Hypoxia promotes non-small cell lung cancer cell stemness, migration, and invasion via promoting glycolysis by lactylation of SOX9.

BACKGROUND: Lung cancer is the deadliest form of malignancy and the most common subtype is non-small cell lung cancer (NSCLC). Hypoxia is a typical feature of solid tumor microenvironment. In the current study, we clarified the effects of hypoxia on stemness and metastasis and the molecular mechanism. METHODS: The biological functions were assessed using the sphere formation assay, Transwell assay, and XF96 extracellular flux analyzer. The protein levels were detected by western blot. The lactylation modification was assessed by western blot and immunoprecipitation. The role of SOX9 in vivo was explored using a xenografted tumor model. RESULTS: We observed that hypoxia promoted sphere formation, migration, invasion, glucose consumption, lactate production, glycolysis, and global lactylation. Inhibition of glycolysis suppressed cell stemness, migration, invasion, and lactylation. Moreover, hypoxia increased the levels of SOX9 and lactylation of SOX9, whereas inhibition of glycolysis reversed the increase. Additionally, knockdown of SOX9 abrogated the promotion of cell stemness, migration, and invasion. In tumor-bearing mice, overexpression of SOX9 promoted tumor growth, and inhibition of glycolysis suppressed tumor growth. CONCLUSION: Hypoxia induced the lactylation of SOX9 to promote stemness, migration, and invasion via promoting glycolysis. The findings suggested that targeting hypoxia may be an effective way for NSCLC treatment and reveal a new mechanism of hypoxia in NSCLC.

Multicenter phase I dose escalation and expansion study of pyrotinib in combination with camrelizumab and chemotherapy as first-line treatment for HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma.

Background: Pembrolizumab plus trastuzumab and chemotherapy showed remarkable efficacy as first-line therapy for advanced HER2-positive gastric cancer. Pyrotinib is an irreversible pan-HER inhibitor. This single-arm, open-label phase 1 dose-escalation (1a) and expansion (1b) study investigated camrelizumab, an anti-PD-1 antibody, plus pyrotinib and chemotherapy as first-line treatment for advanced HER2-positive gastric and gastroesophageal junction (G/GEJ) adenocarcinoma. Methods: Between June 2020 and June 2022, 41 patients with previously untreated HER2-positive locally advanced unresectable or metastatic G/GEJ adenocarcinoma were enrolled. In phase 1a, patients underwent a 3 + 3 escalating dose design, receiving oral pyrotinib (240 mg, 320 mg, or 400 mg daily), intravenous camrelizumab (200 mg), and CapeOX (oxaliplatin 130 mg/m2 on day 1 and capecitabine 1000 mg/m2 twice daily for two weeks) every 3 weeks until progression, intolerable toxicity or consent withdrawal. The recommended phase 2 dose (RP2D) of pyrotinib was determined and used in the phase 1b. The primary endpoints were the safety, maximum tolerated dose (MTD), RP2D, and confirmed objective response rate (ORR). This trial was registered with chictr.org, number ChiCTR2000029717. Findings: Among 41 patients, 10 were in phase 1a (3 at 240 mg, 3 at 400 mg, and 4 at 320 mg due to one patient withdrawing consent), and 31 were in phase 1b. In phase 1a, the MTD of pyrotinib was 320 mg daily due to dose-limiting toxicities (diarrhea [n = 3] and vomiting [n = 1]) observed at 400 mg. Based on all available data, the RP2D of pyrotinib was set at 320 mg. Among 41 patients, 20 patients (48.8%) developed grade ≥3 treatment-emergent adverse events (TEAEs), and four patients (9.8%) had any grade serious adverse events. No deaths occurred due to TEAEs. Among 27 patients who received the RP2D of pyrotinib and had a post-baseline tumor assessment, two patients (7.4%) achieved a confirmed complete response, and 19 patients (70.4%) achieved a confirmed partial response, resulting in a confirmed ORR of 77.8% (95% CI: 57.7-91.4). Interpretation: Pyrotinib plus camrelizumab and chemotherapy showed promising efficacy in the first-line treatment of advanced HER2-positive G/GEJ cancer. The safety profile was consistent with known toxicities of the agents, and no new or unexpected safety signals were identified. Funding: This study was funded by the Beijing Xisike Clinical Oncology Research Foundation (Y-HR2019-0377).

