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CircRNA B cell linker regulates cisplatin sensitivity in nonsmall cell lung cancer via microRNA-25-3pBarH‑like homeobox 2 axis.

Cisplatin (DDP) was a commonly used drug in the treatment of nonsmall cell lung cancer (NSCLC). However, the current resistance of patients to DDP seriously affected its therapeutic effect. Circular RNAs (circRNAs) have been reported to regulate drug resistance in cells. The purpose of this paper is to study the effect of circRNA B cell linker (circBLNK) in DDP resistance of NSCLC. The abundances of circBLNK, microRNA-25-3p (miR-25-3p) and BarH‑like homeobox 2 (BARX2) were examined by quantitative real-time PCR and western blot analysis. Cell proliferation and apoptosis were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay, EdU assay and flow cytometry. Transwell assay was applied to assess cell migration and invasion. Protein levels were quantified by western blot analysis. Dual-luciferase reporter assay was enforced to confirm the links among circBLNK, miR-25-3p and BARX2. The mice models were enforced to evaluate tumorigenicity. Herein, circBLNK and BARX2 were lower-expressed, whereas miR-25-3p was higher-expressed in A549DDP and H1299DDP cells than their homologous parental NSCLC cells. CircBLNK increases improved DDP sensitivity of NSCLC cells by promoting cell apoptosis and inhibiting proliferation, migration and invasion. Moreover, we confirmed that circBLNK regulated BARX2 by inhibiting miR-25-3p. Accordingly, overexpression of circBLNK improved DDP sensitivity of NSCLC cells via miR-25-3pBARX2 axis. Besides, circBLNK reduced cell resistance to DDP, thereby inhibiting tumor development in mice. CircBLNK promoted the DDP sensitivity of NSCLC via regulating miR-25-3pBARX2 axis.

Solvated electron-induced synthesis of cyclodextrin-coated Pd nanoparticles mechanistic, catalytic, and anticancer studies.

Herein, using

Retracted MicroRNA‑629 inhibition suppresses the viability and invasion of non‑small cell lung cancer cells by directly targeting RUNX3.

Following the publication of this paper, it was drawn to the Editors attention by a concerned reader that certain of the data shown for the cell invasion assays in Figs. 4D and 5D were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to

Dual inhibition of EGFR‑VEGF An effective approach to the treatment of advanced non‑small cell lung cancer with EGFR mutation (Review).

On a global scale, the incidence and mortality rates of lung cancer are gradually increasing year by year. A number of bad habits and environmental factors are associated with lung cancer, including smoking, second‑hand smoke exposure, occupational exposure, respiratory diseases and genetics. At present, low‑dose spiral computed tomography is routinely the first choice in the diagnosis of lung cancer. However, pathological examination is still the gold standard for the diagnosis of lung cancer. Based on the classification and stage of the cancer, treatment options such as surgery, radiotherapy, chemotherapy, targeted therapy and immunotherapy are available. The activation of the EGFR pathway can promote the survival and proliferation of tumor cells, and the VEGF pathway can promote the formation of blood vessels, thereby promoting tumor growth. In non‑small cell lung cancer (NSCLC) with EGFR mutation, EGFR activation can promote tumor growth by promoting VEGF upregulation through a hypoxia‑independent mechanism. The upregulation of VEGF can make tumor cells resistant to EGFR inhibitors. In addition, the expression of the VEGF signal is also affected by other factors. Therefore, the use of a single EGFR inhibitor cannot completely inhibit the expression of the VEGF signal. In order to overcome this problem, the combination of VEGF inhibitors and EGFR inhibitors has become the method of choice. Dual inhibition can not only overcome the resistance of tumor cells to EGFR inhibitors, but also significantly increase the progression‑free survival time of patients with NSCLC. The present review discusses the associations between the EGFR and VEGF pathways, and the characteristics of dual inhibition of the EGFR‑VEGF pathway.

Retracted Tripartite motif 16 inhibits hepatocellular carcinoma cell migration and invasion.

Following the publication of this paper, it was drawn to the Editors attention by a concerned reader that various panels showing the western blotting data in Figs. 1D, 3A, 6A and C, 9B and 10A, the Transwell migration and invasion assays in Fig. 10C, and the HE staining images from the lung portrayed in Fig. 5B were strikingly similar to data largely appearing in different form in other articles by different authors from different research institutions. Moreover, the data panels showing the Transwell migration and assay experiments in Figs. 3C and D and 4C and D showed several overlapping sections, such that the data appeared to have been selected from a small number of original sources to represent differently performed experiments. Owing to the fact that the contentious data in the above article had already been published prior to its submission to

Isofraxidin enhances hyperthermia‑induced apoptosis via redox modification in acute monocytic leukemia U937 cells.

The cell‑killing potential of most chemotherapeutic agents is enhanced by a temperature elevation. Isofraxidin (IF) is a coumarin compound widely found in plants, such as the Umbelliferae or Chloranthaceae families. IF induces anticancer effects in lung and colorectal cancer. To the best of our knowledge, the combined effects of hyperthermia (HT) and IF on heat‑induced apoptosis have not been reported. Acute monocytic leukemia U937 cells were exposed to HT with or without IF pre‑treatment. Apoptosis was measured by Annexin V‑FITCPI double staining assay using flow cytometry and cell viability was observed by cell counting kit assay, DNA fragmentation. The mechanism involved in the combination was explored by measuring changes in the mitochondrial membrane potential, (MMP), intracellular ROS generation, expression of apoptosis related protein, and intracellular calcium ion level. It was demonstrated that IF enhanced HT‑induced apoptosis in U937 cells. The results demonstrated that combined treatment enhanced mitochondrial membrane potential loss and transient superoxide generation increased protein expression levels of caspase‑3, caspase‑8 and phosphorylated‑JNK and intracellular calcium levels. Moreover, the role of caspases and JNK was confirmed using a pan caspase inhibitor (zVAD‑FMK) and JNK inhibitor (SP600125) in U937 cells. Collectively, the data demonstrated that IF enhanced HT‑induced apoptosis via a reactive oxygen species mediated mitochondriacaspase‑dependent pathway in U937 cells.

Cluster Bomb Based Bismuth Nano-in-Micro Spheres Formed Dry Powder Inhalation for Thermo-Radio Sensitization Effects of Lung Metastatic Breast Cancer.

Lung metastatic breast cancer (LMBC) is mainly diagnosed through CT imaging and radiotherapy could be the most common method in the clinic to inhibit tumor proliferation. While the sensitivity of radiotherapy is always limited due to the hypoxic tumor microenvironment and high doses of irradiation easily induce systemic cytotoxicity. Metal-based materials applied as radiosensitizers have been widely investigated to improve efficiency and reduce the doses of irradiation. Herein, it is aimed to overcome these problems by designing biodegradable lipid-camouflaged bismuth-based nanoflowers (DP-BNFs) as both a photo-thermo-radiosensitizer to develop a novel photothermal therapy (PTT) and radiotherapy combination strategy for LMBC treatment. To achieve effective lung deposition, Cluster Bomb structure-based DP-BNFs nano-in-micro dry powder inhalation (DP-BNFLat-MPs) are formulated through spray-dried technology. The DP-BNFs cluster in the microsphere to improve their tumor-targeted lung deposition with a high fine particle fraction followed by burst releasing of DP-BNFs for targeting delivery and LMBC therapy. The DP-BNFLat-MPs exhibit excellent photothermal conversion efficiency, radiotherapy enhancement, and CT imaging ability in vitro, which synergistically inhibit cell proliferation and metastasis. In vitro and in vivo data prove that combining PTT and radiotherapy with DP-BNFLat-MPs as a thermo-radio dual-sensitizer significantly enhances LMBC tumor metastasis inhibition with good biocompatibility and low toxicity.

Cancer-associated fibroblasts in acute leukemia.

Although the prognosis for acute leukemia has greatly improved, treatment of relapsedrefractory acute leukemia (RR AL) remains challenging. Recently, increasing evidence indicates that the bone marrow microenvironment (BMM) plays a crucial role in leukemogenesis and therapeutic resistance therefore, BMM-targeted strategies should be a potent protocol for treating RR AL. The targeting of cancer-associated fibroblasts (CAFs) in solid tumors has received much attention and has achieved some progress, as CAFs might act as an organizer in the tumor microenvironment. Additionally, over the last 10 years, attention has been drawn to the role of CAFs in the BMM. In spite of certain successes in preclinical and clinical studies, the heterogeneity and plasticity of CAFs mean targeting them is a big challenge. Herein, we review the heterogeneity and roles of CAFs in the BMM and highlight the challenges and opportunities associated with acute leukemia therapies that involve the targeting of CAFs.

Airway Detection in COPD at Low-Dose CT Using Deep Learning and Multiparametric Freeze and Grow.

To present and validate a fully automated airway detection method at low-dose CT in patients with chronic obstructive pulmonary disease (COPD). In this retrospective study, deep learning (DL) and freeze-and-grow (FG) methods were optimized and applied to automatically detect airways at low-dose CT. Four data sets were used two data sets consisting of matching standard- and low-dose CT scans from the Genetic Epidemiology of COPD (COPDGene) phase II (2014-2017) cohort ( At low-dose CT, 56 294 of 62 480 (90.1%) airways of the reference total airway count (TAC) and 32 109 of 37 864 (84.8%) airways of the peripheral TAC (TAC A low-cost, automated CT-based airway detection method was suitable for investigation of airway phenotypes at low-dose CT.

Dysbiosis of the lower airway flora is associated with lung cancer, of which the relationship between Streptococcus, especially pathogenic Bronchoalveolar lavage fluid (BALF) samples were prospectively collected from patients with pulmonary nodules during diagnostic bronchoscopy, and finally included 70 patients diagnosed with primary lung cancer and 20 patients with benign pulmonary nodules as the disease control group. The differential flora was screened by 16S ribosomal RNA (rRNA) gene amplicon sequencing. An 16S rRNA sequencing analysis showed that the abundance of Streptococcus in the lower airway flora of lung cancer patients was significantly increased. After exposure to The data provided by this study show that

A Dosimetric Study Comparing Different Radiotherapy Planning Techniques With and Without Deep Inspiratory Breath Hold for Breast Cancer.

To analyze whether deep inspiratory breath hold (DIBH) would be dosimetrically beneficial irrespective of radiotherapy planning techniques for patients with left breast cancers requiring adjuvant radiotherapy. Planning CT scans were taken in free-breathing (FB) as well as deep-inspiration breath hold (DIBH) for patients requiring adjuvant radiotherapy for left breast cancers. After registration, three radiotherapy plans - 3D-conformal radiotherapy (3DCRT), intensity modulated RT (IMRT), and volumetric modulated arc-therapy (VMAT) - were generated for both FB and DIBH scans for each patient. The dose-volume parameters were collected from the dose-volume histogram and analyzed. A paired The study was conducted on thirteen patients. The mean dose of the left lung was reduced with DIBH by 32%, 24%, and 6% (8.6 Gy, 6.6 Gy, and 6.4 Gy) with 3DCRT, IMRT, and VMAT, respectively. The mean heart dose was reduced by 3.3 Gy (2.2 vs 5.5 Gy), 2.2 Gy (7.5 vs 9.7 Gy), and 1.2 Gy (5.8 vs 7 Gy) with 3DCRT, IMRT, and VMAT with DIBH. Similarly, the left anterior descending artery (LAD) mean dose was relatively reduced by 80%, 34%, and 20% when compared with the FB scans for 3DCRT, IMRT, and VMAT respectively, with max dose in the 3DCRT plan. DIBH appears to have maximum benefit in achieving a better sparing of organs-at-risk for patients being considered for 3DCRT, and to a lesser extent with even IMRT and VMAT techniques.

Determinants of long COVID among adults hospitalized for SARS-CoV-2 infection A prospective cohort study.

Factors associated with long-term sequelae emerging after the acute phase of COVID-19 (so called long COVID) are unclear. Here, we aimed to identify risk factors for the development of COVID-19 sequelae in a prospective cohort of subjects hospitalized for SARS-CoV-2 infection and followed up one year after discharge. A total of 324 subjects underwent a comprehensive and multidisciplinary evaluation one year after hospital discharge for COVID-19. A subgroup of 247324 who consented to donate a blood sample were tested for a panel of circulating cytokines. In 122 patients (37.8%) there was evidence of at least one persisting physical symptom. After correcting for comorbidities and COVID-19 severity, the risk of developing long COVID was lower in the 109 subjects admitted to the hospital in the third wave of the pandemic than in the 215 admitted during the first wave, (OR 0.69, 95%CI 0.51-0.93, p0.01). Univariable analysis revealed female sex, diffusing capacity of the lungs for carbon monoxide (DLCO) value, body mass index, anxiety and depressive symptoms to be positively associated with COVID-19 sequelae at 1 year. Following logistic regression analysis, DLCO was the only independent predictor of residual symptoms (OR 0.98 CI 95% (0.96-0.99), p0.01). In the subgroup of subjects with normal DLCO (> 80%), for whom residual lung damage was an unlikely explanation for long COVID, the presence of anxiety and depressive symptoms was significantly associated to persistent symptoms, together with increased levels of a set of pro-inflammatory cytokines interferon-gamma, tumor necrosis factor-alpha, interleukin (IL)-2, IL-12, IL-1β, IL-17. In logistic regression analysis, depressive symptoms (p0.02, OR 4.57 1.21-17.21) and IL-12 levels (p0.03, OR 1.06 1.00-1.11) 1-year after hospital discharge were independently associated with persistence of symptoms. Long COVID appears mainly related to respiratory sequelae, prevalently observed during the first pandemic wave. Among patients with little or no residual lung damage, a cytokine pattern consistent with systemic inflammation is in place.

