Oncogenic fatty acid oxidation senses circadian disruption in sleep-deficiency-enhanced tumorigenesis.

Circadian disruption predicts poor cancer prognosis, yet how circadian disruption is sensed in sleep-deficiency (SD)-enhanced tumorigenesis remains obscure. Here, we show fatty acid oxidation (FAO) as a circadian sensor relaying from clock disruption to oncogenic metabolic signal in SD-enhanced lung tumorigenesis. Both unbiased transcriptomic and metabolomic analyses reveal that FAO senses SD-induced circadian disruption, as illustrated by continuously increased palmitoyl-coenzyme A (PA-CoA) catalyzed by long-chain fatty acyl-CoA synthetase 1 (ACSL1). Mechanistically, SD-dysregulated CLOCK hypertransactivates ACSL1 to produce PA-CoA, which facilitates CLOCK-Cys194 S-palmitoylation in a ZDHHC5-dependent manner. This positive transcription-palmitoylation feedback loop prevents ubiquitin-proteasomal degradation of CLOCK, causing FAO-sensed circadian disruption to maintain SD-enhanced cancer stemness. Intriguingly, timed ß-endorphin resets rhythmic Clock and Acsl1 expression to alleviate SD-enhanced tumorigenesis. Sleep quality and serum ß-endorphin are negatively associated with both cancer development and CLOCK/ACSL1 expression in patients with cancer, suggesting dawn-supplemented ß-endorphin as a potential chronotherapeutic strategy for SD-related cancer.

Metastasis-associated 1 localizes to the sarcomeric Z-disc and is implicated in skeletal muscle pathology.

Metastasis-associated 1 (MTA1), a subunit of the nucleosome remodeling and histone deacetylation (NuRD) corepressor complex, was reported to be expressed in the cytoplasm of skeletal muscles. However, the exact subcellular localization and the functional implications of MTA1 in skeletal muscles have not been examined. This study aims to demonstrate the subcellular localization of MTA1 in skeletal muscles and reveal its possible roles in skeletal muscle pathogenesis. Striated muscles (skeletal and cardiac) from C57BL/6 mice of 4-5 weeks were collected to examine the expression of MTA1 by Western blotting and immunohistochemistry. Immunofluorescence and immunoelectron microscopy were performed for MTA1, α-actinin (a Z-disc marker protein), and SMN (survival of motor neuron) proteins. Gene Expression Omnibus (GEO) data sets were analyzed using the GEO2R online tool to explore the functional implications of MTA1 in skeletal muscles. MTA1 expression was detected by Western blotting and immunohistochemistry in skeletal and cardiac muscles. Subcellular localization of MTA1 was found in the Z-disc of sarcomeres, where α-actinin and SMN were expressed. Data mining of GEO profiles suggested that MTA1 dysregulation is associated with multiple skeletal muscle defects, such as Duchenne muscular dystrophy, Emery-Dreifuss muscular dystrophy, nemaline myopathy, and dermatomyositis. The GEO analysis also showed that MTA1 expression gradually decreased with age in mouse skeletal muscle precursor cells. The subcellular localization of MTA1 in sarcomeres of skeletal muscles implies its biological roles in sarcomere structures and its possible contribution to skeletal muscle pathology.

Genomic heterogeneity of multiple synchronous lung cancers in Chinese population.

INTRODUCTION: It is clinically challenging to infer the phylogenetic relationship between different tumor lesions of patients with multiple synchronous lung cancers (MSLC), whether these lesions are the result of independently evolved tumor or intrapulmonary metastases. METHODS: We used the Illumina X10 platform to sequence 128 stage I lung cancer samples collected from 64 patients with MSLC. All samples were analyzed for mutation spectra and phylogenetic inference. RESULTS: We detected genetic aberrations within genes previously reported to be recurrently altered in lung adenocarcinoma including, EGFR, ERBB2, TP53, BRAF, and KRAS. Other putative driver mutations identified were enriched in RTK-RAS signaling, TP53 signaling, and cell cycle. Also, we found some interesting cases, two cases that carried EGFR L858R and T790M co-mutation in one tumor and another tumor with only EGFR 19del, and 1 case with two KRAS hotspots in the same tumor. Due to the short follow-up time and early stage, further investigation is needed to determine whether this unique mutation profile will affect their progression-free survival (PFS) and overall survival (OS). Regarding genetic evolution analysis among 64 tumor samples, 50 of them display distinct mutational profiles, suggesting these are independently evolved tumors, which is consistent with histopathological assessment. On the other hand, six patients were identified to be intrapulmonary metastasis as the mutations harbored in different lesions are clonally related. CONCLUSION: In summary, unlike intrapulmonary metastases, patients with MSLC harbor distinct genomic profiles in different tumor lesions, and we could distinguish MSLC from intrapulmonary metastases via clonality estimation.