Associations between disrupted functional brain network topology and cognitive impairment in patients with rectal cancer during chemotherapy.

Introduction: Cognitive impairment has been identified in patients with non-central nervous system cancer received chemotherapy. Chemotherapy-induced changes in the brain are considered as the possible causes of the cognitive deficits of patients. This study aimed to explore chemotherapy-related functional brain changes and cognitive impairment in rectal cancer (RC) patients who had just finished chemotherapy treatment. Methods: In this study, RC patients after chemotherapy (on the day patients received the last dose of chemotherapy) (n=30) and matched healthy controls (HCs) (n=30) underwent cognitive assessments, structural magnetic resonance imaging (MRI) and resting-state functional MRI. The functional brain networks were constructed by thresholding the partial correlation matrices of 90 brain regions in the Anatomical Automatic Labeling template and the topologic properties were evaluated by graph theory analysis. Moreover, correlations between altered topological measures and scores of cognitive scales were explored in the patient group. Results: Compared with HCs, RC patients had lower scores of cognitive scales. The functional brain network had preserved small-world topological features but with a tendency towards higher path length in the whole network. In addition, patients had decreased nodal global efficiency (Eglo(i)) in the left superior frontal gyrus (dorsolateral), superior frontal gyrus (orbital part), inferior frontal gyrus (opercular part), inferior frontal gyrus (triangular part) and right inferior frontal gyrus (triangular part). Moreover, values of Eglo(i) in the superior and inferior frontal gyrus were positively associated with cognitive function in the patient group. Conclusion: These results suggested that cognitive impairment was associated with disruptions of the topological organization in functional brain networks of RC patients who had just finished chemotherapy, which provided new insights into the pathophysiology underlying acute effects of chemotherapy on cognitive function.

Functional changes of the prefrontal cortex, insula, caudate and associated cognitive impairment (chemobrain) in NSCLC patients receiving different chemotherapy regimen.

Introduction: Chemotherapy-induced cognitive impairment (CICI), termed "chemobrain", is highly prevalent in cancer patients following the administration of chemotherapeutic agents. However, the potential pathophysiological mechanisms underlying CICI remain unknown. This study aimed to explore the functional changes of the brain and associated cognitive impairment in non-small cell lung cancer (NSCLC) patients receiving different chemotherapy regimen. Methods: A total of 49 NSCLC patients (25 patients receiving pemetrexed plus carboplatin chemotherapy (PeCC) and 24 patients receiving paclitaxel plus carboplatin chemotherapy (PaCC)) and 61 healthy controls (HCs) were recruited and underwent resting-state functional magnetic resonance imaging (rs-fMRI) scanning, as well as cognitive function tests including Mini Mental State Exam (MMSE), Montreal Cognitive Assessment (MoCA), Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog). Brain functional activities were measured by regional homogeneity (ReHo) values, which were calculated and compared between groups. In addition, the associations between ReHo values of changed brain regions and scores of cognitive scales were evaluated. Results: NSCLC patients showed decreased scores of MMSE, MoCA and FACT-Cog and decreased ReHo values in the bilateral superior frontal gyrus (medial), middle frontal gyrus, left inferior frontal gyrus (orbital part) and increased ReHo values in the bilateral insula and caudate. Compared with HCs, patients receiving PeCC demonstrated decreased ReHo values in the right superior frontal gyrus (dorsolateral), left superior frontal gyrus (medial orbital), middle frontal gyrus, insula and rectus gyrus while patients receiving PaCC presented increased ReHo values in the right rolandic operculum, left insula and right caudate. Compared with patients receiving PaCC, patients receiving PeCC had decreased ReHo values in the left superior frontal gyrus (orbital part), middle frontal gyrus and increased ReHo values in the left inferior temporal gyrus, lingual gyrus. Moreover, positive relationships were found between ReHo values of the left and right superior frontal gyrus (medial) and the total scores of FACT-Cog in the patient group. Conclusion: The findings provided evidences that carboplatin-based chemotherapy could cause CICI accompanied by functional changes in the prefrontal cortex, insula, caudate. These might be the pathophysiological basis for CICI of NSCLC patients and were affected by the differences of chemotherapeutic agent administration through different biological mechanisms.

Plasmonic fiber-optic sensing system for in situ monitoring the capacitance and temperature of supercapacitors.

