A gene-based score for the risk stratification of stage IA lung adenocarcinoma.

OBJECTIVE: We aim to molecularly stratify stage IA lung adenocarcinoma (LUAD) for precision medicine. METHODS: Twelve multi-institution datasets (837 cases of IA) were used to classify the high- and low-risk types (based on survival status within 5 years), and the biological differences were compared. Then, a gene-based classifying score (IA score) was trained, tested and validated by several machine learning methods. Furthermore, we estimated the significance of the IA score in the prognostic assessment, chemotherapy prediction and risk stratification of stage IA LUAD. We also developed an R package for the clinical application. The SEER database (15708 IA samples) and TCGA Pan-Cancer (1881 stage I samples) database were used to verify clinical significance. RESULTS: Compared with the low-risk group, the high-risk group of stage IA LUAD has obvious enrichment of the malignant pathway and more driver mutations and copy number variations. The effect of the IA score on the classification of high- and low-risk stage IA LUAD was much better than that of classical clinicopathological factors (training set: AUC = 0.9, validation set: AUC = 0.7). The IA score can significantly predict the prognosis of stage IA LUAD and has a prognostic effect for stage I pancancer. The IA score can effectively predict chemotherapy sensitivity and occult metastasis or invasion in stage IA LUAD. The R package IAExpSuv has a good risk probability prediction effect for both groups and single stages of IA LUAD. CONCLUSIONS: The IA score can effectively stratify the risk of stage IA LUAD, offering good assistance in precision medicine.

Surface structure change properties: Auto-soft bionic fibrous membrane in reducing postoperative adhesion.

Peritoneal adhesion is the most common adverse effect following abdominal surgery or inflammation. The occurrence in clinical trials has been successfully reduced using barriers. However, the shortcomings of frequently used adhesion barriers, such as rapid degradation rate of gel barrier and inadequate operation ability of solid barrier, cannot be ignored. In this study, a fibrous membrane with an ECM-like structure was prepared. The adhesion properties were reduced significantly by changing the surface structure. The fibrous membrane caused less inflammatory response and much less peripheral adhesion and intestinal obstruction compared to the casting film and the commercial film with smooth surface, though with the same components. Because of the auto-soft bionic structure and similarity in the mechanical modulus of the tissues, the fibrous membrane was more flexible when it adhered to the tissues, showed excellent effectiveness and biocompatibility. In addition to the rat and miniature pig models, a randomized, placebo-controlled, and multicenter clinical pilot study with 150 patients confirmed that because of its flexibility, biodegradability, and similarity to mechanical modulus and structure with tissues involved, the fibrous membrane served as a favorable implant for preventing post-operation adhesion.

PM2.5 induces the distant metastasis of lung adenocarcinoma via promoting the stem cell properties of cancer cells.

Lung cancer is the most common cancer in China and second worldwide, of which the incidence of lung adenocarcinoma is rising. As an independent factor, air pollution has drawn the attention of the public. An increasing body of studies has focused on the effect of PM2.5 on lung adenocarcinoma; however, the mechanism remains unclear. We collected the PM2.5 in two megacities, Beijing (BPM) and Shijiazhuang (SPM), located in the capital of China, and compared the different components and sources of PM2.5 in the two cities. Vehicle emissions are the primary sources of BPM, whereas SPM is industrial emissions. We found that chronic exposure to PM2.5 promotes the tumorigenesis and metastasis of lung adenocarcinoma in patient-derived xenograft (PDX) models, as well as the migration and invasion of lung adenocarcinoma cell lines. SPM has more severe effects in vivo and in vitro. The underlying mechanisms are related to the stem cell properties of cancer cells, the epithelial-mesenchymal transition (EMT) process, and the corresponding miRNAs. It is hopeful to provide a theoretical basis for improving air pollution in China, especially in the capital area, and is of the significance of long-term survival of lung cancer patients.

Tumor hijacks macrophages and microbiota through extracellular vesicles.