Feasibility of an improved knotless method of chest drain wound closure:a prospective cohort clinical trial.

OBJECTIVE: Chest tube management plays a key role in minimising erioperative period. We have improved the knotless method to chest tube wounds. In this article, we demonstrate the clinical bility and safety of this method. METHOD: From 13 October 2018-3 January 2019, patients were ecutively included in our study at the First Affiliated Hospital of n Medical University, Dalian, China. They were separated into approximately equally sized groups-the knotless group and the entional group. Our improved knotless method was performed ose the chest tube wounds of patients in the knotless group, and onventional method using the pre-existing U-shaped string to the chest tube wounds of patients in the conventional group. Patient clinical information, tube-related complications, retreatment s and cosmetic scores were compared between the groups. RESULTS: The cohort comprised 102 patients; 47 in the knotless group and 55 in the conventional group. There were no statistically significant differences in patient clinical information or tube-related complications between the two groups (p>0.05; both comparisons). In the knotless group, retreatment times were shorter (p<0.001) and cosmetic scores were higher (p<0.001). CONCLUSION: This study showed that our new knotless method is safe and has wide clinical feasibility. The new method also improved patient cosmetic scores. Furthermore, it decreased the patients' economic burdens.

Prognostic Value of Pretreatment Serum Carcinoembryonic Antigen Level in 1130 Patients With Non-small Cell Lung Cancer: A Propensity Score Matching Cohort Study and Cumulative Meta-analysis.

OBJECTIVES: Carcinoembryonic antigen (CEA) is the most frequently used tumor marker for non-small cell lung cancer (NSCLC). The current study aimed to provide the highest-level evidence of the prognostic value of pretreatment serum CEA level for NSCLC through the appropriate statistical methodology and large-sample cohorts. METHODS: The current retrospective cohort study with 1130 patients with NSCLC treated by thoracic surgery with pretreatment serum CEA concentrations above/below 5 ng/mL. Propensity score matching, Kaplan-Miere survival analysis, and Cox proportional hazard regression models were used to study the intergroup variance. The overall/disease-free hazard ratios (HRs) of the current study were combined with the previously published studies using cumulative meta-analysis to provide the highest-level evidence. RESULTS: Intergroup confounding variables were well controlled by propensity score matching, and the survival differences were statistically significant. The Cox univariate analysis showed that the overall and disease-free HRs of the high CEA towards patients with low CEA were 1.595 (95% CI: 1.329-1.863, P = 0.004) and 1.498 (95% CI: 1.271-1.881, P = 0.004). The HRs of multivariate analysis were adjusted to 1.586 (95% CI: 1.398-1.812, P = 0.016) and 1.413 (95% CI: 1.22-1.734, P = 0.022) respectively. The cumulative meta-analysis showed that the cumulative overall HR was in accord with previous studies, and the cumulative disease-free HR turn to be statistically significant. CONCLUSIONS: Pretreatment serum CEA level was an independent influence factor of overall/disease-free survival of patients with NSCLC, and even for patients with the same pTNM stages or pathologic stages, it is used for prognosis.

A New Risk Score Model Based on Pyrogenic Signatures for the Prediction of Survival and Immune Microenvironment Features in Lung Adenocarcinoma.