Compared with ex situ measurement, the in situ measurement is more suitable for inspecting complex electrochemical reactions and improving the intelligent energy storage management. However, most of the in situ investigation instruments are bulky and expensive. Here we demonstrate a miniaturized, portable, and low-cost fiber-optic sensing system for in situ monitoring the capacitance and temperature. It can help evaluate the self-discharge rate in supercapacitors (SCs). The fiber-optic sensing system with two probes are implanted inside the SCs to monitor the capacitance and temperature, respectively. The dual fiber-optic probes can work independently and avoid cross-interference through structure design. The fiber-optic localized surface plasmon resonance (LSPR) probe near the electrode surface can detect the capacitance in real-time by monitoring ion aggregation on the opposite electrode. The fiber-optic surface plasmon resonance (SPR) probe encapsulated in the thermosensitive liquid can independently detect the temperature change. The measurement uncertainties of the two sensing probes are 5.6 mF and 0.08 ℃, respectively. The proposed tiny and flexible fiber-optic sensing system provides a promising method for in situ monitoring the critical parameters. It is also a powerful tool for investigating electrochemical reactions in various energy storage devices.

Chemotherapy-induced functional brain abnormality in colorectal cancer patients: a resting-state functional magnetic resonance imaging study.

Introduction: Chemotherapy-induced cognitive impairment (i.e., "chemobrain") is a common neurotoxic side-effect experienced by many cancer survivors who undergone chemotherapy. However, the central mechanism underlying chemotherapy-related cognitive impairment is still unclear. The purpose of this study was to investigate the changes of intrinsic brain activity and their associations with cognitive impairment in colorectal cancer (CRC) patients after chemotherapy. Methods: Resting-state functional magnetic resonance imaging data of 29 CRC patients following chemotherapy and 29 matched healthy controls (HCs) were collected in this study, as well as cognitive test data including Mini Mental State Exam (MMSE), Montreal Cognitive Assessment (MoCA) and Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog). The measure of fractional amplitude of low-frequency fluctuation (fALFF) was calculated and compared between groups. The correlations between the fALFF of impaired brain region and cognitive performance were also analyzed. Results: Compared with HCs, CRC patients following chemotherapy showed decreased fALFF values in the left anterior cingulate gyrus (ACG) and middle frontal gyrus, as well as increased fALFF values in the left superior frontal gyrus (orbital part) and middle occipital gyrus. Moreover, positive associations were identified between fALFF values of the left ACG and the total scores of MMSE, MoCA and FACT-Cog in the patient group. Conclusion: These findings indicated that CRC patients after chemotherapy had decreased intrinsic brain activity in the left ACG, which might be vulnerable to the neurotoxic side-effect of chemotherapeutic drugs and related to chemotherapy-induced cognitive impairment.

Topological Abnormalities of Pallido-Thalamo-Cortical Circuit in Functional Brain Network of Patients With Nonchemotherapy With Non-small Cell Lung Cancer.

INTRODUCTION: Some previous studies in patients with lung cancer have mainly focused on exploring the cognitive dysfunction and deficits of brain function associated with chemotherapy. However, little is known about functional brain alterations that might occur prior to chemotherapy. Therefore, this study aimed to evaluate brain functional changes in patients with nonchemotherapy before chemotherapy with non-small cell lung cancer (NSCLC). METHODS: Resting-state functional MRI data of 35 patients with NSCLC and 46 matched healthy controls (HCs) were acquired to construct functional brain networks. Graph theoretical analysis was then applied to investigate the differences of the network and nodal measures between groups. Finally, the receiver operating characteristic (ROC) curve analysis was performed to distinguish between NSCLC and HC. RESULTS: Decreased nodal strength was found in the left inferior frontal gyrus (opercular part), inferior frontal gyrus (triangular part), inferior occipital gyrus, and right inferior frontal gyrus (triangular part) of patients with NSCLC while increased nodal strength was found in the right pallidum and thalamus. NSCLC also showed decreased nodal betweenness in the right superior occipital gyrus. Different hub regions distribution was found between groups, however, no hub regions showed group differences in the nodal measures. Furthermore, the ROC curve analysis showed good performance in distinguishing NSCLC from HC. CONCLUSION: These results suggested that topological abnormalities of pallido-thalamo-cortical circuit in functional brain network might be related to NSCLC prior to chemotherapy, which provided new insights concerning the pathophysiological mechanisms of NSCLC and could serve as promising biological markers for the identification of patients with NSCLC.

