cancer Subscale (FACT-LCS) was adopted to assess the influence of acupuncture on patients' quality of life (QOL). Adverse events and safety of treatments were monitored throughout the trial. RESULTS: Our pilot study demonstrated feasibility among patients with appropriate inclusion criteria and good compliance with acupuncture treatment. A significant reduction in the BFI-C score was observed at 2 weeks in the 14 participants who received active acupuncture compared with those receiving the placebo (P < 0.01). At week 6, symptoms further improved according to the BFI-C (P < 0.001) and the FACT-LCS (P = 0.002). There were no significant differences in the incidence of adverse events in either group (P > 0.05). CONCLUSION: Fatigue is a common symptom experienced by lung cancer patients. Acupuncture may be a safe and feasible optional method for adjunctive treatment in cancer palliative care, and appropriately powered trials are warranted to evaluate the effects of acupuncture.