The tumor microenvironment (TME) is a biological system with sophisticated constituents. In addition to tumor cells, tumor-associated macrophages (TAMs) and microbiota are also dominant components. The phenotypic and functional changes of TAMs are widely considered to be related to most tumor progressions. The chronic colonization of pathogenic microbes and opportunistic pathogens accounts for the generation and development of tumors. As messengers of cell-to-cell communication, tumor-derived extracellular vesicles (TDEVs) can transfer various malignant factors, regulating physiological and pathological changes in the recipients and affecting TAMs and microbes in the TME. Despite the new insights into tumorigenesis and progress brought by the above factors, the crosstalk among tumor cells, macrophages, and microbiota remain elusive, and few studies have focused on how TDEVs act as an intermediary. We reviewed how tumor cells recruit and domesticate macrophages and microbes through extracellular vehicles and how hijacked macrophages and microbiota interact with tumor-promoting feedback, achieving a reciprocal coexistence under the TME and working together to facilitate tumor progression. It is significant to seek evidence to clarify those specific interactions and reveal therapeutic targets to curb tumor progression and improve prognosis.

Tumor associated macrophage and microbe: The potential targets of tumor vaccine delivery.

The occurrence and development of tumors depend on the tumor microenvironment (TME), which is made of various immune cells, activated fibroblasts, basement membrane, capillaries, and extracellular matrix. Tumor associated macrophages (TAMs) and microbes are important components in TME. Tumor cells can recruit and educate TAMs and microbes, and the hijacked TAMs and microbes can promote the progression of tumor reciprocally. Tumor vaccine delivery remodeling TME by targeting TAM and microbes can not only enhance the specificity and immunogenicity of antigens, but also contribute to the regulation of TME. Tumor vaccine design benefits from nanotechnology which is a suitable platform for antigen and adjuvant delivery to catalyze new candidate vaccines applying to clinical therapy at unparalleled speed. In view of the characteristics and mechanisms of TME development, vaccine delivery targeting and breaking the malignant interactions among tumor cells, TAMs, and microbes may serve as a novel strategy for tumor therapy.

Room-Temperature Magnetic Field Effect on Excitonic Photoluminescence in Perovskite Nanocrystals.

Magnetic-field-enhanced spin-polarized electronic/optical properties in semiconductors are crucial for fabricating various spintronic devices. However, this spin polarization is governed by weak spin exchange interactions and easily randomized by thermal fluctuations; therefore, it is only produced at cryogenic temperatures, which severely limits the applications. Herein, a room-temperature intrinsic magnetic field effect (MFE) on excitonic photoluminescence is achieved in CsPbX3 :Mn (X = Cl, Br) perovskite nanocrystals. Through moderate Mn doping, the MFE is enhanced by exciton-Mn interactions, and through partial Br substitution, the MFE is stabilized at room temperature by exciton orbital ordering. The orbital ordering significantly enhances the g-factor difference between electrons and holes, which is evidenced by a parallel orbit-orbit interaction among excitons generated by circular polarized laser excitation. This study provides a clear avenue for engineering spintronic materials based on orbital interactions in perovskites.

Nanotechnology: Breaking the Current Treatment Limits of Lung Cancer.

Lung cancer is one of the most rapidly growing malignancies in terms of morbidity and mortality. Although traditional treatments have been used for more than 50 years, it is still far from solving the problems of postoperative risks and systemic toxicity. Emerging targeting and immunotherapy are developing continuously and are gaining recognition; eventually, they face the inevitable challenge of drug resistance. Nanotechnology has several important effects on lung cancer treatment, owing to its unique properties. Several nanoparticle-based treatments have successfully become cancer treatments. Good biocompatibility with higher specific surface area can carry substantial amounts of lung cancer treatment medications while avoiding medication toxicity; editable and modified characteristics give rise to multifunctional nanomedicines; excellent photoelectric effects make lung cancer a multimodal treatment. This article summarizes the breakthroughs achieved by nanotechnology, targeted therapy, and immunotherapy, reflecting the importance and necessity of nanotechnology in the treatment of lung cancer.

Artificial intelligence assisted display in thoracic surgery: development and possibilities.