ß-Elemene Restrains PTEN mRNA Degradation to Restrain the Growth of Lung Cancer Cells via METTL3-Mediated N6 Methyladenosine Modification.

Lung cancer is one of the most fatal malignancies and the leading cause of cancer death worldwide. ß-Elemene, a well-known anticancer drug, has drawn a great deal of attention from researchers attributed to its limited side impacts. N6-Methyladenosine (m6A) modification is the most common RNA modification and plays a vital role in the pathogenesis of multiple tumors. However, the functional link between ß-elemene and the m6A modification in lung cancer development remains unexplored. In this study, we investigated whether m6A modification was responsible for the impacts of ß-elemene on lung cancer. Firstly, outcomes suggested that ß-elemene restrained the malignant behaviors of A549 together with H1299 cells. Thereafter, we observed that ß-elemene markedly regulated METTL3, YTHDF1, and YTHDC1 among various m6A modulators. METTL3 was selected for further study because of its oncogenic function in lung cancer. RT-qRCR and western blot assays exhibited that the mRNA and protein expression levels of METTL3 were lessened by the administration of ß-elemene. Mechanistically, ß-elemene exerted the restrictive impacts on the cell growth of lung cancer in vivo and in vitro through targeting METTL3. More importantly, ß-elemene contributed to the augmented PTEN expression via suppressing its m6A modification. To sum up, we provided strong clues that ß-elemene promoted PTEN expression to retard lung cancer progression by the regulation of METTL3-mediated m6A modification.

Clinical and pathological characteristics of multiple primary malignant neoplasms cases.

OBJECTIVES: To investigate the clinical and pathological features of multiple primary malignant neoplasms (MPMNs) cases. METHODS: The clinical data of 24 105 tumour patients admitted to Jiangsu Cancer Hospital in 2018 were retrospectively reviewed, and 270 patients with MPMNs were selected as the research subjects. Among them, 101 cases of synchronous carcinoma (SC) and 92 cases of metachronous carcinoma (MC) were divided into groups for statistical analysis. Univariate and multivariate cox regression analyses were conducted using SPSS 22.0 software. RESULTS: Among 24 105 cases, there was a male-to-female ratio of 1.45:1. Compared with MC cases, SC patients have a higher proportion of male cases. Primary neoplasms in gastric cancer, head and neck cancer, oesophageal cancer and colon cancer occupied most cases in male MPMNs, while primary breast cancer ranked first in female MPMNs. In addition, the leading secondary neoplasms were duodenal carcinoma, lung cancer and male MPMNs and lung cancer in female MPMNs. As for SC MPMNs, primary neoplasms were occupied by lung cancer, gastric cancer and oesophageal cancer, while the secondary neoplasms were mostly consisted of oesophageal cancer and lung cancer. Finally, the MC MPMNs were mostly consisted of breast cancer and gastric cancer as primary neoplasms, while lung cancer and oesophageal cancer as secondary neoplasms. CONCLUSIONS: Screening for primary cancer should be strengthened over the age of 50 years for male patients with gastric cancer or female patients with breast cancer to reduce or monitor the occurrence of MPMNs.

IL-33 Promotes the Growth of Non-Small Cell Lung Cancer Cells Through Regulating miR-128-3p/CDIP1 Signalling Pathway.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths, and it is also the most frequently diagnosed cancer. Previous studies indicate that IL-33 plays a crucial role in the development of NSCLC. In recent years, the role of miRNAs in cancer has become increasingly clear. However, reports focused on the relation between IL-33 and miRNAs in NSCLC have been limited. METHODS: The expression of IL-33 and miR-128-3p was detected by qPCR. MTT, EdU, and colony formation assays were used to detect the proliferation ability of NSCLC cells. Transwell assay was used to investigate the migration and invasion of NSCLC cells. The expression of bax, cyt-c, and caspase 3 was detected by Western blot. Finally, in vivo tumor xenograft was used to detect the effects of IL-33 and miR-128-3p on tumor growth capacity. RESULTS: IL-33 was notably increased in the serum and tumor tissue of NSCLC patients. The in vitro function study revealed that IL-33 significantly promotes the proliferation, migration, and invasion of the NSCLC cells. In vivo experiments further confirmed the pro-tumor effect of IL-33 on NSCLC. The study on the underlying mechanism elucidated that IL-33 regulates the expression of miR-128-3p, which can directly target and inhibit the expression of CDIP1. Furthermore, IL-33 regulates the expression of downstream apoptotic proteins such as bax, cyt-c, and caspase3. Rescue experiments demonstrated that miR-28-3p can reverse the effect of IL-33. CONCLUSION: These findings indicated that IL-33 and miR-128-3p may play a potential role in the diagnosis and treatment of NSCLC.