Purpose: Lung adenocarcinoma (LUAD) accounts for about 40-50% of all lung cancer cases with poor prognoses. Pyroptosis plays important roles in tumor development and anti-tumor processes. This study aims to investigate the prognostic value of pyroptosis-related genes in survival and tumor immune microenvironment (TIME) in LUAD. Patients and Methods: Three datasets were collected, of which 59 normal samples and 513 LUAD samples as experimental group, 163 LUAD samples for validation analysis, and 43 non-small cell lung cancer (NSCLC) samples included in the immunotherapy cohort. A total of 33 pyrolysis-related genes were included in univariate Cox regression analysis. Five pyroptosis-related genes, including NLRC4, NLRP1, NOD1, PLCG1 and CASP9 were screened using Lasso to construct a pyroptosis-related risk score model. Functional enrichment and immune microenvironment analyses were performed. Another 5 tissue samples of LUAD patients were collected for qRT-PCR validation. Results: According to the median risk score, the samples were divided into high-risk group and low-risk group, and the immune cell infiltration in the low-risk group was significantly higher than that in the high-risk group. Then, a nomogram was established based on clinical characteristics and risk score, which demonstrated high accuracy in 1-year OS. The risk score was significantly correlated with overall survival, immune-cell infiltration, and tumor mutation burden (TMB). qRT-PCR results showed that the expression of pyroptosis-related genes in tissues of LUAD patients was consistent with the trend in the experimental group. Conclusion: The risk score model may predict the overall survival of LUAD patients with good accuracy. Our results also demonstrate effectiveness in evaluating the response to immunosuppressive therapy, and may help improve the overall prognosis and treatment outcome of LUAD.

UPF1 regulates FOXO1 protein expression by promoting PBK transcription in non-small cell lung cancer.

Up-frameshift protein 1 (UPF1) is essential for nonsense-mediated messenger RNA decay (NMD). It is best known for its cytoprotective role in degrading aberrant and specific RNAs. UPF1 is dysregulated in multiple tumors, which correlates with poor prognosis and low overall survival.However,the role of UPF1 in lung cancer remains unclear.Current study shows that UPF1 could be a potential target for oncology therapies. The results also demonstrated the potential efficiency of UPF1 in regulating the proliferation and metastasis of lung cancer. Our findings suggest that those functions can be attributed to the inhibition of the stability of FOXO1 protein. In addition, PBK participates in the regulation of FOXO1 by UPF1.This result provides a new therapeutic strategy for lung cancer patients.

Erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of stage IIIA-N2 EGFR-mutant non-small-cell lung cancer: final overall survival analysis of the EMERGING-CTONG 1103 randomised phase II trial.

EMERGING-CTONG 1103 showed improved progression-free survival (PFS) with neoadjuvant erlotinib vs. chemotherapy for patients harbouring EGFR sensibility mutations and R0 resected stage IIIA-N2 non-small cell lung cancer (NSCLC) (NCT01407822). Herein, we report the final results. Recruited patients were randomly allocated 1:1 to the erlotinib group (150 mg/day orally; neoadjuvant phase for 42 days and adjuvant phase to 12 months) or to the GC group (gemcitabine 1250 mg/m2 plus cisplatin 75 mg/m2 intravenously; 2 cycles in neoadjuvant phase and 2 cycles in adjuvant phase). Objective response rate (ORR), complete pathologic response (pCR), PFS, and overall survival (OS) were assessed along with safety. Post hoc analysis was performed for subsequent treatments after disease recurrence. Among investigated 72 patients (erlotinib, n = 37; GC, n = 35), the median follow-up was 62.5 months. The median OS was 42.2 months (erlotinib) and 36.9 months (GC) (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.47-1.47; p = 0.513). The 3- and 5-year OS rates were 58.6% and 40.8% with erlotinib and 55.9% and 27.6% with GC (p3-y = 0.819, p5-y = 0.252). Subsequent treatment was administered in 71.9% and 81.8% of patients receiving erlotinib and GC, respectively; targeted therapy contributed mostly to OS (HR, 0.35; 95% CI, 0.18-0.70). After disease progression, the ORR was 53.3%, and the median PFS was 10.9 months during the EGFR-TKI rechallenge. During postoperative therapy, grade 3 or 4 adverse events (AEs) were 13.5% in the erlotinib group and 29.4% in the GC group. No serious adverse events were observed. Erlotinib exhibited clinical feasibility for resectable IIIA-N2 NSCLC over chemotherapy in the neoadjuvant setting.

Comparison between functional lung volume measurement and segment counting for predicting postoperative pulmonary function after pulmonary resection in lung cancer patients.