Characterization of lung adenocarcinoma based on immunophenotyping and constructing an immune scoring model to predict prognosis.

CT-Based Radiomics Can Predict the Efficacy of Anlotinib in Advanced Non-Small-Cell Lung Cancer.

Anlotinib is a small-molecule RTK inhibitor that has achieved certain results in further-line treatment, but many patients do not respond to this drug and lack effective methods for identification. Although radiomics has been widely used in lung cancer, very few studies have been conducted in the field of antiangiogenic drugs. This study aims to develop a new model to predict the efficacy of patients receiving anlotinib by combining pretreatment computed tomography (CT) radiomic characters with clinical characters, in order to assist precision medicine of pulmonary cancer. 254 patients from seven institutions were involved in the study. Lesions were selected according to the RECIST 1.1 criteria, and the corresponding radiomic features were obtained. We constructed prediction models based on clinical, NCE-CT, and CE-CT radiomic features, respectively, and evaluated the prediction performance of the models for training sets, internal validation sets, and external validation sets. In the RAD score only model, the area under curve(AUC) of the NCE-CT cohort was 0.740 (95% CI 0.622, 0.857) for the training set, 0.711 (95% CI 0.480, 0.942) for the internal validation set, and 0.633(95% CI 0.479, 0.787) for the external validation set, while that of the CE-CT cohort was 0.815 (95% CI 0.705, 0.926) for the training set, 0.771 (95% CI 0.539, 1.000) for the internal validation set, and 0.701 (95% CI 0.489, 0.913) for the external validation set. In the RAD score-combined model, the AUC of the NCE-CT cohort was 0.796 (95% CI 0.691, 0.901) for the training set, 0.579 (95% CI 0.309, 0.848) for the internal validation set, and 0.590 (95% CI 0.427, 0.753) for the external validation set, while that of the CE-CT cohort was 0.902 (95% CI 0.828, 0.977) for the training set, 0.865 (95% CI 0.696, 1.000) for the internal validation set, and 0.837 (95% CI 0.682, 0.992) for the external validation set. In conclusion, radiomics has accurate predictions for the efficacy of anlotinib. CE-CT-based radiomic models have the best predictive potential in predicting the efficacy of anlotinib, and model predictions become better when they are combined with clinical characteristics.

Screening of Key Prognosis Genes of Lung Adenocarcinoma Based on Expression Analysis on TCGA Database.

The data of lung adenocarcinoma- (LUAD-) related gene expression profiles were mined from the Cancer Genome Atlas (TCGA) database using bioinformatics methods and potential biomarkers related to the occurrence, development, and prognosis of LUAD were screened out to explore the key prognostic genes and clinical significance. Following the LUAD gene expression profile data that were initially exported from the TCGA database, R software DESeq2 was employed to analyze the difference between the expression profiles of LUAD and normal tissues. The R package clusterProfiler was subsequently utilized to perform gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of the differential genes. A protein-protein interaction (PPI) network was constructed via the String database, and cytohubba, a plugin of Cytoscape, was applied to screen hub genes using the MCC algorithm. The Gene Expression Profile Data Interactive Analysis (GEPIA) was used to analyze expressions of 10 candidate genes in LUAD samples and healthy lung samples, and the selected genes were employed for survival analysis. A total of 1,598 differential genes were identified through differential analyses and data mining, with 1,394 genes upregulated and 204 downregulated. A total of 10 hub genes CCNA2, CDC20, CCNB2, KIF11, TOP2A, BUB1, BUB1B, CENPF, TPX2, and KIF2C were obtained using the cytohubba plugin. The results of the GEPIA analysis indicated that compared with normal lung tissue, the mRNA expression level of the described hub genes in LUAD tissue was significantly increased ( The previously described key genes related to LUAD identified in the TCGA database may be used as potential prognostic biomarkers, which will contribute to further comprehension of the occurrence and development of LUAD and provide references for its diagnosis and treatment.

A self-guidance biological hybrid drug delivery system driven by anaerobes to inhibit the proliferation and metastasis of colon cancer.

Colorectal cancer is often accompanied by multiple organ metastasis. Anaerobic

Use of an Endobronchial Blocker Where a Double-Lumen Tube Failed to Ventilate A Case Report of a Distorted Tracheobronchial Anatomy.

One-lung ventilation (OLV) during video-assisted thoracoscopic surgery (VATS) can be accomplished through several different techniques, including bronchial advancement of an endotracheal tube (ETT), use of a double-lumen tube (DLT), or placement of an endobronchial blocker. In most cases, a DLT is a mainstay of isolating and ventilating a single lung during cardiothoracic procedures. The reasons to deploy a DLT over other techniques include ease of placement, less chance of malposition, quick placement time, and quality of lung deflation. However, this case report highlights the importance of a bronchial blocker in a patient where a double-lumen tube failed to ventilate the lungs. Briefly, this young female patient had a right thoracic mass associated with ipsilateral lung collapse and moderate pleural effusion. CT-guided biopsy was planned but was deferred by the radiologist, as the patient was unable to lie in a prone position. The case was then referred to the cardiothoracic surgeon who planned a right VATS and biopsy of the lesion. In the operation theater, after induction of anesthesia, the patient could not be ventilated through a DLT, and high peak airway pressures were encountered. Initially, a size 37 left-sided DLT was used, and subsequently, sizes 35, 32, and 28 were also tried, but all these attempts to ventilate the patient remained futile. A bronchoscopy was done, which did not show any abnormality in the airway. The surgery was postponed due to an inability to ventilate the patient with a double-lumen tube. After a repeat CT scan and draining of 9.3 liters of pleural effusion over a week, the patient was again scheduled for the same procedure but with a changed anesthetic plan. This time around, the anesthetic plan was implemented successfully using a bronchial blocker to isolate the right lung. The surgery went ahead, and the patient had an uneventful postoperative period. The anesthetic management of this patient presented a unique set of challenges, which are shared in this case report.

Paraneoplastic Opsoclonus-Myoclonus Syndrome as a Rare Presentation of Small-Cell Lung Cancer.

Opsoclonus-myoclonus syndrome (OMS), also known as Kinsbourne syndrome or dancing eyes syndrome, is an extremely rare neurological condition that comprises a heterogenous constellation of symptoms including opsoclonus along with diffuse or focal body myoclonus. It is usually referred to as a paraneoplastic entity, but it may also be associated to an infectious, metabolic, or idiopathic cause. Small-cell carcinoma of the lung is the most commonly reported malignancy associated with OMS. The authors describe a case of a 69-year-old male that presented with ataxic gait, phono- and photophobia, vertigo, dizziness, lethargy, nausea, and vomiting. During examination, rapid, multidirectional eye movements slight dysarthria and facial myoclonus were noted. He was admitted to the hospital, and after a thorough study, a diagnosis of OMS was established. Intravenous corticosteroids were started, alongside physiotherapy, and a slight improvement of his symptoms was noted. Imaging revealed a suspicious lesion in the left lung, along with lymphadenopathies and bone metastases. Histology confirmed the diagnosis of stage IV small-cell lung cancer (SCLC). Chemotherapy (ChT) with carboplatin and etoposide was started, and a gradual improvement of his neurological complaints was noted. After six cycles, the disease progressed, and second-line ChT with topotecan was started. After two cycles, the patient experienced significant clinical deterioration and eventually died. In conclusion, OMS is a poorly understood condition with uncertain neurological prognosis. The treatment of the primary neoplasm may improve neurological symptoms. The recognition of paraneoplastic syndromes is of utmost importance since early diagnosis of a malignancy relates to better outcomes.

Antifibrinolytics use during surgery for oncological spine diseases A systematic review.

Data exist of the benefits of antifibrinolytics such as tranexamic acid (TXA) in general spine surgery. However, there are limited data of its use in oncological spine patients. A systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Cochrane, OVID, and Embase databases were searched. Search terms Seven hundred results were reviewed form the different databases, seven were selected. A total of 408 patients underwent spine surgery for OSD and received antifibrinolytics. There was a male predominance (55.2%) and mean age ranged from 43 to 62 years. The most common tumor operated was metastatic renal cancer, followed by breast and lung. Most studies administered TXA as a bolus followed by an infusion during surgery. Median blood loss was of 667 mL (253.3-1480 mL). Patients with TXA required 1-2 units less of transfusion and had 56-63 mL less of postoperative drainage versus no TXA. The median incidence of deep venous thrombosis (DVT) was 2.95% (0-7.9%) and for pulmonary embolism (PE) was 4.25% (0-14.3%). The use of TXA reduced intraoperative blood loss, transfusions and reduced postoperative surgical drainage output compared to no TXA use in patients with OSD. In this review, we found that TXA may diminish intraoperative blood loss, the need for transfusion and postoperative drainage from surgical drains when used in OSD without major increase in rates of DVT or PE.

Carrot and carotene and multiple health outcomes an umbrella review of the evidence.

In recent years, the benefits of carrots and carotene in different areas of health have been examined. The purpose of this umbrella review was to identify the associations between carrots and carotene and multiple health outcomes. The review considered evidence from meta-analyses of interventional and observational studies of carrots and carotene and any health outcome. We comprehensively searched Web of Science, PubMed, and Embase. For each association, we estimated the summary effect size using random and fixed effects models and the 95% confidence interval. A total of 1329 studies were searched, and 30 meta-analyses with 26 health outcomes were identified that met the eligibility criteria. Carrot intake was associated with a lower risk of multiple cancer outcomes including breast cancer, lung cancer, pancreatic cancer, gastric cancer, urothelial cancer, and prostate cancer. Carotene intake was associated with a lower risk of fracture, age-related cataract, sunburn, Alzheimers disease, breast cancer, lung cancer, pancreatic cancer, gastric cancer, esophageal cancer, prostate cancer, and head and neck cancer (HNC). Serum carotene was inversely associated with all-cause mortality, breast cancer, and lung cancer. Our study revealed that carrot or carotene intake could reduce the risk of various negative health outcomes. © 2023 Society of Chemical Industry.

SP140 inhibits STAT1 signaling, induces IFN-γ in tumor-associated macrophages, and is a predictive biomarker of immunotherapy response.

Understanding the role and potential therapeutic targeting of tumor-associated macrophages (TAMs) is crucial to developing new biomarkers and therapeutic strategies for cancer immunotherapies. The epigenetic reader SP140 has emerged as a master regulator of macrophage transcriptional programs however, its role in the signaling of TAMs and response to immunotherapy has not been investigated. We evaluated the correlation between SP140 expression in head and neck squamous cell carcinoma (HNSCC) TAMs and clinical outcomes. We also used complementary bioinformatics and experimental approaches to study the association of SP140 expression with tumor mutation burden, patient survival, immunogenic signature of tumors, and signaling of TAMs. SP140 overexpression or knockdown was implemented to identify the role of SP140 in downstream signaling and production of inflammatory cytokine and chemokines. Chromatin immunoprecipitation and analysis of assay of transposase accessible chromatin sequencing data were used to demonstrate the direct binding of SP140 on the promoters of STAT1. Finally, correlation of SP140 with immune cell infiltrates and response to immune-checkpoint blockade in independent cohorts of HNSCC, metastatic melanoma, and melanoma was assessed. We found that SP140 is highly expressed in TAMs across many cancer types, including HNSCCs. Interestingly, higher expression of SP140 in the tumors was associated with higher tumor mutation burden, improved survival, and a favorable response to immunotherapy. Tumors with high SP140 expression showed enrichment of inflammatory response and interferon-gamma (IFN-γ) pathways in both pan-cancer analysis and HNSCC-specific analysis. Mechanistically, SP140 negatively regulates transcription and phosphorylation of STAT1 and induces IFN-γ signaling. Activating SP140 in macrophages and TAMs induced the proinflammatory macrophage phenotype, increased the antitumor activity of macrophages, and increased the production of IFN-γ and antitumor cytokines and chemokines including interleukin-12 and CXCL10. SP140 expression provided higher sensitivity and specificity to predict antiprogrammed cell death protein 1 immunotherapy response compared with programmed death-ligand 1 in HNSCCs and lung cancer. In metastatic melanoma, higher levels of SP140 were associated with a durable response to immunotherapy, higher immune score estimates, high infiltrations of CD8 Our findings suggest that SP140 could serve as both a therapeutic target and a biomarker to identify immunotherapy responders.

Short-term dynamics of circulating tumor DNA predicting efficacy of sintilimab plus docetaxel in second-line treatment of advanced NSCLC biomarker analysis from a single-arm, phase 2 trial.

Robust biomarker predicting efficacy of immunotherapy is limited. Circulating tumor DNA (ctDNA) sought to effectively monitor therapeutic response as well as disease progression. This study aims to investigate predictive role of ctDNA short-term dynamic change (6 weeks postimmunotherapy) in a single-arm, phase 2 trial of sintilimab plus docetaxel for previously treated advanced non-small cell lung cancer (NSCLC) patients. A total of 33 patients with advanced NSCLC with disease progression during or after any first-line treatment were prospectively enrolled between 2019 and 2020. Patients received sintilimab (200 mg, day 1, every 3 weeks) plus docetaxel (75 mgm Patients with ctDNA clearance at 6th week had decreased tumor volume, while most patients with positive ctDNA at 6th-week experienced an increase in tumor volume. Positive 6th-week ctDNA was associated with significantly shorter progression-free survival (PFS) (91 vs NR days p<0.0001) and overall survival (47 vs 467 days p 0.0039). Clearance of clonal mutations and none new clonal formation at 6th week were associated with longer PFS (mPFS 89 vs 266 days, p 0.003). ctDNA clearance at 6th week was an independent risk factor for progression or death (HR100 (95% CI 4.10 to 2503.00), p0.005). ctDNA status and ctDNA mutation clearance putatively serve as predictive biomarkers for sintilimab combined with docetaxel chemotherapy in pretreated advanced NSCLC patients.