In this golden age of rapid development of artificial intelligence (AI), researchers and surgeons realized that AI could contribute to healthcare in all aspects, especially in surgery. The popularity of low-dose computed tomography (LDCT) and the improvement of the video-assisted thoracoscopic surgery (VATS) not only bring opportunities for thoracic surgery but also bring challenges on the way forward. Preoperatively localizing lung nodules precisely, intraoperatively identifying anatomical structures accurately, and avoiding complications requires a visual display of individuals' specific anatomy for surgical simulation and assistance. With the advance of AI-assisted display technologies, including 3D reconstruction/3D printing, virtual reality (VR), augmented reality (AR), and mixed reality (MR), computer tomography (CT) imaging in thoracic surgery has been fully utilized for transforming 2D images to 3D model, which facilitates surgical teaching, planning, and simulation. AI-assisted display based on surgical videos is a new surgical application, which is still in its infancy. Notably, it has potential applications in thoracic surgery education, surgical quality evaluation, intraoperative assistance, and postoperative analysis. In this review, we illustrated the current AI-assisted display applications based on CT in thoracic surgery; focused on the emerging AI applications in thoracic surgery based on surgical videos by reviewing its relevant researches in other surgical fields and anticipate its potential development in thoracic surgery.

[Preliminary Application of Body Surface Theodolitic Puncture Localization Method in Thoracoscopic Surgery of Pulmonary Ground-glass Nodules].

BACKGROUND: How to locate pulmonary ground-glass nodules in thoracoscopic surgery is an important clinical topic in minimally invasive thoracic surgery. There is no unified localization method at present. This study intends to investigate the accuracy and security of body surface theodolitic puncture localization method in video-assisted thoracoscopic surgery for pulmonary ground-glass nodules. METHODS: The clinical data of 41 patients from August 2018 to December 2019 were analyzed retrospectively, including 28 males and 13 females. After anesthesia, the patient was located by body surface theodolitic puncture, and then partial lobectomy was performed under video-assisted thoracoscopy. The distance from the nodule to the marked suture and the distance from the nodule to the incisal margin were measured, and the accuracy of localization, the rate of complication and the success rate of surgical resection were calculated. RESULTS: A total of 51 nodules in 41 patients were located by body surface theodolitic puncture localization method. The accuracy rate was 96.1%, and the average location time was 8.3 min. Puncture bleeding occurred in 5 cases (12.2%), all of which were successfully stopped by video-assisted thoracoscopy, and there were no other complications. All patients underwent thoracoscopic partial lobectomy, including 33 cases of anatomical segmentectomy and 8 cases of wedge lobectomy. All the patients in operation process smoothly. The distance between nodule and incisal margin was measured, and all specimens were more than 2 cm, reaching a safe distance. The success rate of surgical resection was 100.0%. CONCLUSIONS: In video-assisted thoracoscopic surgery for ground glass nodules of lung, the body surface theodolitic puncture localization method can be accurate, safe and simple.

High-mobility group box 3 (HMGB3) silencing inhibits non-small cell lung cancer development through regulating Wnt/ß-catenin pathway.

It has been reported that high-mobility group box 3 is overexpressed in various cancers. This study aimed to explore its function in non-small cell lung cancer (NSCLC). A546 and H460 cell lines were used for in vivo experiments, scratch healing tests, transwell migration and invasion experiments. It was first found that HMGB3 was highly expressed in tumor tissues in the patients and associated with NSCLC stage. Silencing of HMGB3 significantly slowed the growth, proliferation and invasion of NSCLC in vitro, and repressed cell growth in vivo. Mechanistic studies suggest that the observed effects were mediated by inhibiting the expression of ß-catenin/MMP7/c-Myc in Wnt pathway. Our study highlights the role of HMGB3 in NSCLC, which may provide a therapeutic target for the treatment of NSCLC.

Activator of thyroid and retinoid receptor increases sorafenib resistance in hepatocellular carcinoma by facilitating the Warburg effect.

Sorafenib resistance is a major challenge in the therapy for advanced hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of HCC resistance to sorafenib remain unclear. Activator of thyroid and retinoid receptor (ACTR, also known as SRC-3), overexpressed in HCC patients, plays an important oncogenic role in HCC; however, the link between ACTR and sorafenib resistance in HCC is unknown. Our study demonstrated that ACTR was one of the most upregulated genes in sorafenib-resistant HCC xenografts. ACTR increases sorafenib resistance through regulation of the Warburg effect. ACTR promotes glycolysis through upregulation of glucose uptake, ATP and lactate production, and reduction of the extracellular acidification and the oxygen consumption rates. Glycolysis regulated by ACTR is vital for the susceptibility of HCC to sorafenib in vitro and in vivo. Mechanistically, ACTR knockout or knockdown decreases the expression of glycolytic enzymes. In HCC patients, ACTR expression is positively correlated with glycolytic gene expression and is associated with poorer outcome. Furthermore, ACTR interacts with the central regulator of the Warburg effect, c-Myc, and promotes its recruitment to glycolytic gene promoters. Our findings provide new clues regarding the role of ACTR as a prospective sensitizing target for sorafenib therapy in HCC.