BACKGROUND: Functional lung volume (FLV) obtained from computed tomography images was a breakthrough for lung imaging and functional assessment. We compared the accuracy of the FLV measurement method and the segment-counting (SC) method in predicting postoperative pulmonary function. METHODS: A total of 113 patients who underwent two thoracoscopic surgeries were enrolled in our study. We predicted postoperative pulmonary function by the FLV measurement method and the SC method. Novel formulas based on the FLV measurement method were established using linear regression equations between the factors affecting pulmonary function and the measured values. RESULTS: The predicted postoperative forced vital capacity (ppoFVC) and forced expiratory volume in 1 s (ppoFEV1) measured by the 2 methods showed high concordance between the actual postoperative forced vital capacity (postFVC) and the forced expiratory volume in 1 s (postFEV1) [r = 0.762, P < 0.001 (FLV method) and r = 0.759, P < 0.001 (SC method) for FVC; r = 0.790, P < 0.001 (FLV method) and r = 0.795, P < 0.001 (SC method) for FEV1]. Regression analysis showed that the measured preoperative pulmonary function parameters (FVC, FEV1) and the ratio of reduced FLV to preoperative FLV were significantly associated with the actual postoperative values and could predict these parameters (all P < 0.001). The feasibility of using these equations [postFVC = 0.8 × FVC - 0.784 × ΔFLV/FLV + 0.283 (R2 = 0.677, RSD = 0.338), postFEV1 = 0.766 × FEV1 - 0.694 × ΔFLV/FLV + 0.22 (R2 = 0.743, RSD = 0.265)] to predict the pulmonary function parameters after wedge resection was also verified. CONCLUSIONS: The new FLV measurement method is valuable for predicting postoperative pulmonary function in patients undergoing lung resection surgery, with accuracy and consistency similar to those of the conventional SC method.

VLDLR disturbs quiescence of breast cancer stem cells in a ligand-independent function.

Breast cancer stem cells are responsible for cancer initiation, progression, and drug resistance. However, effective targeting strategies against the cell subpopulation are still limited. Here, we unveil two splice variants of very-low-density lipoprotein receptor, VLDLR-I and -II, which are highly expressed in breast cancer stem cells. In breast cancer cells, VLDLR silencing suppresses sphere formation abilities in vitro and tumor growth in vivo. We find that VLDLR knockdown induces transition from self-renewal to quiescence. Surprisingly, ligand-binding activity is not involved in the cancer-promoting functions of VLDLR-I and -II. Proteomic analysis reveals that citrate cycle and ribosome biogenesis-related proteins are upregulated in VLDLR-I and -II overexpressed cells, suggesting that VLDLR dysregulation is associated with metabolic and anabolic regulation. Moreover, high expression of VLDLR in breast cancer tissues correlates with poor prognosis of patients. Collectively, these findings indicate that VLDLR may be an important therapeutic target for breast cancer treatment.

UPF1 increases amino acid levels and promotes cell proliferation in lung adenocarcinoma via the eIF2α-ATF4 axis.

Up-frameshift 1 (UPF1), as the most critical factor in nonsense-mediated messenger RNA (mRNA) decay (NMD), regulates tumor-associated molecular pathways in many cancers. However, the role of UPF1 in lung adenocarcinoma (LUAD) amino acid metabolism remains largely unknown. In this study, we found that UPF1 was significantly correlated with a portion of amino acid metabolic pathways in LUAD by integrating bioinformatics and metabolomics. We further confirmed that UPF1 knockdown inhibited activating transcription factor 4 (ATF4) and Ser51 phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), the core proteins in amino acid metabolism reprogramming. In addition, UPF1 promotes cell proliferation by increasing the amino-acid levels of LUAD cells, which depends on the function of ATF4. Clinically, UPF1 mRNA expression is abnormal in LUAD tissues, and higher expression of UPF1 and ATF4 was significantly correlated with poor overall survival (OS) in LUAD patients. Our findings reveal that UPF1 is a potential regulator of tumor-associated amino acid metabolism and may be a therapeutic target for LUAD.

Thymoma (World Health Organization Type AB) in multiple endocrine neoplasia type 1: a case report.