Episodic breathlessness in patients with cancer definition, terminology, clinical features - integrative systematic review.

Breatlessness flares directly impair quality of life of patients with cancer. The aim of this review was to analyse and synthesise the available information related to its terminology, definition and clinical features in patients with cancer. Integrative systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Literature search was conducted in MEDLINE PubMed, CINAHLPlus, Web of Science, Cochrane Central Register Controlled Trials CENTRAL, Scopus and OpenAire. Data from 1065 patients with cancer included in 12 studies were analysed. The preferred term for breathlessness flares was episodic dyspnoea (ED). The reported frequency of ED was 20.4% (70.9% in patients reporting background dyspnoea (BD)). ED intensity was moderate to severe with short duration (<10 min) in >80% of patients. The most common trigger was exertion (>90%) followed by emotional or environmental factors. ED management consisted mainly of pharmacological and non-pharmacological measures. This systematic review shows that ED is common in patients with cancer, especially in those with BD. Further studies are urgently needed to better understand this condition and to develop specific therapeutic management. CRD42019126708.

Exercise oxygen desaturation is a predictor of cardiopulmonary complications after lung resection.

To investigate whether oxygen desaturation during low technology tests was associated with complications after lung resection. A retrospective cohort study was conducted on 1097 candidates for pulmonary resection seven metabolic equivalents in the Masters double two-step test were loaded. The predicted postoperative (PPO) forced expiratory volume in 1 s and PPO diffusing capacity of the lung for carbon monoxide were estimated. The patients were divided into three groups those with both values ≥60% (≥60% group (n298)), either value <30% (<30% group (n112)) and others (30%-60% group (n687)). The relationships between postoperative cardiopulmonary complications and exercise stress test based on availability, symptoms and percutaneous oxygen saturation values were investigated in each group. Τhe cardiopulmonary morbidity rates in the ≥60%, 30%-60%, and <30% groups were 7.7%, 14.6%, and 47.3%, respectively. Multivariate analyses revealed that predictors of complications were age (OR 0.96 p<0.001), male sex (OR 1.74 p0.016) and exercise oxygen desaturation (EOD) >4% (OR 2.39 p0.001) in the 30%-60% group, and male sex (OR 3.76 p0.042) and EOD >4% (OR 2.28 p0.030) in the <30% group.The two-flight test (TFT) was performed in 181 patients (22.8%) desaturation >4% in the TFT was also a predictor of complications. A low technology test is also valuable for high-risk patients. EOD >4% is a predictor of postoperative complications. This study is a non-interventional observational study and has not been registered in a public database. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology reporting guidelines.This study was approved by the Ethics Committee of the Juntendo University School of Medicine (no. 2016085).

Lung CAncer SCreening in French women using low-dose CT and Artificial intelligence for DEtection the CASCADE study protocol.

Lung cancer screening (LCS) using low-dose CT has been demonstrated to reduce lung cancer-related mortality in large randomised controlled trials. Moving from trials to practice requires answering practical questions about the level of expertise of CT readers, the need for double reading as in trials and the potential role of artificial intelligence (AI). In addition, most LCS studies have predominantly included male participants with women being under-represented, even though the benefit of screening is greater for them. Thus, this study aims to compare the performance of a single CT reading by general radiologists trained in LCS using AI as a second reader to that of a double reading by expert thoracic radiologists, in a campaign for low-dose CT screening in high-risk women. This observational cohort study will recruit 2400 asymptomatic women aged between 50 and 74 years, current or former smokers with at least a 20 pack-year smoking history, in 4 different French district areas. Assistance with smoking cessation will be offered to current smokers. An initial low-dose CT scan will be performed, with subsequent follow-ups at 1 year and 2 years. The primary objective is to compare CT scan readings by a single LCS-trained, AI-assisted radiologist to that of an expert double reading. The secondary objectives are to evaluate the performance of AI as a stand-alone reader the adherence to screening of female participants the influence on smoking cessation the psychological consequences of screening the detection of chronic obstructive pulmonary disease (COPD), coronary artery disease and osteoporosis on low-dose CT scans and the costs incurred by screening. Ethics approval was obtained from the Comité de Protection des Personnes Sud-Est 1 (ethics approval number 2021-A02265-36 with an amendment on 15 July 2022). Trial results will be disseminated at conferences, through relevant patient groups and published in peer-reviewed journals. NCT05195385.

MiR-124-3p impedes the metastasis of non-small cell lung cancer via extracellular exosome transport and intracellular PI3KAKT signaling.

Metastasis is a significant factor that affects the survival of patients with non-small cell lung cancer (NSCLC). Nevertheless, the molecular regulatory mechanism underlying the metastasis is currently not fully understood. This study aims to identify the important role of miR-124-3p in metastasis of NSCLC, thereby providing a potential therapeutic intervention. Exosome secretion was determined by Nanoparticle Tracking Analysis (NTA) and the uptake was measured by fluorescence inverted microscope. The binding mechanism between miR-124-3p and its upstream or downstream target genes was validated experimentally by Luciferase reporter. Cells migration was evaluated by transwell assays. Transcriptome sequencing on A549 was carried out to verify the potential signaling pathway underlying miR-124-3p regulation. Western blotting analysis was used to assess the level of AKT, p-AKT, PI3K, and p-PI3K protein expression in NSCLC cell lines. The role of miR-124-3p to suppress the tumor metastasis was verified in NSCLC xenograft model. Exosomes were more abundant in serum from patients with advanced lung cancer (n 24 patients) than in these from patients with early-stage lung cancer (n 30 patients), which suggested the potential correlation between amount of exosome secretion and the metastasis of NSCLC. Interestingly, the exosome release, uptake and the migration of NSCLC cells were notably inhibited by miR-124-3p. LINC00511 suppressed the expression of miR-124-3p to facilitate exosome transport due to its role as the competitive endogenous RNA for miR-124-3p. The miR-124-3p could directly target the 3-UTR of Rab27a in NSCLC cells to inhibit exosome secretion and thereby prevent cell migration and invasion. Aside from the inhibition of exosome transport, miR-124-3p inhibited the activation of PI3KAKT signaling in the intracellular environment. Finally, by measuring subcutaneous tumor weight and volume and lung metastasis, we also demonstrated that miR-124-3p inhibited tumor growth in vivo. In NSCLC, miR-124-3p significantly suppressed metastasis through extracellular exosome transport and intracellular PI3KAKT signaling. These findings provide new insights toward a better understanding of the NSCLC metastasis and suggest a potential treatment biomarker for NSCLC.

Bereavement in childhood and young adulthood and the risk of atrial fibrillation a population-based cohort study from Denmark and Sweden.

Adverse childhood life events are associated with increased risks of hypertension, ischemic heart disease, and stroke later in life. Limited evidence also suggests that stress in adulthood may increase the risk of atrial fibrillation (AF). Whether childhood adversity may lead to the development of AF is unknown. We investigated whether the loss of a parent or sibling in childhood is associated with an increased risk of AF and compared this effect to that of similar losses in young adulthood. We studied 6,394,975 live-born individuals included in the Danish (1973-2018) and Swedish Medical Birth Registers (1973-2014). We linked data from several national registers to obtain information on the death of parents and siblings and on personal and familial sociodemographic and health-related factors. We analyzed the association between bereavement and AF using Poisson regression. Loss of a parent or sibling was associated with an increased AF risk both when the loss occurred in childhood and in adulthood the adjusted incident rate ratios and 95% confidence intervals were 1.24 (1.14-1.35) and 1.24 (1.16-1.33), respectively. Bereavement in childhood was associated with AF only if losses were due to cardiovascular diseases or other natural causes, while loss in adulthood was associated with AF not only in case of natural deaths, but also unnatural deaths. The associations did not differ substantially according to age at loss and whether the deceased was a parent or a sibling. Bereavement both in childhood and in adulthood was associated with an increased AF risk.

Interstitial pneumonitis associated with combined regimen of immunotherapy and conventional therapies-pharmacovigilance database analysis with real-world data validation.

Immune checkpoint inhibitor (ICI) therapy combined with conventional therapies is being broadly applied in non-small cell lung cancer (NSCLC) patients. However, the risk of interstitial pneumonitis (IP) following a combined regimen is incompletely characterized. A total of 46,127 NSCLC patients were extracted for disproportionality analyses of IP from the Food and Drug Administrations Adverse Event Reporting System (FAERS) database. A total of 1108 NSCLC patients who received ICI treatment at Nanfang Hospital of Southern Medical University were collected and utilized for real-world validation. Of the 46,127 patients with NSCLC, 3830 cases (8.3% 95% confidence interval CI, 8.05-8.56) developed IP. Multivariable logistic regression analyses revealed that the adjusted ROR of ICI combined with radiation (RT) was the highest (121.69 95% CI, 83.60-184.96 P < 0.0001) among all therapies, while that of ICI combined with chemotherapy (CHEMO) or targeted therapy (TARGET) was 0.90 (95% CI, 0.78-1.04 P 0.160) and 1.49 (95% CI, 0.95-2.23 P 0.065), respectively, using ICI monotherapy as reference. Furthermore, analyses from our validation cohort of 1108 cases showed that the adjusted odds ratio of ICI combined with RT was the highest (12.25 95% CI, 3.34-50.22 P < 0.01) among all the therapies, while that of ICI combined with CHEMO or TARGET was 2.32 (95% CI, 0.89-7.92 P 0.12) and 0.66 (95% CI, 0.03-4.55 P 0.71), respectively, using ICI monotherapy as reference. Compared with ICI monotherapy, ICI combined with RT, rather than with CHEMO or TARGET, is associated with a higher risk of IP in NSCLC patients. Hence, patients receiving these treatments should be carefully monitored for IP.

Patterns of toxicity burden for FDA-approved immune checkpoint inhibitors in the United States.

Immune-related adverse events (irAEs) are a common phenomenon in cancer patients treated with immune checkpoint inhibitors (ICIs). Surprisingly, the toxicity burdens of these irAEs have not been illustrated clearly. In this study, we analyzed irAEs for seven FDA-approved ICIs in cancer treatment to show the pattern of toxicity burden among cancer patients. irAEs associated with seven FDA-approved ICIs, including three PD-1 inhibitors (cemiplimab, nivolumab and pembrolizumab), three PD-L1 inhibitors (atezolizumab, avelumab and durvalumab), and one CTLA-4 inhibitor (ipilimumab), were analyzed based on data from 149,303 reported cases (from January 1, 2015 to June 30, 2022) collected from the FDA Adverse Events Reporting System (FAERS) public dashboard. Proportions of serious irAEs and correlations with tumor type, age and sex were assessed via R package and GraphPad software. irAEs related to anti-PD-1 ICIs required less hospital care resources compared with anti-PD-L1 and anti-CTLA-4 ICIs. Patients treated with pembrolizumab had relatively fewer serious cases. Treatment with ICIs led to the highest probability of serious irAEs in patients with lung cancer. Respiratory, thoracic and mediastinal disorders and gastrointestinal disorders were the two most common groups of disorders caused by the seven ICIs studied. Cardiac disorders was the main type of disorders caused by these ICIs in cancer patients aged 65-85, while reproductive system and breast disease was the main type of disorder in cancer patients aged 18-64. Respiratory, thoracic, mediastinal diseases and reproductive system and breast diseases were the main types of disorders associated with treatment with these ICIs in male and female patients, respectively. Tissue and organ toxicities of ICIs are age and sex specific. There are risks of respiratory and urinary system toxicity in male patients and reproductive system toxicity in female patients treated with the ICIs studied. Future studies on the toxicity burden of ICIs should incorporate age and sex differences to better understand the relevance of ICI toxicity burden to human immune function to develop appropriate tumor immune and therapeutic intervention strategies.

Protocol for Evaluating In Vivo the Activation of the P2RX7 Immunomodulator.

P2RX7 is a purinergic receptor with pleiotropic activities that is activated by high levels of extracellular ATP that are found in inflamed tissues. P2RX7 has immunomodulatory and anti-tumor proprieties and is therefore a therapeutic target for various diseases. Several compounds are developed to either inhibit or enhance its activation. However, studying their effect on P2RX7s activities is limited to in vitro and ex vivo studies that require the use of unphysiological media that could affect its activation. Up to now, the only way to assess the activity of P2RX7 modulators on the receptor in vivo was in an indirect manner. We successfully developed a protocol allowing the detection of P2RX7 activation in vivo in lungs of mice, by taking advantage of its unique macropore formation ability. The protocol is based on intranasal delivery of TO-PRO™-3, a non-permeant DNA intercalating dye, and fluorescence measurement by flow cytometry. We show that ATP enhances TO-PRO™-3 fluorescence mainly in lung immune cells of mice in a P2RX7-dependant manner. The described approach has allowed the successful analysis of P2RX7 activity directly in the lungs of WT and transgenic C57BL6 mice. The provided detailed guidelines and recommendations will support the use of this protocol to study the potency of pharmacologic or biologic compounds targeting P2RX7.

Malignancy risk with tofacitinib versus TNF inhibitors in rheumatoid arthritis results from the open-label, randomised controlled ORAL Surveillance trial.