A pan-cancer analysis of the oncogenic role of Keratin 17 (KRT17) in human tumors.

BACKGROUND: Although new evidence from cells or animals suggests a relationship between Keratin 17 (KRT17) and cancer, no pan-cancer analysis is currently available. METHODS: The expression level of KRT17 in generalized carcinoma was detected by the Tumor Immune Estimation Resource, version 2 (TIMER2) database, and then verified the protein expression of KRT17 in different cancer species in UALCAN database, and analyzed the relationship between the expression level of KRT17 and the clinical stage and survival of different cancers. We further explored the genetic variation of KRT17 in different tumor types included in The Cancer Genome Atlas (TCGA) and the specific mutations in each domain. The changes of KRT17 protein phosphorylation levels and protein expression levels at different phosphorylation sites in different tumors were explored. TIMER2 database was used to explore the potential relationship between the infiltration level of different immune cells and KRT17 gene expression in different TCGA cancer types. Finally, the protein binding to KRT17 and genes related to KRT17 expression were explored by STRING database and TCGA database. RESULTS: KRT17 is overexpressed in most malignancies, and we observed a distinct relationship between KRT17 expression and tumor patient prognosis. Enhanced phosphorylation levels of S13, S24, S32, and S39 were observed in several tumors, such as lung adenocarcinoma (LUAD), colon and ovarian cancers, and uterine corpus endometrial carcinoma (UCEC). Intermediate filament cytoskeleton and keratinization may be simultaneously acting with KRT17 on tumor pathogenesis. CONCLUSIONS: Our pan-cancer analysis provides relatively complete information on the oncogenic functions of KRT17 in various cancers.

Cancer-associated changes of emotional brain network in non-nervous system metastatic non-small cell lung cancer patients: a structural connectomic diffusion tensor imaging study.

BACKGROUND: Emotional distress frequently occur in cancer patients following diagnosis. Previous neuroimaging studies have demonstrated that depression and anxiety are associated with functional and structural brain abnormalities. However, little is known about the cancer-associated changes of emotional brain network in non-small cell lung cancer (NSCLC) patients. The aim of this study was to assess the topological features of brain structural network and emotions in non-nervous system metastatic NSCLC patients prior to chemotherapy. METHODS: Twenty-four treatment-naïve patients with non-nervous system metastatic NSCLC and 25 healthy controls (HC) matched for gender, age and education participated in this study. All subjects underwent diffusion tensor imaging (DTI), and were assessed with the 17 item hamilton depression rating scale (HAMD-17) and hamilton anxiety rating scale (HAMA). Properties of brain network were examined by the method of graph-theoretic analysis. The assessments included small-worldness, clustering coefficient and shortest path length. RESULTS: NSCLC patients had higher scores of HAMD-17 and HAMA when compared with HC. Additionally, we found a small-world topology of brain white matter network in both NSCLC and HC. NSCLC patients had significantly reduced clustering coefficient compared to healthy controls in the left hippocampus. Moreover, increased shortest path length were identified in NSCLC patients, which included the left middle frontal gyrus (orbital part), superior temporal gyrus and right Rolandic operculum, rectus gyrus, lenticular nucleus (putamen). However, no correlations were found between the impaired brain regions and HAMD-17, HAMA scores of NSCLC patients. CONCLUSIONS: Our results indicated impaired topological characteristics in the brain structural network of non-nervous system metastatic NSCLC patients prior to chemotherapy, which might account for the cancer-related emotional distress. Our findings demonstrated that NSCLC might affect brain regions involved in the process of emotion, which identified the basis of emotional changes associated with cancer.

B7-H4 and HHLA2, members of B7 family, are aberrantly expressed in EGFR mutated lung adenocarcinoma.