MIR205HG facilitates carcinogenesis of lung squamous cell carcinoma in vitro revealed by long noncoding RNA profiling.

As a subtype of non-small-cell lung cancer, lung squamous cell carcinoma (LUSC) accounts for one-fifth of all lung cancers. Unfortunately, no specific targetable aberration has yet been identified. Hence, it is of huge urgency and potential to identify aberrantly regulated genes in LUSC. Here, five pairs of LUSC samples and their corresponding adjacent tissues were subject to whole transcriptome sequencing. Our results showed that CTD-2562J17.6 and FENDRR were significantly downregulated while MIR205HG, LNC_000378, RP11-116G8.5, RP3-523K23.2, and RP5-968D22.1 were significantly upregulated in all five LUSC samples. Importantly, MIR205HG was upregulated in LUSC clinical samples as well as in LUSC cell lines. Interestingly, our results demonstrated that the expression level of MIR205HG is positively correlated with the malignancy. In addition, MIR205HG is required for LUSC cell growth and cell migration. Most importantly, our results showed that MIR205HG prohibits LUSC apoptosis via regulating Bcl-2 and Bax. Taken together, our data shed lights on the lncRNA regulatory nexus that controls the carcinogenesis of LUSC and provided potential novel diagnostic markers and therapeutic targets for LUSC.

Elevated SRC3 expression predicts pemetrexed resistance in lung adenocarcinoma.

Lung cancer has been the leading cause of cancer-related death for many years worldwide. Pemetrexed, either as monotherapy or combined with other agents, is the preferred chemotherapy regimen for lung adenocarcinoma. However, both de novo and acquired resistance against pemetrexed frequently occur and lead to poor prognosis of patients. The underlying mechanisms remain poorly characterized. Here, RNA-seq analysis is utilized to compare gene expression levels in an adenocarcinoma cell line A549 with those in its pemetrexed-resistant counterpart, A549/PEM. We show that SRC3 is one of the most significantly upregulated genes in pemetrexed-resistant cells. SRC3 specifically enhances pemetrexed resistance in cultured adenocarcinoma cells. In addition, SRC3 increases pemetrexed resistance by decreasing chemotherapy-induced apoptosis via downregulating ROS level. Mechanistically, SRC3 enhances pemetrexed resistance via regulating Nrf2 and AKT signaling pathway. High SRC3 expression is positively correlated with decreased responsiveness to pemetrexed rather than other chemotherapeutic agents and predicts a poorer clinical outcome in lung adenocarcinoma patients. These data indicate that knockdown of SRC3 may be useful to treat pemetrexed-resistant lung cancer and may also provide a specific biomarker to predict pemetrexed responsiveness in lung cancer.

LncRNA H19 promotes lung cancer proliferation and metastasis by inhibiting miR-200a function.

Lung cancer is the major cause leading to cancer mortality, and the 5-year survival rate for patients with lung cancer still remains low. It is urgent to fully understand the development and progression of lung cancer to discover new therapeutic targets and develop new therapeutic approaches. H19 was documented to be upregulated in lung cancer and related to cell proliferation. However, it is still unclear if H19 has other functions in lung cancer. The mRNA levels of genes were detected by qRT-PCR, and the cell proliferation rate and cell viability were measured through cell count assay and MTT assay. Transwell assays were applied to detect cell abilities to migration and invasion, while luciferase reporter assay and RNA pull-down assay were used to examine interaction between H19 and miR-200a. H19 expression was elevated in the lung cancer tissues and cell lines, while H19 overexpression promoted the lung cancer cell growth, cell migration and invasion, as well as the epithelial mesenchymal transition (EMT). Meantime, RNA pull-down assay showed that H19 interacted with miR-200a, and miR-200a inhibited the activity of H19-fused luciferase. Furthermore, H19 overexpression inhibited miR-200a function and thereby upregulated miR-200a target genes, ZEB1 and ZEB2.H19 sponged and inhibited miR-200a to de-repress expression of ZEB1 and ZEB2, and thereby enhanced lung cancer proliferation and metastasis.