Thymic neoplasms are rarely seen among patients with multiple endocrine neoplasia type 1 (MEN1) and appear to be especially rare when pathological examination reveals a World Health Organization Type AB thymoma. In the case presented here, we report a 39-year-old woman with Type AB thymoma in MEN1. A 7.8-cm-sized mediastinal mass was diagnosed as a thymic neoplasm by computed tomography. In addition, pituitary tumor and hypercalcemia from parathyroid hyperplasia were found. Therefore, the patient was clinically diagnosed with MEN1 syndrome and underwent surgical resection of thymic tumor. At the 1-year follow-up, the patient appeared to be healthy without any sign of reoccurrence. Despite its rare occurrence, our case provides us with a new awareness that thymoma may coexist with MEN1.

Expert consensus on thermal ablation therapy of pulmonary subsolid nodules (2021 Edition).

The Expert Consensus reviews current literatures and provides clinical practice guidelines for thermal ablation of pulmonary subsolid nodules or ground-glass nodule (GGN). The main contents include the following: (1) clinical evaluation of GGN; (2) procedures, indications, contraindications, outcomes evaluation, and related complications of thermal ablation for GGN; and (3) future development directions.

Overexpression of Teashirt Homolog 2 suppresses cell proliferation and predicts the favorable survival of Lung Adenocarcinoma.

Background: Teashirt homolog 2 (TSHZ2) is essential for maintaining cellular homeostasis and regulating transcription on neoplasia development. However, the regulation of TSHZ2 in lung tumorigenesis and the underlying mechanisms remain unclear. Objective: To evaluate the relationship between TSHZ2 expression in patients' tumor tissue and prognosis in lung adenocarcinoma. Methods: TSHZ2 expression in different lung adenocarcinoma cell lines and human tissue were detected by Western blotting. The effect of TSHZ2 on cell proliferation, apoptosis and migration in lung adenocarcinoma cells was measured by CCK8, colony formation, flowcytometric analyses and wound-healing, respectively. TSHZ2 expression in different lung adenocarcinoma cell lines and human tissue from patients was detected using Western blotting and immunohistochemical staining. We also retrospectively analyzed 226 lung adenocarcinoma patients after surgical resection using immunohistochemical staining, and the association of TSHZ2 expression with the patient survival was evaluated. Results: TSHZ2 was lowly expressed in certain lung adenocarcinoma cell lines (PC9 and B203L), but other cells showed a high expression. Low expression of TSHZ2 was also observed in most lung adenocarcinoma tissues compared with adjacent tissues. Furthermore, we found that the overexpression of TSHZ2 plasmids led to the dramatic inhibition of cell proliferation, colony formation ability, migration and apoptosis induction in PC9 lung adenocarcinoma cells. In contrast, no obvious effect was found when the TSHZ2 expression was down-regulated by si-TSHZ2. An elevated TSHZ2 expression was observed in 155(68.6%) tumor tissues samples of lung adenocarcinoma patients. Notably, the lung adenocarcinoma patients with a high TSHZ2 expression tended to have EGFR mutations less frequently and a preferable prognosis to those with a lower expression. Conclusion: A high TSHZ2 expression inhabited cell proliferation and predicted a better prognosis of lung adenocarcinoma, possibly representing a useful therapeutic target for lung adenocarcinoma.

[Expert Consensus for Thermal Ablation of Pulmonary Subsolid Nodules (2021 Edition)].

"The Expert Group on Tumor Ablation Therapy of Chinese Medical Doctor Association, The Tumor Ablation Committee of Chinese College of Interventionalists, The Society of Tumor Ablation Therapy of Chinese Anti-Cancer Association and The Ablation Expert Committee of the Chinese Society of Clinical Oncology" have organized multidisciplinary experts to formulate the consensus for thermal ablation of pulmonary subsolid nodules or ground-glass nodule (GGN). The expert consensus reviews current literatures and provides clinical practices for thermal ablation of GGN. The main contents include: (1) clinical evaluation of GGN, (2) procedures, indications, contraindications, outcomes evaluation and related complications of thermal ablation for GGN and (3) future development directions.
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YBX1 Enhances Metastasis and Stemness by Transcriptionally Regulating MUC1 in Lung Adenocarcinoma.