BACKGROUND: In order to find new immune targets for lung cancer with different EGFR mutant status, we describe differential expression profiles of checkpoint molecules of the new discovery B7 family member to find new immune targets for lung cancer with different EGFR statuses. METHODS: We performed immunohistochemistry with antibodies of B7-H3, B7-H4, VISTA, B7-H6, HHLA2, IDO-1, PD-L1 and CD8 in lung adenocarcinoma tissues constructed from 372 cases in the discovery cohort and 231 cases in the validation set. The differential expression profiles of these indices in EGFR mutant and wild-type lung adenocarcinoma was described and compared. RESULTS: In the discovery cohort, the median IHC scores of B7-H4 and HHLA2 for the EGFR mutant group were significantly higher than those in the wild-type group (median score [interquartile range], mutant vs. wild type: 3.250 [0-7.000] vs. 5.000 [1.000-7.000], P = 0.045 for B7-H4; 8.000 [6.000-10.500] vs. 7.000 [5.000-8.630] P = 0.003 for HHLA2). Meanwhile, the median IHC scores of IDO-1 and PD-L1 in the wild-type group were significantly higher than those in the mutant group (median score [interquartile range], mutant vs. wild type: 1.000 [0-5.000] vs. 3.000 [0-8.500], P = 0.000 for IDO-1; 0 [0-3.500] vs. 3.000 [0-6.000], P = 0.000 for PD-L1). Results above was confirmed in the discovery cohort. The increased CD8 and decreased HHLA2 expression levels were associated with long disease-free survival in lung adenocarcinoma (P = 0.000 for CD8 expression and P = 0.004 for HHLA2 expression). CONCLUSIONS: B7-H4 and HHLA2 are promising immune targets for lung adenocarcinoma, especially for patients with EGFR mutation.

LncRNA KTN1-AS1 promotes the progression of non-small cell lung cancer via sponging of miR-130a-5p and activation of PDPK1.

Non-small cell lung cancer (NSCLC) is the major cause of cancer-associated death worldwide, but its underlying mechanisms remain to be fully elucidated. Long noncoding RNAs (lncRNAs) are known to play an important role in the aberrant regulation of gene expression in many cancers, including NSCLC. Here, we investigated the involvement of the lncRNA KTN1-AS1 in NSCLC. We found that KTN1-AS1 expression was upregulated in NSCLC tissue and was positively associated with poor prognosis. KTN1-AS1 knockdown inhibited cell growth and proliferation, increased apoptosis, and modulated the expression of cell cycle- and apoptosis-related proteins (cyclin A1, cyclin-dependent kinase 2, Bcl2, and Bax) in NSCLC cell lines and tumour xenografts in nude mice. KTN1-AS1 bound to and directly regulated the expression of miR-130a-5p. Notably, miR-130a-5p overexpression suppressed NSCLC cell proliferation and increased apoptosis in vitro and in vivo, and this effect was reversed by KTN1-AS1 overexpression. Finally, we showed that KTN1-AS1 modulated the expression of 3-phosphoinositide-dependent protein kinase 1 (PDPK1), a miR-130a-5p target and key regulator of autophagy in NSCLC cells. Taken together, our results suggest that the KTN1-AS1/miR-130a-5p/PDPK1 pathway may be a potential therapeutic target for NSCLC.

Clinical Evaluation of Serum Tumor Markers in Patients With Advanced-Stage Non-Small Cell Lung Cancer Treated With Palliative Chemotherapy in China.

Aim: This study aims to analyze the prognostic value of seven tumor makers and also investigate the response of palliative chemotherapy in advanced NSCLC patients with advanced disease. Methods: Medical records of 278 advanced NSCLC Chinese patients who received six cycles of palliative chemotherapy were retrospectively reviewed under ethical approval (JSCH2019K-011). Univariate and multivariate Cox regression analyses were performed using SPSS 24 to find the clinical value of these tumor markers and to identify the factors that were associated with progression-free survival (PFS), as well as the response to palliative chemotherapy. Results: In baseline characteristic, the high levels of CEA, CA-125, CA-199, AFP, NSE, CYFRA21-1, and CA15-3 were detected in 209 (75.18%), 139 (50.0%), 62 (22.30%), 18 (6.47%), 155 (55.75%), 176 (63.30%), and 180 (64.74%) patients, respectively. Univariate analysis revealed that patients with high vs. normal levels of all tumor markers had an increased risk of poor prognosis. In the multivariable Cox regression model, the patient with (high vs. normal) CYFRA21-1 levels (HR = 1.454, P = 0.009) demonstrated an increased poor PFS. However, patients with (high vs. normal) CA19-9 levels (HR = 0.524, P < 0.0001) and NSE levels (HR = 0.584, P < 0.0001) presented a decreased risk of PFS. Also, patients receiving 3-drugs regimen had better PFS compared to those on 2-drugs regimen (P = 0.043). Conclusions: The high levels of CYFRA21-1 was correlated with a poor prognostic factor of PFS for Advanced NSCLC patients. However, the high levels of CA19-9 and NSE were associated with a better prognostic factor of PFS. Additionally, smoking habits and tumor status had a poor prognostic factor of PFS. Moreover, we found that antiangiogenic therapy has high efficacy with first-line chemotherapy and longer PFS of NSCLC patients.