LncRNA MALAT1 Promotes Lung Cancer Proliferation and Gefitinib Resistance by Acting as a miR-200a Sponge.

INTRODUCTION: Lung cancer is a major public health problem, as the second causes of cancer related death worldwide, with relatively low survival rates, and accessible drug resistance. Long non-coding RNAs (LncRNAs) have been identified as activator in lung cancer with elusive mechanisms. We aimed to detect the regulation of LncRNA MALAT1 in the proliferation and gefitinib resistance in lung cancer cells. METHODS: MALAT1 in A549 and HCC 1299 human lung adenocarcinoma cell lines was silenced by shRNA or overexpressed using plasmid, and the cell viability and cell proliferation were evaluated by MTT assay and soft agar colony formation assay. RNA levels were detected by RT-PCR, and the protein expression was measured by western blot. The binding between MALAT1 and miR-200a was validated by luciferase reporter assays using pSi-Chech 2 vectors. RESULTS: The cell viability and proliferation of A549 cells transfected with MALAT1 shRNA were significantly lower than the control. The MALAT1 expression in gefitinib resistant A549 cells was upregulated. miR-200a significantly inhibited the fluorescence of pSi-Check 2 vector with MALAT1 gene, suggesting the direct binding between MALAT1 and miR-200a. In addition, LncRNA MALAT1 promotes ZEB1 expression in A549 cells. CONCLUSION: Our study showed that MALAT1 promoted the proliferation and gefitinib resistance of lung cancer cells by sponging miR-200a, which regulates expression of ZEB1 in the A549 cells. This MALAT1/miR-200a axis could serve as new therapeutic target for lung cancer treatment.

MiR-150-5p regulates melanoma proliferation, invasion and metastasis via SIX1-mediated Warburg Effect.

Aerobic glycolysis is a hallmark of cancer. Sine oculis homeobox 1 (SIX1), a key transcription factor in terms of regulating aerobic glycolysis (the Warburg Effect), plays a critical role in tumorigenesis of various cancer types, including breast cancer, liver cancer, and lung cancer. However, the upstream regulating mechanisms of SIX1 in melanoma remain to be determined. MicroRNAs (miRNAs) have emerged as key regulators in tumorigenesis and progression. Here, we initially showed that microRNA-150-5p (miR-150-5p) inhibits SIX1 expression by directly targeting its 3'-UTR in melanoma cells. miR-150-5p suppressed melanoma cell proliferation, migration, and invasion through inhibition of SIX1. Mechanistically, miR-150-5p dampens glycolysis by decreasing the glucose uptake, lactate production, ATP generation, and extracellular acidification rate (ECAR), and increasing oxygen consumption rate (OCR) by targeting SIX1. Importantly, glycolysis regulated by miR-150-5p/SIX1 axis is critical for its regulation of melanoma growth and metastasis both in vitro and in vivo. Collectively, our study demonstrates the importance of miR-150-5p/SIX1 axis in melanoma, which could be a promising therapeutic target in melanoma.

A Pilot Study of Pulmonary Segmentectomy With Indocyanine Green Near-Infrared Angiography.

OBJECTIVES: Video-assisted thoracoscopic surgery (VATS) pulmonary segmentectomy is commonly used in treating small ground-glass opacity (GGO) nodules in lung. The identification of the intersegmental plane is one of the challenges. In this pilot study, we aimed to evaluate the feasibility of indocyanine green (ICG) angiography in VATS segmentectomy. METHODS: Nineteen GGO patients were enrolled, and VATS segmentectomy with ICG near-infrared angiography were performed between July 2017 and December 2017. Conventional 3-port VATS was used. ICG was injected intravenously after dominant arties were ligated. Intersegmental plane was identified and divided by stapler and electrocautery. RESULTS: All patients had perfect intersegmental plane visualization. The mean operation time was 140.8 minutes, and the mean blood loss was 23.7 mL. No complications due to ICG occurred. The mean chest tube duration was 4.6 days. No severe complications occurred in the perioperative period. The mean chest tube drainage duration was 4.6 days. Prolonged postoperative air leak (>5 days), which required no surgical intervention, occurred in 2 cases. There were no severe complications or in-hospital deaths. CONCLUSIONS: VATS segmentectomy with ICG near-infrared angiography is a reasonable treatment option to treat small GGO in lung, especially due to its good surgical view maintenance.