Abnormal expression of the transcription factor Y-box-binding protein-1 (YBX1) is associated with the proliferation, migration, aggressiveness, and stem-like properties of various cancers. These characteristics contribute to the tumorigenesis and metastasis of cancer. We found that the expression levels of Mucin-1 (MUC1) and YBX1 were positively correlated in lung adenocarcinoma cells and lung adenocarcinoma tissue. Our retrospective cohort study of 176 lung adenocarcinoma patients after surgery showed that low expression of both YBX1 and MUC1 was an independent predictor of the prognosis and recurrence of lung adenocarcinoma. In lung adenocarcinoma cells, the silencing/overexpression of YBX1 caused a simultaneous change in MUC1, and MUC1 overexpression partially reversed the decreased tumor cell migration, aggressiveness, and stemness caused by YBX1 silencing. Moreover, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays proved that MUC1 was the downstream target of YBX1 and that YBX1 bound to the -1480~-1476 position in the promoter region of MUC1 to regulate its transcription. Furthermore, in mouse xenograft models and a lung cancer metastasis model, MUC1, which is downstream of YBX1, partially reversed the decreased number and size of tumors caused by YBX1 silencing. In conclusion, our findings indicated a novel mechanism by which YBX1 promotes the stemness and metastasis of lung adenocarcinoma by targeting MUC1 and provided a combination approach for diagnosis different from traditional single tumor biomarkers to predict patient prognosis and provide clinical treatment targets.

Expert consensus workshop report: Guidelines for preoperative assisted localization of small pulmonary nodules.

Along with increasing incidence of operable small pulmonary nodules, it becomes difficult to localize nodules via palpation. Accurate localization of small pulmonary nodules has remained a big challenge in lung surgery. Therefore, several techniques for preoperative localizing small pulmonary nodules have evolved, but the advantages and disadvantages of each method remain unclear. We reviewed computed tomography-guided percutaneous and bronchoscopic preoperative assisted localization for small pulmonary nodules. Original, peer-reviewed, and full-length articles in English and Chinese were searched with PubMed and Wanfang data. Case reports and case series with <20 patients were excluded. All localization techniques showed good reliability, but some carry a high rate of major or minor complications and drawbacks. No ideal localization technique is available; thus, the choice of preoperative assisted localization technique still depends on surgeons' preference and local availability of both specialists and instruments.

New additional scoring formula on the Pathological Features in Stage I Lung Adenocarcinoma Patients: Impact on Survival.

Background: Histological heterogeneity of lung adenocarcinoma may result in different prognosis among patients with the same TNM pathological stage. However, no objective evaluation system of lung adenocarcinoma based on pathological features has been widely accepted for assessing the prognosis. Methods: We retrospectively analyzed 179 patients with stage I lung adenocarcinoma after complete surgical resection. The pathological classification was according to the IASLC/ATS/ERS adenocarcinoma classifications, and the detailed abundance ratio using HE staining of primary tumor specimens was recorded. A new additional scoring formula on the pathological features (ASP) was established. The association of the ASP score with the patients' survival was examined. Results: The ASP scoring was significantly associated with smoking history (p=0.004), lymphatic vessel invasion (p<0.001), vascular invasion, differentiation (p<0.001) and Ki67 (p<0.001). The patients in the high-ASP-score group tended to have vascular invasion (odds ratio [OR]: 1.637, 95% confidence interval [CI]: 1.923-13.745, p=0.001) and high Ki67 expression (OR: 2.625, 95%CI: 1.328-5.190, p=0.006) by logistic regression analyses. The prognosis differed significantly in the Kaplan-Meier survival curves, and the 5-year survival rates in the low and high ASP score groups were 97.8% and 89.6%, respectively (p=0.018). Based on the univariate analysis, female (OR: 0.111, 95%CI: 0.014-0.906, p=0.040), long smoking history (OR: 7.250, 95%CI: 1.452-36.195, p=0.016), poor differentiation characteristics correlation (OR: 12.691, 95%CI: 1.557-103.453, p=0.018), and high ASP score (OR: 5.788, 95%CI: 1.138-29.423, p=0.034) were shown to be independently associated with an unfavorable prognosis. Conclusion: The ASP score can effectively screen high-risk patients for complete surgical resection of stage I lung adenocarcinoma.