To evaluate malignancies and their associations with baseline risk factors and cardiovascular risk scores with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA). In an open-label, randomised controlled trial (ORAL Surveillance NCT02092467), 4362 patients with RA aged ≥50 years with ≥1 additional cardiovascular risk factor received tofacitinib 5 (N1455) or 10 mg two times per day (N1456) or TNFi (N1451). Incidence rates (IRs patients with first events100 patient-years) and HRs were calculated for adjudicated malignancies excluding non-melanoma skin cancer (NMSC), NMSC and subtypes. Post hoc analyses for malignancies excluding NMSC, lung cancer and NMSC included risk factors identified via simplemultivariable Cox models and IRsHRs categorised by baseline risk factors, history of atherosclerotic cardiovascular disease (HxASCVD) and cardiovascular risk scores. IRs for malignancies excluding NMSC and NMSC were higher with tofacitinib (combined and individual doses) versus TNFi. Risk of lung cancer (most common subtype with tofacitinib) was higher with tofacitinib 10 mg two times per day versus TNFi. In the overall study population, the risk of malignancies excluding NMSC was similar between both tofacitinib doses and TNFi until month 18 and diverged from month 18 onwards (HR (95% CIs) for combined tofacitinib doses 0.93 (0.53 to 1.62) from baseline to month 18 vs 1.93 (1.22 to 3.06) from month 18 onwards, interaction p0.0469). Cox analyses identified baseline risk factors across treatment groups for malignancies excluding NMSC, lung cancer and NMSC interaction analyses generally did not show statistical evidence of interaction between treatment groups and risk factors. HxASCVD or increasing cardiovascular risk scores were associated with higher malignancy IRs across treatments. Risk of malignancies was increased with tofacitinib versus TNFi, and incidence was highest in patients with HxASCVD or increasing cardiovascular risk. This may be due to shared risk factors for cardiovascular risk and cancer. NCT02092467, NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02281552, NCT02187055, NCT02831855, NCT00413699, NCT00661661.

Extracardiac findings with increased perfusion during clinical O-15-H

Coincidental extracardiac findings with increased perfusion were reported during myocardial perfusion imaging (MPI) with various retention radiotracers. Clinical parametric O-15-H All patients (2963) were scanned with O-15-H Malignant and benign extracardiac coincidental findings with increased perfusion are readily visible and frequently seen on O-15-H

Prediction of high-grade patterns of stage IA lung invasive adenocarcinoma based on high-resolution CT features a bicentric study.

This study aims to predict the high-grade pattern (HGP) of stage IA lung invasive adenocarcinoma (IAC) based on the high-resolution CT (HRCT) features. The clinical, pathological, and HRCT imaging data of 457 patients (from bicentric) with pathologically confirmed stage IA IAC (459 lesions in total) were retrospectively analyzed. The 459 lesions were classified into high-grade pattern (HGP) (n 101) and non-high-grade pattern (n-HGP) (n 358) groups depending on the presence of HGP (micropapillary and solid) in pathological results. The clinical and pathological data contained age, gender, smoking history, tumor stage, pathological type, and presence or absence of tumor spread through air spaces (STAS). CT features consisted of lesion location, size, density, shape, spiculation, lobulation, vacuole, air bronchogram, and pleural indentation. The independent predictors for HGP were screened by univariable and multivariable logistic regression analyses. The clinical, CT, and clinical-CT models were constructed according to the multivariable analysis results. The multivariate analysis suggested the independent predictors of HGP, encompassing tumor size (p 0.001 OR 1.090, 95% CI 1.035-1.148), density (p < 0.001 OR 9.454, 95% CI 4.911-18.199), and lobulation (p 0.002 OR 2.722, 95% CI 1.438-5.154). The AUC values of clinical, CT, and clinical-CT models for predicting HGP were 0.641 (95% CI 0.583-0.699) (sensitivity 69.3%, specificity 79.2%), 0.851 (95% CI 0.806-0.896) (sensitivity 79.2%, specificity 79.6%), and 0.852 (95% CI 0.808-0.896) (sensitivity 74.3%, specificity 85.8%). The logistic regression model based on HRCT features has a good diagnostic performance for the high-grade pattern of stage IA IAC. • The AUC values of clinical, CT, and clinical-CT models for predicting high-grade patterns were 0.641 (95% CI 0.583-0.699), 0.851 (95% CI 0.806-0.896), and 0.852 (95% CI 0.808-0.896). • Tumor size, density, and lobulation were independent predictive markers for high-grade patterns. • The logistic regression model based on HRCT features has a good diagnostic performance for the high-grade patterns of invasive adenocarcinoma.

The Cancer Research UK Stratified Medicine Programme as a model for delivering personalised cancer care.

Genomic screening is routinely used to guide the treatment of cancer patients in many countries. However, several multi-layered factors make this effort difficult to deliver within a clinically relevant timeframe. Here we share the learnings from the CRUK-funded Stratified Medicine Programme for advanced NSCLC patients, which could be useful to better plan future studies.

Fitting additive risk models using auxiliary information.

There has been a growing interest in incorporating auxiliary summary information from external studies into the analysis of internal individual-level data. In this paper, we propose an adaptive estimation procedure for an additive risk model to integrate auxiliary subgroup survival information via a penalized method of moments technique. Our approach can accommodate information from heterogeneous data. Parameters to quantify the magnitude of potential incomparability between internal data and external auxiliary information are introduced in our framework while nonzero components of these parameters suggest a violation of the homogeneity assumption. We further develop an efficient computational algorithm to solve the numerical optimization problem by profiling out the nuisance parameters. In an asymptotic sense, our method can be as efficient as if all the incomparable auxiliary information is accurately acknowledged and has been automatically excluded from consideration. The asymptotic normality of the proposed estimator of the regression coefficients is established, with an explicit formula for the asymptotic variance-covariance matrix that can be consistently estimated from the data. Simulation studies show that the proposed method yields a substantial gain in statistical efficiency over the conventional method using the internal data only, and reduces estimation biases when the given auxiliary survival information is incomparable. We illustrate the proposed method with a lung cancer survival study.

FOLFOX-bevacizumab chemotherapy in patients with metastatic neuroendocrine tumors.

Neuroendocrine tumors (NETs) are highly vascularized neoplasms. While FOLFOX chemotherapy has shown efficacy in patients with advanced NETs, its combination with antiangiogenics has been scarcely described. Here, we report the efficacy and tolerance of FOLFOX-bevacizumab in this setting. We retrospectively studied all consecutive patients with metastatic NET treated by FOLFOX-bevacizumab in two expert centers from 2013 to 2020. We assessed time to treatment failure (TTF), objective response rate (ORR) and toxicity. We explored factors associated with TTF and ORR using multivariate analyses. We included 57 patients (35.1% female, median age 61.7 years), with pancreatic (66.7%), small-intestine (14%) or lung (7%) NETs. Most patients (57.9%) had extra-hepatic metastases and G3 NETs accounted for 40.3% of cases. Patients received a median of 17 cycles of treatment, including a median of seven cycles of bevacizumab andor 5-fluorouracile maintenance. Median TTF was 15.5 months (95% CI 9.8-21.2) and was shorter in patients age > 60 years (HR 2.56, 95% CI 1.16-5.64), p .020) and >1 previous systemic treatment line (HR 4.15, 95% CI 1.96-8.78), p < .001). The ORR was 42.9% and was higher in cases of performance status at 0 (OR 5.25, 95% CI 1.13-24.35), p .034) and G3 NET (OR 5.39, 95% CI 1.23-23.52), p .025). The FOLFOX-bevacizumab combination has promising efficacy in patients with progressive metastatic NETs and notably for G3 NETs, for which optimal treatment as yet remains ill-defined. Hence, it could be a relevant alternative to alkylating-based chemotherapy in this setting and should be further explored prospectively.

The Performance of an Extended Next Generation Sequencing Panel Using Endobronchial Ultrasound-Guided Fine Needle Aspiration Samples in Non-Squamous Non-Small Cell Lung Cancer A Pragmatic Study.

Samples from endobronchial ultrasound-guided fine needle aspiration (EBUS-TBNA) are frequently used for next generation sequencing (NGS) in patients with non-small cell lung cancer (NSCLC) to look for genetic driver mutations. The objective of the current study was to evaluate the performance of extended NGS panels using EBUS-TBNA samples in a real-world setting and identify factors associated with the success of NGS. This study included all patients who underwent EBUS and were diagnosed with non-squamous NSCLC with mediastinal metastasis from 2016 to 2019 at the University of Pennsylvania. We reviewed demographic information, imaging studies, procedure reports, pathology and NGS reports. Logistic regression was used to analyze factors associated with the success of NGS panels. The success rates of NGS using EBUS-TBNA samples were 92.5%, and 91.5% for DNA and RNA NGS panels respectively. Samples from higher N stage (N2 and N3 lymph nodes) and with higher tumor cellularity (>25%) resulted in higher success rate for DNA NGS. The effect of tumor cellularity remained borderline significant after entering multivariable logistic regression. The short-axis diameter of the sampled lymph node on CT scan, FDG-avidity on PET CT and >3 EBUS passes per lymph node during the procedure were not associated with NGS success. Both DNA and RNA extended-panel NGS had high performance using EBUS-TBNA samples. Sampling more advanced nodal stations and obtaining samples with higher tumor cellularity were associated with higher success rate of DNA NGS. Other imaging or procedural factors did not affect NGS performance.

Confirmation of Intracranial Neuroendocrine Metastasis Utilizing

Neuroendocrine tumors (NETs) are rare neoplasms with an exceedingly low incidence of intracranial metastasis. We present a 79-year-old female with a biopsy-proven pulmonary neuroendocrine tumor who presented with an intracranial mass in the posterior fossa that was DOTATATE avid on a

Mature Red Blood Cells Contain Long DNA Fragments and Could Acquire DNA from Lung Cancer Tissue.

Red blood cells (RBC) are commonly known as cells with no nucleus or mitochondria and are assumed to be a transportation vehicle. This study confirms that RBC contain long DNA fragments inside with stain by both microscope and flow cytometry, which covers most nuclear and mitochondrial genome regions by next-generation sequencing (NGS). Such characteristics demonstrate a significant difference compared with A549 cell line or paired peripheral blood mononuclear cell as nucleated cells. To further explore the characteristics of RNA DNA, DNA from 20 RBC samples is sequenced by NGS. Interestingly, several gaps and multiple regions with copy number variation are observed significantly different between different samples, which could be used to distinguish samples with different health status accurately. Using an in vitro co-culture system, it is shown that RBC could absorb DNA-bearing tumorigenic mutations from cancer cell lines but requires cell-to-cell contact. Finally, based on a small scale clinical trial, it is confirmed that common genetic mutations of cancer tissues could be detected in RBC from patients with early-stage non-small-cell lung cancer. This study highlights a new biological phenomenon involving RBC and its translational potential as a novel liquid biopsy technology platform for early cancer screening and diagnosis of malignancy.

Recommendations for optimizing the use of cytology in the diagnosis and management of patients with lung cancer.

Non-small cell lung cancer (NSCLC) is one of the oncological entities with the greatest evolution in molecular diagnosis due to the large number of diagnostic biomarkers and new treatments approved by international regulatory agencies. An accurate, early diagnosis using the least amount of tissue is the goal for the establishing and developing precision medicine for these patients. Rapid on-site evaluation (ROSE) provides cytological samples of optimal quantity and quality for a complete diagnosis of NSCLC. The usefulness of cytological samples has been demonstrated, not only for massive parallel sequencing but also for the quantification of the expression of programmed death-ligand 1 (PD-L1) and tumour mutational burden (TMB). Pre-analytical, analytical, and post-analytical recommendations are made for the management and appropriate use of cytological samples in order to obtain all the information necessary for the diagnosis and treatment of patients with NSCLC according to current quality parameters.

Management of basal cell carcinoma with pulmonary metastasis.

A man in his 50s presented with an ulcerative lesion within the left axillary fold that had progressively worsened over 18 months. Biopsy revealed an ulcerative basal cell carcinoma (BCC), which was surgically managed. CT chest scans done 7 months later assessed post-treatment of radiotherapy. This revealed pulmonary lesions, which were biopsy-proven metastatic BCC. Sonidegib, a hedgehog signalling inhibitor, was used for first-line treatment. Due to progressive disease, sonidegib was ceased. Cemiplimab, a checkpoint inhibitor, was used as second-line treatment based on a phase II trial demonstrating efficacy in the setting of metastatic BCC. CT reports were initially consistent with response but after 6 months of cemiplimab treatment, repeat CT chest scans revealed a decrease in size of the previously cited pulmonary lesions.This is a rare case of BCC metastases which has limited treatment options. This case provides insight of the patient experience on such treatment.

T lymphocytes induce human cancer cells derived from solid malignant tumors to secrete galectin-9 which facilitates immunosuppression in cooperation with other immune checkpoint proteins.

Galectin-9 is a member of the family of lectin proteins and crucially regulates human immune responses, particularly because of its ability to suppress the anticancer activities of T lymphocytes and natural killer cells. Recent evidence demonstrated that galectin-9 is highly expressed in a wide range of human malignancies including the most aggressive tumors, such as high-grade glioblastomas and pancreatic ductal adenocarcinomas, as well as common malignancies such as breast, lung and colorectal cancers. However, solid tumor cells at rest are known to secrete either very low amounts of galectin-9 or, in most of the cases, do not secrete it at all. Our aims were to elucidate whether T cells can induce galectin-9 secretion in human cancer cells derived from solid malignant tumors and whether this soluble form displays higher systemic immunosuppressive activity compared with the cell surface-based protein. A wide range of human cancer cell lines derived from solid tumours, keratinocytes and primary embryonic cells were employed, together with helper and cytotoxic T cell lines and human as well as mouse primary T cells. Western blot analysis, ELISA, quantitative reverse transcriptase-PCR, on-cell Western and other measurement techniques were used to conduct the study. Results were validated using in vivo mouse model. We discovered that T lymphocytes induce galectin-9 secretion in various types of human cancer cells derived from solid malignant tumors. This was demonstrated to occur Our results underline a crucial role of galectin-9 in anticancer immune evasion. As such, galectin-9 and regulatory pathways controlling its production should be considered as key targets for immunotherapy in a large number of cancers.