LncRNA-PCAT-1 promotes non-small cell lung cancer progression by regulating miR-149-5p/LRIG2 axis.

Long noncoding RNAs (lncRNAs) are key players in the development and progression of human cancers. The lncRNA PCAT-1 has been shown to be upregulated in human non-small cell lung cancer (NSCLC); however, its role and molecular mechanisms in NSCLC cell progression remain unclear. Here, we found that the higher expression of PCAT-1 led to a significantly poorer survival time, and multivariate analysis revealed that PCAT-1 was an independent risk factor of prognosis in NSCLC. Furthermore, we also found that the knockdown of PCAT-1 remarkably suppressed cell growth by inducing cell cycle arrest and apoptosis promotion in NSCLC cells. Moreover, the bioinformatics analysis and luciferase reporter assay revealed that PCAT-1 directly bound to the miR-149-5p, which has been reported to act as a tumor suppressor in diverse cancers. In addition, our results confirmed that the tumor-promoting effects of PCAT-1 in NSCLC cells are at least partly through negative modulation of miR-149-5p. Finally, mechanistic investigations showed that PCAT-1 upregulated the expression of miR-149-5p target gene leucine-rich repeats and immunoglobulin (Ig)-like domains 2 (LRIG2) through competitively "spongeing" miR-149-5p. Therefore, we concluded that PCAT-1 may promote the development of NSCLC through the miR-149-5p/LRIG2 axis.

Sedimentary record of plutonium in the North Yellow Sea and the response to catchment environmental changes of inflow rivers.

Plutonium (Pu) isotopes were first determined in surface and core sediment samples collected from the northern North Yellow Sea (NYS) to elucidate their source terms and deposition process as well as the response to catchment environmental changes of inflow rivers. 240Pu/239Pu atom ratios in all sediments showed the typical global fallout value of ∼0.18 without any influences from the nuclear weapons tests conducted recently in the North Korea or early in the Pacific Proving Ground. The large variation of 239+240Pu activities (0.022-0.515 mBq/g) observed in surface sediments should be mainly attributed to the re-suspension and transportation of fine sediments influenced by the Liaonan Costal Current. Based on the two 239+249Pu depth profiles with easily observed onset fallout levels (1952) and global fallout peaks (1963), 239+240Pu served as a valid time mark in the coastal sedimentary system. Riverine input Pu contributed only 15-27% to the total global fallout inventory (92.5-108.8 Bq/m2) in the northern NYS, much lower than that in the Yangtze River estuary (77-80%), indicating a better soil conservation in the northeast China due to higher forest coverage compared to the Yangtze River's drainage basin. The increase of riverine input Pu after 1980s reflected the more intense soil erosion degree caused by the land use and cover change due to the increment of human activities in the northeast China at the same period. Our results demonstrated that plutonium is a good indicator for studying sedimentary process and its response to the environment in the coastal area.

CSN5/Jab1 facilitates non-small cell lung cancer cell growth through stabilizing survivin.

CSN5/JAB1 is a critical subunit of the COP9 signalosome (CSN) and is essentially involved in diverse types of cancer, but little is known about the role of CSN5 in non-small cell lung cancer (NSCLC). In the current study, we found that CSN5 expression was higher in NSCLC tissues compared to the corresponding non-tumor tissues. High CSN5 expression level is closely correlated with tumor progression and poor survival in NSCLC patients. We also found that knockdown of CSN5 remarkably suppressed cell growth by inducing cell cycle arrest and apoptosis promotion in NSCLC cells. Mechanistic investigations revealed that CSN5 directly bound survivin and decreased its ubiquitination to enhance the protein stability of survivin. Additionally, our results confirmed that the tumor-promoting effects of CSN5 in NSCLC cells is at least partly through stabilization of survivin. Overall, our data suggested that CSN5 functions as an oncogenic gene in NSCLC, which could be a potential diagnostic and therapeutic target for NSCLC.