Insight into the vacancy effects on mechanical and electronic properties of V5Si3 silicides from first-principles calculations.

As so far, the development and application prospects of transition metal silicon-based materials have received the considerable attention. V-Si silicides are one of the most important silicon-based high-temperature materials. Brittle behavior hinders their wide application. In present work, the influence of vackancies on mechanical properties, brittle/ductile behavior and electronic properties of V5Si3 silicides is studied using the first-principles calculations. The vacancy formation energy, elastic constants, elastic modulus, brittle/ductile behavior and electronic behavior of the perfect V5Si3 and V5Si3 with vacancies were comparatively calculated and discussed, respectively. The thermodynamic data and phonon frequencies demonstrate that the V5Si3 with different vacancies can exhibit the structural stability. Although the vacancies weaken the hardness of V5Si3, the vacancies improve the brittle behavior of the parent V5Si3. Especially, the Si-Va1 and Si-Va2 vacancies in V5Si3 induced brittle-to-ductile transition for V5Si3 desilicides. The electronic structures explain the mechanism of the difference of mechanical properties for different vacancies.

EGFR E746-A750 deletion in lung cancer represses antitumor immunity through the exosome-mediated inhibition of dendritic cells.

EGFR-mutant lung cancer (LC) patients display a poor response to PD-1/PD-L1 blockade. In the absence of independent genetic validation, whether EGFR mutation distorts host antitumor immunity is unknown. Here, we showed that in the clinic, LC with the E746-A750 deletion mutation (EGFR-19del) displayed a temporal association with the loss of intratumoral CD8+ T cells. In a xenograft model, EGFR-19del-expressing Lewis lung cancer (LLC) tumors had a low T cell density at the early stage of tumor development, along with dendritic cells (DCs) exhibiting variant phenotypes in the tumors and draining lymph nodes (LNs). Importantly, EGFR-19del DCs were observed in the LNs of tumor-bearing mice and LC patients. The proliferative activity of T cells within the LN was significantly dampened. In vitro experiments indicated that the function of DCs was repressed by EGFR-19del LLC cells through exosome uptake in which exosomes derived from the EGFR-19del LLC cells could efficiently transfer active EGFR-19del to the surface of the DCs. Injection of EGFR-19del tumor-derived exosomes promoted LLC tumor progression and induced immunosuppression. The combination of gefitinib and GM-CSF treatment recovered tumor T cell infiltration in EGFR-19del tumors by rescuing the function of DCs and increasing the efficacy of anti-PD-L1 treatment. Together, these results indicated that LC with the EGFR E746-A750 deletion mutation induced anergic DCs to repress antitumor immunity through exosomes.

LncRNA DHRS4-AS1 Inhibits the Stemness of NSCLC Cells by Sponging miR-224-3p and Upregulating TP53 and TET1.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death. This study aimed to examine the roles of DHRS4-AS1/miR-224-3p signaling in the cancer cell stemness of NSCLC. Real-time PCR showed that DHRS4-AS1 was downregulated in cancerous tissues, and bioinformatics analysis revealed that high DHRS4-AS1 expression indicated a good prognosis for NSCLC patients. Sphere and colony formation assays showed that DHRS4-AS1 overexpression significantly suppressed NSCLC cell colony formation and stem cell-like properties. DHRS4-AS1 also abrogated the expression of OCT4, SOX2, CD34, and CD133, markedly inhibited the expression of epithelial-mesenchymal transition (EMT)-related factors, N-cadherin, ZEB1, and Vimentin, and increased E-cadherin expression in spheres. Furthermore, luciferase reporter assays and real-time PCR analysis demonstrated that DHRS4-AS1 and miR-224-3p were antagonistically repressed in NSCLC cells. RNA immunoprecipitation (RIP) analysis revealed that DHRS4-AS1 interacted with miR-224-3p. DHRS4-AS1 partially reversed the miR-224-3p-decreased TP53 and TET1, resulting in the inhibition of tumor growth in vivo. Finally, TP53 and TET1 were antagonistically regulated by DHRS4-AS1 and miR-224-3p in NSCLC cells. In conclusion, TP53- and TET1-associated DHRS4-AS1/miR-224-3p axis is an essential mechanism by which NSCLC modulates cancer cell stemness.