Lymphangioleiomyomatosis (LAM) Cell Atlas.

Lymphangioleiomyomatosis (LAM) is a rare lung disease of women, causing cystic remodelling of the lung and progressive respiratory failure. The cellular composition, microenvironment and cellular interactions within the LAM lesion remain unclear. To facilitate data sharing and collaborative LAM research, we performed an integrative analysis of single-cell data compiled from lung, uterus and kidney of patients with LAM from three research centres and developed an LAM Cell Atlas (LCA) Web-Portal. The LCA offers a variety of interactive options for investigators to search, visualise and reanalyse comprehensive single-cell multiomics data sets to reveal dysregulated genetic programmes at transcriptomic, epigenomic and cell-cell connectome levels.

Unprecedented long-term survival in a patient with malignant pleural mesothelioma treated with subsequent systemic chemo- and immunotherapeutic regimens.

Pleural mesothelioma is a rare disease with a dismal prognosis and few therapeutic options. Until recently the median overall survival for a pleural mesothelioma patient was up to 2 years, with few exceptional cases of patients achieving a longer survival. Here, we report the clinical case of a patient whose survival spanned over 10 years. The patient underwent several systemic treatments, including three different chemotherapy lines (cisplatin-pemetrexed, vinorelbine and platinum rechallenge) and two immunotherapy regimens using immune checkpoint inhibitors (anti CTLA-4 tremelimumab and anti PD-1 nivolumab). At the time this report was written, the patient was off-treatment, asymptomatic and with a stable radiological disease. Our case demonstrates that a prolonged survival with a preserved quality of life may be reached in selected patients through the exploitation of the available treatments in an expertise setting.

Design, synthesis and antitumor activity of novel thiophene- triazine derivatives bearing arylurea unit as potent PI3KmTOR inhibitorss.

In this article, we designed and synthesized a series of novel thiophene-triazine derivatives bearing arylurea unit as potent dual PI3KmTOR inhibitors. The cytotoxicity of all the target compounds were evaluated against nine cancer cell lines (breast cancer cell line MCF-7, lung cancer cell lines A549, NCI-H460, H2228 and H1975, cervical cancer cell lines Hela and Hela-MDR, ovarian cancer cell lines Ovcar-2 and glioma U87MG) and the kinase inhibitory activity against PI3KmTOR kinases was also tested. The results demonstrated that most of the target compounds exhibited moderate to excellent activity and high selectivity against one or more cancer cell lines. Among them, seven compounds displayed better activity than lead compound GDC-0941. The inhibitory activity of the most promising compound on nine cancer cell lines was 302.5 times better than that of GDC-0941 with the IC

pH-responsive nanoparticles based on POEOMA-b-PDPA block copolymers for RNA encapsulation, protection and cell delivery.

The use of gene-based products, such as DNA or RNA, is increasingly being explored for various innovative therapies. However, the success of these strategies is highly dependent on the effective delivery of these biomolecules to target cells. Therefore, the development of pH-responsive nanoparticles comprises the creation of intelligent delivery systems with high therapeutic efficiency. In this work, the pH-responsiveness of the poly(2-(diisopropylamino)ethyl methacrylate)) (PDPA) block was investigated for the encapsulation and delivery of small RNAs (sRNA) to cancer cells. The pH responsiveness was dependent on the protonation profile of the tertiary amines of PDPA, which directly affected the electrostatic interactions established with RNA. Thus, block copolymers based on poly(oligo(ethylene oxide) methyl ether methacrylate) (POEOMA) and PDPA, POEOMA-b-PDPA, were synthesized by supplemental activator and reducing agent atom transfer radical polymerization (SARA ATRP). The structure of the block copolymers was characterized by size exclusion chromatography and

Changes in the Level of Methylation of a Group of microRNA Genes as a Factor in the Development and Progression of Non-Small Cell Lung Cancer.

We studied changes in the level of methylation of a number of microRNA genes hypermethylated in non-small cell lung cancer and its histological subtypes as well as the relationship of methylation of a group of microRNA genes with clinical and morphological features of the tumor with smoking status. A significantly high level of methylation of 7 genes (MIR124-13, MIR125B-1, MIR129-2, MIR137, MIR1258, and MIR339) was revealed in adenocarcinoma and squamous cell lung cancer in comparison with samples of adjacent histologically unchanged lung tissue. In squamous cell lung cancer, a significantly high level of methylation of the MIR124-2 gene in the tumor was also shown. In addition, differences in the methylation profile of adenocarcinoma and squamous cell carcinoma at stages III-IV of the oncological process were revealed. A high level of methylation of the MIR137 and MIR1258 genes was shown for adenocarcinoma and MIR339, MIR129-2, and MIR124-2 for squamous cell carcinoma. Significant differences in the level of methylation of MIR124-2 and MIR375 genes were revealed for smoking patients with squamous cell lung cancer.

Reciprocal FGF19-GLI2 signaling induces epithelial-to-mesenchymal transition to promote lung squamous cell carcinoma metastasis.

Metastatic lung squamous cell carcinoma (LUSC) is one of the most common causes of cancer death worldwide. As yet, however, the molecular mechanism underlying LUSC metastasis remains elusive. In this study, we report a novel mechanism involving signaling interactions between FGF19 and GLI2 that could drive the progression of LUSC. The expression of FGF19 in human LUSC samples was assessed by immunohistochemistry. The concentration of FGF19 in serum samples was assessed by ELISA. RNA sequencing, scratch wound-healing, trans-well, GO analysis, GSEA, luciferase reporter, Western blotting, immunofluorescence and immunohistochemistry assays, as well as an animal model were used to investigate the molecular mechanism underlying FGF19 driven LUSC progression. The therapeutic effect of a GLI2 inhibitor was determined using both in vitro cellular and in vivo animal experiments. We found that FGF19, a member of the fibroblast growth factor family, plays a crucial role in the invasion and metastasis of LUSC, and identified GLI2 as an important downstream effector of FGF19 involved in metastasis. Surprisingly, we found that FGF19 and GLI2 could reciprocally induce the expression of each other, and form a positive feedback loop to promote LUSC cell invasion and metastasis. These findings were corroborated by an association between a poor prognosis of LUSC patients and FGF19GLI2 co-expression. In addition, we found that the GLI inhibitor GANT61 could effectively reduce FGF19-mediated LUSC invasion and metastasis. Our data suggest that FGF19 may serve as a novel biomarker for predicting metastatic LUSC. Intervening with the FGF19-GLI2 feedback loop may be a strategy for the treatment of FGF19-driven LUSC metastasis.

Therapeutic efficacy of cyclin-dependent kinase inhibition in combination with ionizing radiation for lung cancer.

To evaluate the therapeutic efficacy of cyclin-dependent kinase (CDK) inhibition in combination with ionizing radiation for lung cancer. Human lung adenocarcinoma (A549) and squamous cell carcinoma (H520) cells were used to evaluate the therapeutic efficacy of CDK inhibition in combination with ionizing radiation in vitro using colony formation assay, γH2AX immunofluorescence staining, western blotting, and cell cycle phase analysis. We also performed in vivo evaluations of ectopic tumor growth. In vitro pretreatment with the CDK inhibitor, seliciclib, before irradiation significantly decreased the survival of A549 and H520 cells in a dose-dependent manner. Although CDK inhibition alone did not increase the intensity of γH2AX foci, its combination with ionizing radiation increased DNA double-strand breaks, as shown by γH2AX immunofluorescence staining and western blotting. The combination of CDK inhibition and ionizing radiation-induced G2M arrest and increased apoptosis, as evidenced by the increased proportion of cells in G2M arrest, subG1 apoptotic population, and expression of apoptotic markers (cleaved PARP-1 and cleaved caspase-3). Mechanistic studies showed reduced expression of cyclin A with combined treatment, indicating cell cycle shifting effects. An in vivo xenograft model showed that the combination of CDK inhibition and ionizing radiation delayed xenograft tumor growth, and increased the proportion of cleaved PARP-1- and cleaved caspase-3-positive cells, compared to either treatment alone. We provide preclinical tumoricidal evidence that the combination of CDK inhibition and ionizing radiation is an efficacious treatment for lung cancer.

Anti-proliferative effects of beta-blocker propranolol on human lung cancer and noncancer cells.

Propranolol (PRO) has been recently discovered to possess anti-tumorigenic effects in cancer patients. So, we aimed to enlighten the in vitro effects of propranolol in A549 lung cancer cells and BEAS2B nontumoral lung cells. The gene expression levels of apoptotic proteins caspases 3, 8, and 9 (CASP3, 8, 9), apoptosis inducing factor (AIF), and DNA damage inducible transcript 3 (DDIT3) and cell cycle regulatory proteins WEE1 G2 checkpoint kinase (WEE1) and cyclin dependent kinase inhibitor 1A (CDKN1A) were analyzed with quantitative reverse-transcription PCR to assess the effect of PRO on A549 tumor and BEAS2B nontumoral cells. The protein levels of caspase 3 and AIF1 were detected with Western blot. PRO exerted its anti-tumorigenic effects against A549 cells by arresting cell cycle via CDNK1A and by inducing apoptosis via caspase-dependent (CASP3) and -independent pathways (AIF, DDIT3). As to nontumoral BEAS2B cells, PRO decreased the cell viability at a lesser extent compared to tumoral cells. In contrast to tumor cells, PRO reduced the protein levels of CASP3 and AIF1. Notably, at 48th hour of PRO treatment, we observed a sustained expression of elevated DDIT3 mRNA levels at 24h in BEAS2B cells unlike in A549 cells. We suggest that DDIT3 and CDKN1A play a critical role during cell fate decision after PRO treatment by protecting nontumoral cells against apoptosis and by triggering apoptosis in tumor cells. The selective action mechanism of PRO with less cytotoxicity in nontumoral lung cells puts it forward as a promising adjuvant agent in lung cancer therapy (Tab. 1, Fig. 4, Ref. 50). Text in PDF www.elis.sk Keywords propranolol, BEAS2B, A549, lung cancer, apoptosis, DDIT3.

Lung Cancer Screening Initiative in Slovakia Guidelines of screening implementation.

Lung cancer (LC) represents a major healthcare issue worldwide. It is the leading cause of cancer-related mortality in Slovakia and European Union. Data from multiple randomized controlled trials have shown significant evidence of a mortality benefit in LC using screening with low-dose computed tomography of the chest (LDCT). Therefore, European healthcare authorities, relevant expert societies, and professional organizations recommend implementing national LC screening (LCS) programs in their member countries. This article outlines the basic methodology, guidelines, and practical aspects of LCS implementation strategies in Slovakia. We describe fundamental principles to identify asymptomatic high-risk patients reduce false positive and false negative results, decrease benign resection rates, and avoid unnecessary invasive procedures. The efficacious utilization of public resources to secure the highest possible quality standards of LDCT plays a crucial role in successfully implementing a nationwide LCS program (Tab. 1, Fig. 4, Ref. 31). Text in PDF www.elis.sk Keywords lung cancer, screening, early detection, smoking cessation.

Video-Assisted Thoracic Surgery Core Needle Biopsy for Pulmonary Nodules in Patients with Impaired Lung Function Is It Feasible and Safe

The number of patients with incidentally identified pulmonary nodules is increasing. This study attempted to confirm the usefulness and safety of video-assisted thoracic surgery (VATS) core needle biopsy of pulmonary nodules. Data from 18 patients diagnosed with pulmonary nodules who underwent VATS core need biopsy were retrospectively reviewed. Of the 18 patients, 15 had malignancies (primary lung cancer, n14 metastatic lung cancer, n1), and 3 had benign nodules. Mortality and pleural metastasis did not occur during the follow-up period. In patients with solitary pulmonary nodules that require tissue confirmation, computed tomography-guided percutaneous cutting needle biopsy or diagnostic pulmonary resection sometimes may not be feasible choices due to the location of the solitary pulmonary nodule or the patients impaired pulmonary function, VATS core needle biopsy may be performed in these patients as an alternative method.

Thrombospondin-1 mimic peptide PKHB1 induced endoplasmic reticulum stress-mediated but CD47-independent apoptosis in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is one of the most common malignancies with high morbidity and mortality. PKHB1, a serum-stable Thrombospondin-1 (TSP-1) mimic peptide, has shown some effective ability in triggering cell death against several cancers. Here, we aimed to study the potential biological function of PKHB1 and its molecular mechanism in NSCLC. Our results revealed that PKHB1 significantly suppressed NSCLC cell proliferation, cell migration, and induced apoptosis in a dose-dependent manner. Additionally, we found that PKHB1 treatment resulted in mitochondrial transmembrane potential depolarization, Ca

The value of serum TRAP1 in diagnosing small cell lung cancer and tumor immunity.

This study set out to investigate the clinical significance of serum tumor necrosis factor receptor-associated protein 1 (TRAP1) in diagnosing small cell lung cancer (SCLC) with different clinical stages, and to compare the diagnostic efficiency with neuron-specific enolase (NSE), carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9). Besides, to analyze the role of serum TRAP1 in tumor immunity. A total of 91 patients with SCLC, 99 patients with non-small cell lung cancer (NSCLC), 102 patients with pulmonary nodules (PN), and 75 healthy people were included. The concentrations of serum TRAP1 was detected by enzyme-linked immunosorbent assay (ELISA). NSE, CEA, and CA19-9 were detected by chemiluminescence. The results showed that level of TRAP1 in Group SCLC was lower than other three groups (

Spinal Metastases and the Evolving Role of Molecular Targeted Therapy, Chemotherapy, and Immunotherapy.

Metastatic involvement of the spine is a common complication of systemic cancer progression. Surgery and external beam radiotherapy are palliative treatment modalities aiming to preserve neurological function, control pain and maintain functional status. More recently, with development of image guidance and stereotactic delivery of high doses of conformal radiation, local tumor control has improved however recurrent or radiation refractory disease remains a significant clinical problem with limited treatment options. This manuscript represents a narrative overview of novel targeted molecular therapies, chemotherapies, and immunotherapy treatments for patients with breast, lung, melanoma, renal cell, prostate, and thyroid cancers, which resulted in improved responses compared to standard chemotherapy. We present clinical examples of excellent responses in spinal metastatic disease which have not been specifically documented in the literature, as most clinical trials evaluate treatment response based on visceral disease. This review is useful for the spine surgeons treating patients with metastatic disease as knowledge of these responses could help with timing and planning of surgical interventions, as well as promote multidisciplinary discussions, allowing development of an individualized treatment strategy to patients presenting with widespread multifocal progressive disease, where surgery could lead to suboptimal results.

A critical systematic review for inhaled corticosteroids on lung cancer incidence not yet concluded story.

To systematically review studies on inhaled corticosteroids (ICS) and lung cancer incidence in chronic airway disease patients. We conducted electronic bibliographic searches on OVID-MEDLINE, EMBASE, and the Cochrane Database before May 2020 to identify relevant studies. Detailed data on the study population, exposure, and outcome domains were reviewed. Of 4,058 screened publications, thirteen eligible studies in adults with chronic obstructive pulmonary disease (COPD) or asthma evaluated lung cancer incidence after ICS exposure. Pooled hazard ratio and odds ratio for developing lung cancer in ICS exposure were 0.81 (95% confidence interval, 0.64-1.02 I295.7%) from 10 studies and 1.02 (95% confidence interval 0.50-2.07 I294.7%) from 3 studies. Meta-regression failed to explain the substantial heterogeneity of pooled estimates. COPD and asthma were variously defined without spirometry in 11 studies. Regarding exposure assessment, 3 and 10 studies regarded ICS exposure as a time-dependent and fixed variable, respectively. Some studies assessed ICS use for the entire study period, whereas others assessed ICS use for 6 months to 2 years within or before study entry. Smoking was adjusted in four studies, and only four studies introduced 1-2 latency years in their main or subgroup analysis. Studies published to date on ICS and lung cancer incidence had heterogeneous study populations, exposures, and outcome assessments, limiting the generation of a pooled conclusion. The beneficial effect of ICS on lung cancer incidence has not yet been established, and understanding the heterogeneities will help future researchers to establish robust evidence on ICS and lung cancer incidence.

Clinical Impact of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Associated

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs)-associated We conducted a retrospective cohort study using multi-institutional electronic medical records database. We included patients aged older than 20 years diagnosed with lung cancer and treated with EGFR-TKIs (gefitinib, erlotinib, afatinib). We defined EGFR-TKI initiation date as the index date and occurrence of diarrhea with CDI or without CDI as the event date. We followed patients from the index date until the event date, ICU admission, death, or 12312019. We included 2242 diarrhea patients, 51 were EGFR-TKI with CDI cohort, and 2191 were diarrhea without CDI cohort. Patients who were concurrently taking antibiotics (hazard ratio HR, 3.30 95% CI, 1.67-6.5) and systemic steroids (HR, 4.9 95% CI, 2.65-9.06) had an increased risk of CDI. First-generation EGFR-TKIs tended to be associated with an increased risk of CDI compared with afatinib (HR, 1.81, 95% CI, 0.94-3.47). EGFR-TKI with CDI had a higher ICU admission rate (HR, 3.42, 95% CI, 1.98-5.91) and mortality rate (HR, 2.34, 95% CI, 1.67-3.28) than diarrhea without CDI. Patients with CDI had higher ICU admission rates and mortality rates than those without CDI. Concurrent use of antibiotics and systemic steroids were risk factors for CDI among patients with lung cancer receiving EGFR-TKIs. Afatinib was not associated with a higher risk of CDI than first-generation EGFR-TKIs.

Combination Use of First-Line Afatinib and Proton-Pump Inhibitors Reduces Overall Survival Among Patients with EGFFR Mutant Lung Cancer.

Previous retrospective studies reported that proton-pump inhibitors (PPIs) may decrease the efficacy of first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) including gefitinib and erlotinib. Afatinib had a wider soluble pH range, with possible fewer interactions with antacids. However, clinical data were limited. Thus, this study aimed to evaluate the negative impact of PPIs on afatinib. This retrospective cohort study included patients who are newly diagnosed with non-small cell lung cancer (NSCLC) from 2014 to 2019 using the Chang Gung Research Database. We identified patients who were treated with first-line afatinib and analyzed the association between the PPI and afatinib treatment outcomes. A total of 1418 patients were treated with first-line afatinib and followed up for 6 years. First-line afatinib was administered to 918 eligible patients, and 330 had afatinib with PPIs. The combination use of PPIs and afatinib significantly decreased the overall survival (OS) compared with that of patients using afatinib only (median OS 33.2 and 25.1 months, The concurrent use of PPIs was associated with lower OS in patients with EGFR-mutant lung cancer under the first-line afatinib treatment but not associated with TTF.

Retracted Clinical Efficacy and Safety Analysis of PD-1PD-L1 Inhibitor vs. Chemotherapy in the Treatment of Advanced Non-Small-Cell Lung Cancer A Systematic Review and Meta-Analysis.

This retracts the article DOI 10.115520229500319..

Shedding light on structure, function and regulation of human sirtuins a comprehensive review.

Sirtuins play an important role in signalling pathways associated with various metabolic regulations. They possess mono-ADP-ribosyltransferase or deacylase activity like demalonylase, deacetylase, depalmitoylase, demyristoylase and desuccinylase activity. Sirtuins are histone deacetylases which depends upon nicotinamide adenine dinucleotide (NAD) that deacetylate lysine residues. There are a total of seven human sirtuins that have been identified namely, SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 and SIRT7. The subcellular location of mammalian sirtuins, SIRT1, SIRT6, and SIRT7 are in the nucleus SIRT3, SIRT4, and SIRT5 are in mitochondria, and SIRT2 is in cytoplasm. Structurally sirtuins contains a

Camptothecin-Loaded and Manganese Dioxide-Coated Polydopamine Nanomedicine Used for Magnetic Resonance Imaging Diagnosis and Chemo-Photothermal Therapy for Lung Cancer.

Camptothecin (CPT) is a cytotoxic quinolone alkaloid (isolated from a traditional Chinese medicine Camptotheca acuminata), used for the treatment of various malignancies, which inhibits DNA topoisomerase I (Topo I). However, its drawbacks, such as poor water solubility, stability, and highly toxic side effects, limit its clinical application. Therefore, CPT needs to be prepared as a nanomedicine to improve solubility, reduce side effects, and synergize with other therapies to improve efficacy. In this work, we constructed CPT NPs (nanoparticles), which were CPT-loaded and manganese dioxide (MnO CPT NPs improve the water solubility and stability of CPT and reduce its toxic effects. It has good biocompatibility, excellent photothermal conversion ability for photothermal therapy (PTT) and pH release in the tumor microenvironment. It can inhibit tumor cell proliferation, induce apoptosis and result in ferroptosis of tumor cells. More significantly, this nanomedicine can provide information for the location and diagnosis of tumors via magnetic resonance imaging. In general, the nanomedicine integrated with diagnosis and treatment has excellent anticancer effect. Altogether, this nanomedicine possesses the ability to diagnose and therapy through magnetic resonance imaging and chemo-photothermal therapy, respectively. In addition, the integrated diagnosis and treatment nanomedicine has potential clinical application prospects through treating lung cancer with high efficiency and low side effect. It can support the construction of related nano-delivery systems.

Research on Augmented Reality Assisted Precise Thoracoscopic Resection of Pulmonary Nodules.

To break with traditional preoperative localization, a porcine animal model to evaluate the safety of augmented reality (AR) assisted localization of solitary pulmonary nodules (SPN) was used. Before the experiment, Microsoft HoloLens AR system was used to bring the CT image into the laboratory after 3D reconstruction. The virtual model was fitted with real body surface markers, and the virtual positioning auxiliary line and auxiliary locator were used to perform puncture positioning before surgery. Data related to actual puncture path and expected planned path were recorded in the experiment. SPSS 26.0 was used to calculate the puncture accuracy under AR assisted positioning, and the results obtained were acceptable in segmentectomy or wedge pneumonectomy. Its feasibility in animal models will also be evaluated, and its safety and efficacy will need to be further studied in clinical trials.

Osteoporotic Vertebral Fracture Misdiagnosed as Metastatic Vertebral Fracture.

The purpose of this study was to report a patient with osteoporotic vertebral compression fracture (OVCF) which was misdiagnosed as metastatic vertebral compression fracture (MVCF). A 64-year male was admitted to our clinic for complaints of numbness, pain, and activity limitation in bilateral lower extremities. One year ago, he had a medical history of lung adenocarcinoma and bone metastasis. A month ago, he developed back pain and lower-limb paralysis. X-ray, computer tomography (CT), and magnetic resonance imaging (MRI) showed thoracic 11 (T11) vertebral compression fracture. Furthermore, emission computed tomography (ECT) indicated MVCF preoperatively. However, the histopathology findings suggested OVCF postoperatively. Consequently, the patient was discharged without chemoradiotherapy. During the 14-months follow-up period, no relapsed spinal neoplasm or recurrence of vertebral fracture was observed. In conclusion, OVCF in patients with a history of lung cancer is easily misdiagnosed as MVCF. It is important to differentiate OVCF from MVCF by clinical symptoms, laboratory examination, and imaging features before operation. Histological findings are the gold standard for accurate diagnosis. Key Words Osteoporosis, Vertebral fracture, Metastasis.

A Case of Primary Epithelioid Sarcoma of the Pleura.

BACKGROUND Epithelioid sarcoma is a rare tumor and that is extremely rare as a primary pleural neoplasm. On imaging, it may appear similar to malignant pleural mesothelioma thus, it can be difficult to diagnose. CASE REPORT A 64-year-old Asian woman, who had a treatment history of cervix adenocarcinoma, was admitted with dyspnea and right massive pleural effusion. Chest drainage was performed, and malignant cells were found in the pleural effusion. The malignant cells were thought to be metastasized from previous cervical cancer. We continued pleural drainage however, the volume of the pleural effusion did not decrease. On the 5th hospital day, the chest tube became occluded. Computed tomography showed structures similar to empyema. Pleural irrigation and fibrinolytic therapy did not improve her condition. Empyema curettage was performed on the 14th hospital day. The resected pleura was submitted for pathological examination and showed tumor lesion but not metastatic adenocarcinoma of the cervix. The intrathoracic tumor grew extremely rapidly, and the patient died of respiratory failure on postoperative day 8 (22nd hospital day) before a diagnosis could be made. The final pathological diagnosis obtained on the 34th hospital day was epithelioid sarcoma. CONCLUSIONS For patients who appear to have empyema complicated by neoplastic lesions, a histopathological examination should also be performed to ensure accurate diagnosis. In addition, if a tumorous lesion is detected and it is neither metastatic nor malignant pleural mesothelioma, pleural epithelioid sarcoma should be added to the differential diagnosis in the presence of a rapidly growing and histologically difficult-to-diagnose pleural tumor.

Combination Treatment with Iodine 125 Seeds Implant and Systemic Therapy vs. Systemic Therapy Alone for Non-small Cell Lung Cancer A Systematic Review and Meta-analysis.

Combination treatment with iodine 125 seeds implant and systemic therapy in patients with non-small-cell lung cancer (NSCLC) is a promising treatment practice. The present study aimed to assess the relative efficacy and toxicity of combination treatment versus systemic therapy alone in patients with NSCLC. Databases including PubMed, EBSCO, Web of Science, EMBASE, Cochrane Library, CNKI, and WanFang were searched for relevant randomised controlled trials (RCTs). Risk ratios (RR) were obtained for evaluating indicators in the present meta-analysis including complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), overall response rate (ORR), disease control rate (DCR), one-year and two-year overall survival (OS) rate and complications. A total of 17 eligible RCTs incorporating 1315 patients who underwent combination treatment or systemic therapy alone were ultimately included in this meta-analysis based on our selection criteria. The results showed that CR (RR 1.89, 95% confidence interval CI 1.53 - 2.33, p <0.001), PR (RR 1.28, 95%CI 1.12 - 1.46, p 0.0002), ORR (RR 1.46, 95%CI 1.34 - 1.58, p <0.001), DCR (RR 1.11, 95%CI 1.04 - 1.18, p 0.001), two-year OS (RR 1.52, 95% CI 1.30 - 1.77, p <0.001) were higher and SD (RR 0.53, 95%CI 0.42 - 0.66, p <0.001) and PD (RR 0.39, 95%CI 0.29 - 0.55, p <0.001) were lower in the combination treatment group than in control group. Meanwhile, there was no significant difference in one-year OS (RR 1.13, 95% CI 0.98-1.31, p 0.10). In terms of adverse events, the combination therapy significantly increased the incidence of pneumothorax (RR 4.91, 95% CI 2.63 - 9.17, p <0.001) however, no significant differences were found in the incidence of myelosuppression and gastrointestinal symptoms. Combination treatment with iodine 125 seeds implant and systemic therapy can significantly improve clinical response and prolong two-year OS in NSCLC patients without increasing the incidence of myelosuppression and gastrointestinal symptoms, except pneumothorax. Key Words Brachytherapy, Radioactive seeds, NSCLC, Systemic therapy.