Inhibitor of ghrelin receptor reverses gefitinib resistance in lung cancer.

Gefitinib is the first-generation EGFR tyrosine kinase inhibitor (EGFR-TKI), which is used in the treatment of NCSLC patients through interrupting EGFR signaling pathway. Although gefitinib prolongs patients' progression-free survival (PFS), acquired resistance occurs in advanced NSCLC patients. In this study, we mainly investigated the effects of antagonist for ghrelin-R (D-lys-3-GHRP-6) on conquering acquired gefitinib resistance in human lung cancer cells. We found that GHSR was overexpressed in our established HCC827/GR cells compared with parental cells, accompanied with increase of p-AKT and p-ERK1/2. Treatment of D-lys-3-GHRP-6 significantly decreased p-AKT and p-ERK1/2 expression in HCC827/GR cells. H1650 cells and HCC827/GR cells were treated with control, gefitinib, D-lys-3-GHRP-6 and D-lys-3-GHRP-6 + gefitinib, respectively. In H1650 and HCC827/GR cells, combination of D-lys-3-GHRP-6 and gefitinib significantly inhibited cell proliferation and Bcl2 protein level, induced the cell apoptosis and cleaved-caspase3 protein level compared with control group, while there was no significant difference between control and gefitinib group.

Comparative Effectiveness of Pemetrexed-platinum Doublet Chemotherapy With or Without Bevacizumab as First-line Therapy for Treatment-naive Patients With Advanced Nonsquamous Non-small-cell Lung Cancer in China.

PURPOSE: Bevacizumab plus platinum-based doublet chemotherapy is recommended by the National Comprehensive Cancer Network as a category 1 regimen and is widely used in patients with advanced nonsquamous non-small-cell lung cancer (NS-NSCLC). In China, a common first-line chemotherapy for NS-NSCLC is the pemetrexed-platinum doublet regimen (Pem-Pt). However, limited evaluation exists to show the effectiveness of the Pem-Pt + bevacizumab (Bev) regimen in advanced NS-NSCLC. This study describes the treatment patterns, effectiveness, and safety profile of Pem-Pt + Bev in patients with NS-NSCLC in China in clinical practice. METHODS: Data from eligible patients with advanced NS-NSCLC who received Pem-Pt with (136 patients) or without (97 patients) bevacizumab from January 2012 to March 2017 were retrospectively evaluated. The effectiveness outcomes included the assessment of progression-free survival (PFS) and objective response rate (ORR) in the overall population, the percentage of patients with pleural effusion or brain metastasis, as well as the percentage of patients receiving maintenance therapy. Moreover, the intracranial remission rate in patients with brain metastasis was estimated. Finally, the adverse events with the 2 treatments were addressed. FINDINGS: Compared with the Pem-Pt regimen, the Pem-Pt + Bev regimen was associated with a significantly longer median PFS and a higher ORR in the overall population (P = 0.0002). An improvement in ORR was observed in Pem-Pt + Bev-treated patients with brain metastasis (P = 0.0045). Moreover, patients receiving Pem-Pt + Bev and maintenance therapy not only showed a longer median PFS than that in those whose treatment was interrupted after induction but also a longer median PFS than that in patients who received Pem-Pt and maintenance therapy. The safety profile was acceptable in all groups, with no observations of hypertension, proteinuria, severe bleeding (1 case of grade I epistaxis was reported with Pem-Pt + Bev), or any unexpected findings reported. IMPLICATIONS: These results from clinical practice further support the concept that pemetrexed-platinum doublet plus bevacizumab could be an effective and tolerable regimen in patients with advanced NS-NSCLC in China.