MiR-138-5p suppresses the progression of lung cancer by targeting SNIP1.

MicroRNAs (miRNAs) play crucial roles in the development of various cancers. Here, we aimed to evaluate the roles of miR-138-5p in lung cancer progression and the value of miR-138-5p in lung cancer diagnosis. Quantitative real-time PCR was performed to examine the expressions of miR-138-5p and smad nuclear interacting protein 1 (SNIP1) mRNA. The diagnostic value of miR-138-5p was analyzed using receiver operating characteristic (ROC) curve analysis, sensitivity, and specificity. We explored the effect of miR-138-5p on cell proliferation and metastasis by CCK-8, colony formation, wound healing and transwell assays. Western blot was employed to detect the protein expression of SNIP1 and related genes. Lung cancer cell growth was evaluated in vivo using xenograft tumor assay. MiR-138-5p was decreased in the serum of patients with non-small cell lung cancer (NSCLC) and in NSCLC cells and tissues. The area under the ROC curve of serum miR-138-5p in the diagnosis of NSCLC was 0.922. This finding indicates the high diagnostic efficiency for lung cancer. MiR-138-5p suppressed but its inhibitor promoted cell proliferation and migration compared with control treatment in vitro and in vivo. MiR-138-5p directly binds to the 3-untranslated region of SNIP1 and negatively regulated the expression of SNIP1, thereby inhibiting the expression of cyclin D1 and c-Myc. Moreover, overexpression of SNIP1 rescues the miR-138-5p-mediated inhibition in NSCLC cells. The results suggested that miR-138-5p suppressed lung cancer cell proliferation and migration by targeting SNIP1. Serum miR-138-5p is a novel and valuable biomarker for NSCLC diagnosis.

Total coumarins of Pileostegia tomentella induces cell death in SCLC by reprogramming metabolic patterns, possibly through attenuating β-cateninAMPKSIRT1.

Small-cell lung cancer (SCLC) is a high malignant and high energy-consuming type of lung cancer. Total coumarins of Pileostegia tomentella (TCPT) from a traditional folk medicine of Yao minority, is a potential anti-cancer mixture against SCLC, but the pharmacological and molecular mechanism of TCPT remains largely unknown. Screening of viability inhibition of TCPT among 7 cell lines were conducted by using CCK-8 assays. Anti-proliferative activities of TCPT in SCLC were observed by using colony formation and flow cytometry assays. Morphological changes were observed by transmission electron microscope and Mito-Tracker staining. High Throughput RNA-seq analysis and bio-informatics analysis were applied to find potential targeted biological and signaling pathways affected by TCPT. The mRNA expression of DEGs and protein expression of signalling proteins and metabolic enzymes were verified by qPCR and Western blot assays. Activity of rate-limiting enzymes and metabolite level were detected by corresponding enzyme activity and metabolites kits. Xenograft nude mice model of SCLC was established to observe the in vivo inhibition, metabolism reprogramming and mechanism of TCPT. TCPT treatment shows the best inhibition in SCLC cell line H1688 rather than other 5 lung cancer cell lines. Ultrastructural investigation indicates TCPT induces mitochondria damage such as cytoplasm shrinkage, ridges concentration and early sight of autolysosome, as well as decrease of membrane potential. Results of RNA-seq combined bio-informatics analysis find out changes of metabolism progression affected the most by TCPT in SCLC cells, and these changes might be regulated by β-cateninAMPKSIRT1 axis. TCPT might mainly decline the activity and expression of rate-limiting enzymes, OGDH, PDHE1, and LDHAB to reprogram aerobic oxidation pattern, resulting in reduction of ATP production in SCLC cells. Xenograft nude mice model demonstrates TCPT could induce cell death and inhibit growth in vivo. Assimilate to the results of in vitro model, TCPT reprograms metabolism by decreasing the activity and expression of rate-limiting enzymes (OGDH, PDHE1, and LDHAB), and attenuates the expression of β-catenin, p-β-catenin, AMPK and SIRT1 accordance with in vitro data. Our results demonstrated TCPT induces cell death of SCLC by reprograming metabolic patterns, possibly through attenuating master metabolic pathway axis β-cateninAMPKSIRT1.

MicroRNA-1 attenuates the growth and metastasis of small cell lung cancer through CXCR4FOXM1RRM2 axis.

Small cell lung cancer (SCLC) is an aggressive lung cancer subtype that is associated with high recurrence and poor prognosis. Due to lack of potential drug targets, SCLC patients have few therapeutic options. MicroRNAs (miRNAs) provide an interesting repertoire of therapeutic molecules however, the identification of miRNAs regulating SCLC growth and metastasis and their precise regulatory mechanisms are not well understood. To identify novel miRNAs regulating SCLC, we performed miRNA-sequencing from donorpatient serum samples and analyzed the bulk RNA-sequencing data from the tumors of SCLC patients. Further, we developed a nanotechnology-based, highly sensitive method to detect microRNA-1 (miR-1, identified miRNA) in patient serum samples and SCLC cell lines. To assess the therapeutic potential of miR-1, we developed various in vitro models, including miR-1 sponge (miR-1Zip) and DOX-On-miR-1 (Tet-ON) inducible stable overexpression systems. Mouse models derived from intracardiac injection of SCLC cells (miR-1Zip and DOX-On-miR-1) were established to delineate the role of miR-1 in SCLC metastasis. In situ hybridization and immunohistochemistry were used to analyze the expression of miR-1 and target proteins (mouse and human tumor specimens), respectively. Dual-luciferase assay was used to validate the target of miR-1, and chromatin immunoprecipitation assay was used to investigate the protein-gene interactions. A consistent downregulation of miR-1 was observed in tumor tissues and serum samples of SCLC patients compared to their matched normal controls, and these results were recapitulated in SCLC cell lines. Gain of function studies of miR-1 in SCLC cell lines showed decreased cell growth and oncogenic signaling, whereas loss of function studies of miR-1 rescued this effect. Intracardiac injection of gain of function of miR-1 SCLC cell lines in the mouse models showed a decrease in distant organ metastasis, whereas loss of function of miR-1 potentiated growth and metastasis. Mechanistic studies revealed that CXCR4 is a direct target of miR-1 in SCLC. Using unbiased transcriptomic analysis, we identified CXCR4FOXM1RRM2 as a unique axis that regulates SCLC growth and metastasis. Our results further showed that FOXM1 directly binds to the RRM2 promoter and regulates its activity in SCLC. Our findings revealed that miR-1 is a critical regulator for decreasing SCLC growth and metastasis. It targets the CXCR4FOXM1RRM2 axis and has a high potential for the development of novel SCLC therapies. MicroRNA-1 (miR-1) downregulation in the tumor tissues and serum samples of SCLC patients is an important hallmark of tumor growth and metastasis. The introduction of miR-1 in SCLC cell lines decreases cell growth and metastasis. Mechanistically, miR-1 directly targets CXCR4, which further prevents FOXM1 binding to the RRM2 promoter and decreases SCLC growth and metastasis.

Afatinib plus osimertinib in the treatment of osimertinib-resistant non-small cell lung carcinoma a phase I clinical trial.

Conquering acquired resistance to osimertinib remains a major challenge in treating patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Thus, we aimed to determine the safety and efficacy of combination treatment with osimertinib and afatinib for patients with acquired resistance to osimertinib. This open-label phase I study was a feasibility study of the combination of afatinib and osimertinib for patients with advanced EGFR-positive NSCLC who had progressive disease after receiving osimertinib. The primary endpoint was to determine the maximum tolerated dose (MTD). We enrolled patients who received afatinib at three different dose levels (level 1, 20 mg level 2, 30 mg level 3, 40 mg) combined with osimertinib at a standard dose of 80 mg once per day. Thirteen patients were enrolled in this study. The MTD was defined as 30 mg afatinib when combined with daily oral administration of osimertinib (80 mg). The most frequent adverse events were diarrhea (76.9%), anemia (76.9%), and rash (69.2%). Considering the toxicity profiles during all treatment periods, the recommended oral dose of afatinib was determined as 20 mg daily, with an osimertinib dose of 80 mg. For all evaluable patients (n 12), the response rate was 7.7% and the disease-control rate was 46.2%. Combination therapy with osimertinib and afatinib was tolerable however, the synergistic effect of afatinib with osimertinib may be limited in osimertinib-resistant patients. Japan Registry of Clinical Trials ID jRCTs051180008, registered date 08112018.

Increased adipose catecholamine levels and protection from obesity with loss of Allograft Inflammatory Factor-1.

Recent studies implicate macrophages in regulation of thermogenic, sympathetic neuron-mediated norepinephrine (NE) signaling in adipose tissues, but understanding of such non-classical macrophage activities is incomplete. Here we show that male mice lacking the allograft inflammatory factor-1 (AIF1) protein resist high fat diet (HFD)-induced obesity and hyperglycemia. We link this phenotype to higher adipose NE levels that stem from decreased monoamine oxidase A (MAOA) expression and NE clearance by AIF1-deficient macrophages, and find through reciprocal bone marrow transplantation that donor Aif1

The Role of Brain Radiotherapy Before First-Line Afatinib Therapy, Compared to Gefitinib or Erlotinib, in Patients with EGFR-Mutant Non-Small Cell Lung Cancer.

Brain metastasis is common in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) at initial presentation. A previous study showed that brain radiotherapy (RT) before first-generation (first-G) EGFR-tyrosine kinase inhibitor (TKI) therapy is associated with longer overall survival than TKI therapy alone. However, there is no data regarding the role of additional brain RT before afatinib therapy. Between October 2014 and June 2019, EGFR-mutant NSCLC patients with brain metastases who started first-G EGFR-TKIs (gefitinib or erlotinib) or afatinib as first-line therapy were retrospectively analyzed. This study compared overall survival and intracranial progression-free survival (PFS) between patients who received EGFR-TKIs alone and EGFR-TKIs with brain RT and either a first-G EGFR-TKI or afatinib, respectively. The median follow-up duration was 29.6 months (range, 1.5-116.9 months). In the first-G EGFR-TKI group (n155), 94 (60.6%) patients received the first-G EGFR-TKI alone and 61 (39.4%) patients received brain RT prior to their first-G EGFR-TKI. In the afatinib group (n204), 126 (61.8%) patients received afatinib alone and 78 (38.2%) patients received brain RT prior to afatinib. There was no difference in overall survival rates between the groups with RT (35.6 months 95% confidence interval CI, 27.9%-43.3%) and without RT (31.4 months 95% CI, 23.9%-38.9%) in the afatinib group (p0.58), but there was a significant difference in overall survival in the first-G EGFR-TKI group in a manner favoring additional brain RT (41.1 months 95% CI, 30.5%-51.7% vs. 25.8 months 95% CI, 20.1%-31.5% p0.02). Meanwhile, median intracranial PFS was not different between patients who received EGFR-TKI therapy alone vs. EGFR-TKI therapy with brain RT in both the first-G EGFR-TKI (p0.39) and afatinib (p0.24) groups. Afatinib therapy alone showed comparable survival outcomes to those of afatinib with brain RT. The current study suggests that brain RT could be an optional, not mandatory, treatment modality when afatinib therapy is considered in patients with EGFR-mutant NSCLC.

The Incidence and Risk Factors of Chronic Pulmonary Infection after Radiotherapy in Patients with Lung Cancer.

This study aimed to investigate cumulative incidence and risk factors associated with CPI development after radiotherapy for lung cancer. We retrospectively analyzed 1,872 patients with lung cancer who (1) received radiotherapy for lung cancer from 2010-2014, (2) had a follow-up period of ≥3 months after radiotherapy, (3) and did not have CPI at the time of radiotherapy. CPI was defined as pulmonary tuberculosis, non-tuberculous mycobacterial pulmonary disease, chronic pulmonary aspergillosis, or pulmonary actinomycosis. The cumulative incidence of CPI and overall survival (OS) were estimated using the Kaplan-Meier method, and a multivariable Cox proportional hazards analysis was performed to identify risk factors associated with CPI development. The median follow-up period was 2.3 years with OS rates of 55.6% and 37.6% at 2 and 5 years, respectively. CPI developed in 59 patients at a median of 1.8 years after radiotherapy, with cumulative incidence rates of 1.1%, 3.4%, 5.0%, and 6.8% at 1, 3, 5, and 7 years, respectively. A lower body mass index, interstitial lung disease, prior pulmonary tuberculosis, larger clinical target volume, history of lung cancer surgery or radiation pneumonitis, and use of inhaled corticosteroids were independent risk factors for CPI development. The long-term survival rate of lung cancer patients receiving radiotherapy was not low, but the cumulative incidence of CPI gradually increased to 6.8% at 7 years after radiotherapy. Therefore, close monitoring of CPI development is required in surviving patients with risk factors.

A Novel Myricetin Derivative with Anti-cancer Properties Induces Cell Cycle Arrest and Apoptosis in A549 Cells.

Lung cancer is the leading cause of cancer-related deaths worldwide, synthesizing and screening of novel anti-cancer drugs provides an alternative therapeutic strategy for renewal of the chemotherapy regimens against lung cancer. To this end, several compounds were synthesized based on the modification of the original myricetin, and their anti-tumor activity against the human non-small cell lung cancer (NSCLC) A549 cells were measured. Among the myricetin derivatives, S4-10 has displayed the highest antitumor efficacy in dose-dependent manner. The proliferation of A549 cells were significantly attenuated by given 6 µM of S4-10 both in vitro and in vivo. Further, the treatment of S4-10 also results in the inhibition of cell migration and invasiveness and the induction of cell apoptosis and G2 cycle arrest of A549 cells. Moreover, we found that S4-10 inhibits the progression of A549 cells through the sterol biosynthetic-cell apoptosis axis. These findings shed the light of developing S4-10 as a promising treatment agent for NSCLC.

Navigating the liquid biopsy Minimal Residual Disease (MRD) in non-small cell lung cancer Making the invisible visible.

Liquid biopsy has gained increasing interest in the growing era of precision medicine as minimally invasive technique. Recent findings demonstrated that detecting minimal or molecular residual disease (MRD) in NSCLC is a challenging matter of debate that need multidisciplinary competencies, avoiding the overtreatment risk along with achieving a significant survival improvement. This review aims to provide practical consideration for solving data interpretation questions about MRD in NSCLC thanks to the close cooperation between biologists and oncology clinicians. We discussed with a translational approach the critical point of view from benchside, bedside and bunchside to facilitate the future applicability of liquid biopsy in this setting. Herein, we defined the clinical significance of MRD, focusing on relevant practical consideration about advantages and disadvantages, speculating on future clinical trial design and standardization of MRD technology.

Mortality of asthma, COPD, and asthma-COPD overlap during an 18-year follow up.

We studied asthma, COPD, and asthma-COPD overlap (ACO) to predict mortality in a cohort of Finnish adults with an 18-year follow up. A national health examination survey representing Finnish adults aged ≥30 years was performed in 2000-2001. The study cohort included 5922 participants (73.8% of the sample) with all relevant data, including a comprehensive clinical examination and spirometry. These participants were followed continuously from baseline until end of 2018 for total, cardiovascular, cancer, and respiratory mortality through a record linkage. Asthma, COPD, and ACO were defined based on the survey data, including spirometry and register data. There were three separate groups of obstructive subjects (one definition excluding the others). Asthma and COPD were significantly associated with higher total mortality in Coxs model adjusted for sex, age, smoking, education level, BMI, leisure time physical activity, cardiovascular disease, diabetes, and hypertension. Hazard ratios (HR) (95% confidence interval CI) for asthma, COPD, and ACO were 1.29 (1.05-1.58), 1.50 (1.20-1.88), and 1.26 (0.97-1.65), respectively. Additionally, asthma (HR 1.47, 95% CI 1.09-1.97) and COPD (HR 1.53, 95% CI 1.08-2.16) were associated with cardiovascular mortality. Although ACO did not predict mortality in the whole cohort, there was a significant association with mortality risk among those with hs-CRP 1-2.99 mgl. Asthma or COPD predicts higher total mortality and premature death from cardiovascular diseases.

SB226, an inhibitor of tubulin polymerization, inhibits paclitaxel-resistant melanoma growth and spontaneous metastasis.

Extensive preclinical studies have shown that colchicine-binding site inhibitors (CBSIs) are promising drug candidates for cancer therapy. Although numerous CBSIs were generated and evaluated, but so far the FDA has not approved any of them due to undesired adverse events or insufficient efficacies. We previously reported two very potent CBSIs, the dihydroquinoxalinone compounds 5 m and 5t. In this study, we further optimized the structures of compounds 5 m and 5t and integrated them to generate a new analog, SB226. X-ray crystal structure studies and a tubulin polymerization assay confirmed that SB226 is a CBSI that could disrupt the microtubule dynamics and interfere with microtubule assembly. Biophysical measurements using surface plasmon resonance (SPR) spectroscopy verified the high binding affinity of SB226 to tubulin dimers. The in vitro studies showed that SB226 possessed sub-nanomolar anti-proliferative activities with an average IC

The mechanism of Bai He Gu Jin Tang against non-small cell lung cancer revealed by network pharmacology and molecular docking.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related burden and deaths, thus effective treatment strategies with lower side effects for NSCLC are urgently needed. To systematically analyze the mechanism of Bai He Gu Jin Tang (BHGJT) against NSCLC by network pharmacology and molecular docking. The active compounds of BHGJT were obtained by searching the Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine and Encyclopaedia of Traditional Chinese Medicine. Search tool for interactions of chemicals was used for acquiring the targets of BHGJT. The component-target network was mapped by Cytoscape. NSCLC-related genes were obtained by searching Genecards, DrugBank and Therapeutic Target Database. The protein-protein interaction network of intersection targets was established based on Search Tool for Recurring Instances of Neighboring Genes (STRING), and further, the therapeutic core targets were selected by topological parameters. The hub targets were transmitted to Database for Annotation, Visualization and Integrated Discovery for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Finally, AutoDock Vina and MglTools were employed for molecular docking validation. Two hundred fifty-six compounds and 237 putative targets of BHGJT-related active compounds as well as 1721potential targets of NSCLC were retrieved. Network analysis showed that 8 active compounds of BHGJT including kaempferol, quercetin, luteolin, isorhamnetin, beta-sitosterol, stigmasterol, mairin and liquiritigenin as well as 15 hub targets such as AKR1B10 and AKR1C2 contribute to the treatment of BHGJT against NSCLC. GO functional enrichment analysis shows that BHGJT could regulate many biological processes, such as apoptotic process. Three modules of the endocrine related pathways including the inflammation, hypoxia related pathways as well as the other cancer related pathways based on Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis might explain the biological mechanisms of BHGJT in treating BHGJT. The results of molecular docking verified that AKR1B10 and AKR1C2 had the strongest binding activity with the 8 key compounds of NSCLC. Our study reveals the mechanism of BHGJT in treating NSCLC involving multiple components, multiple targets and multiple pathways. The present study laid an initial foundation for the subsequent research and clinical application of BHGJT and its active compounds against NSCLC.

Clinical features and outcomes of male patients with lymphangioleiomyomatosis A review.

Lymphangioleiomyomatosis (LAM) is a rare disease involving multiple systems, which is divided into sporadic LAM (S-LAM) and tuberous sclerosis complex-LAM, mostly affecting women who are in childbearing age stage. Data on male patients are limited and scattered. Therefore, it is necessary to conduct a systematic review to investigate the clinical features, diagnosis, treatment, and outcomes of LAM in male. We performed a literature review by searching for all the published reported cases of LAM in male during the past 35 years (April 1986-October 2021). 36 male patients described in 26 references were included in this article. The median age of onset was 34 years (interquartile range 1-79). The most common initial manifestations were cough, dyspnea, respite, and hemoptysis, with pulmonary complications such as pneumothorax and chylothorax. Five patients (13.9%) were asymptomatic at admission. Nearly half of the 36 male patients had thin-walled air-filled cysts that were visible throughout both lungs. Considering the abovementioned atypical clinical features, misdiagnosis was committed in 8 patients (22.2%). In addition, patients with tuberous sclerosis complex lymphangioleiomyomatosis often have no pulmonary manifestations at onset but present multiple extrapulmonary manifestations and have higher rates of renal angiomyolipomas than patients with S-LAM (P < 0.01). Eventually, 4 patients with S-LAM eventually died. Physicians should increase the awareness of LAM in male. Early monitoring of various systems should be recommended to ensure early management and active follow-up. Tuberous sclerosis complex patients should immediately be tracked for the onset of LAM disease to improve prognosis.

Tislelizumab combined with anlotinib in the second-line treatment of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a malevolent tumor originated from pleura and often leads to poor prognosis. Chemotherapy of pemetrexed and cisplatin combined with antiangiogenic therapy of bevacizumab is recommended as the first-line regimen by guidelines. However, there are few sustainable second-line anti-tumor theraies that bring distinct survival benefit after the occurrence of drug resistance as the reported mPFS (median progression-free survival) scarcely exceeds 6 months. Immune checkpoint inhibitors are extensively investigated in pan-cancer, and dual immunotherapy has been listed in the first-line recommendation of MPM in several guidelines, while MPM patients benefit modestly from immune checkpoint inhibitors combination or monotherapy in second-line practice. We report a 59-year-old male patient who was diagnosed with unresectable MPM in April 2021. He received firstly pemetrexed combined with platinum and bevacizumab, which barely curbed disease progression When the first line treatment failed, he was switched to tislelizumab combined with anlotinib. Tislelizumab combined with anlotinib significantly relieved his clinical symptoms, and imaging examination further validated the improvement. Until present, the second-line treatment PFS is more than 10 months. The case firstly demonstrated the efficacy of tislelizumab combined with anlotinib in the second-line management of MPM. Thus, immunotherapy combined with small-molecule multi-target anti-angiogenic medication may be alternative for the second-line schemes of MPM.

Research trends and areas of focus on cryoablation and oncology A bibliometric analysis from 2001 to 2020.

Cryoablation is an interdisciplinary, widely used treatment approach for several types of solid tumors, making it difficult to obtain a comprehensive picture of its current status and popular research topics. This study aimed to use a bibliometric approach to understand important research themes and trends in cryoablation and oncology. Literature studies on cryoablation and oncology from 2001 to 2020 were extracted from the Web of Science. A bibliometric analysis was performed based on the annual publication volume, several journal articles and local citation score, and distribution of keywords and trends in the literature using tools such as COOC version 9.94, VOSviewer version 1.6.17, and the bibliometrix version 3.1.3 R package. This study included 2793 publications. Total yearly publications have plateaued over the last 20 years. Five research themes were presented in the keyword network, including clinical applications of cryoablation in liver, lung, kidney, prostate, and skin cancers and comparison of cryoablation with other energy ablations. After 2012, 2 new research topics emerged synergy between cryoablation and immunotherapy in tumors and cryoablation of Barrett esophagus. The high cited literatures are dominated by studies related to cryoablation for renal and prostate cancer treatment, but they also reflect the recent increasing interest in immunotherapy and bone metastases. Twenty important journals were identified, with Cryobiology publishing the most articles. Bibliometric analysis of studies related to tumor cryoablation can help researchers rapidly comprehend popular topics and determine future trends, guiding future research directions.

The investigation of levels of endothelial cell-specific molecule, progranuline, clusterin, and human epididymis protein 4 in the differential diagnosis of malignant pleural effusions.

Progranulin (PGRN), endothelial cell-specific molecule-1, clusterin (CLU), and human epididymis protein 4 (HE-4) are novel proteins reported to have diagnostic and prognostic potential in lung cancer. Here, we aimed to identify the markers with high sensitivity and specificity in distinguishing malignant pleural fluids from other pleural fluids. This prospective, descriptive study was conducted at a medical faculty hospital between 2016 and 2019. The study population consisted of 90 patients <18 years of age with pleural effusion (PE). Levels of pleural fluids of PGRN, endothelial cell-specific molecule-1, CLU, and HE-4 were measured with enzyme-linked immunosorbent assay kits under the manufacturers manual. Of 90 patients, 54 were men, and 36 were women (mean age 65 ± 16 years). Of pleural fluids investigated, 23 (25%) and 67 (74%) were transudates and exudates, respectively. Of exudates, while 27 (40%) and 19 (28%) were parapneumonic PE and tuberculous PE, respectively, 20 (29%) were malignant pleural effusion (MPE). Levels of all biomarkers in exudate fluids were found significantly higher than those of transudate fluids. CLU, HE-4, and PGRN levels in MPE were also found significantly higher than benign fluids (P < .05). Cutoff values were achieved by receiver operating characteristics analysis for CLU, HE-4, and PGRN to distinguish between malignant and benign groups. For diagnosis of MPE, the sensitivity and specificity values were found as 0.66 and 0.67 for a cutoff value of CLU of 18.29 mgL (P .00), as 0.76 and 0.76 for a cutoff value of HE-4 of 9.33 mgL (P .00), and as 0.66 and 0.67 for a cutoff value of PGRN of 105.91 mgL (P .001). HE-4 having high sensitivity and specificity can be a potential diagnostic marker in distinguishing between malignant and benign effusions, and these findings can constitute a basis for future research.

Implantation of computed tomography-guided high-dose-rate 192Ir brachytherapy in oldest old patients with advanced non-small cell lung cancer A case report and literature review.

With the increasing aging and the popularization of medical diagnosis, the growing number of oldest old with lung cancer needs to be focused on. Several medical and physiological challenges often accompanying the oldest old cancer patients make the choice of the optimal treatment daunting. The current research suggests that people who get adequate treatment can benefit, but it is worth discussing which treatment will benefit them more. High-dose-rate (HDR) 192Ir brachytherapy deserves attention in this context owing to its association with less trauma and reduced complications. An 86-years-old woman with a right glandular lung carcinoma presented with progressive lesions 11 months after chemotherapy. Because of her old age and poor performance status (eastern cooperative oncology group performance status 3), she received HDR 192Ir brachytherapy for her right lung lesion without any common complications, such as pneumothorax and hemorrhage. She continued on 0.25 g oral gefitinib each day after received brachytherapy treatment. The right lung lesion keeps a partial response until 18 months later now. HDR 192Ir brachytherapy can potentially be used as a safe and effective choice for the oldest old with advanced non-small cell lung cancer. It can especially benefit cancer patients with concurrent chemotherapy or targeted therapy.

Efficacy and safety of endostar combined with cisplatin in treatment of non-small cell lung cancer with malignant pleural effusion A meta-analysis.

Although there are new treatments for non-small cell lung cancer with malignant pleural effusion, these therapies are prone to recurrent pleural effusion and poor in efficacy. And recombinant human endostatin is a new type of anti-tumor angiogenesis drug independently developed in my country. It has the effect of inhibiting tumor angiogenesis, inhibiting tumor proliferation and differentiation, and effectively inhibiting the formation and recurrence of malignant pleural effusion. Therefore, this study is aim to systematically review the efficacy and safety of intrapleural injection of endostar combined with cisplatin in the treatment of non-small cell lung cancer (NSCLC) with malignant pleural effusion. Databases including Cochrane Library, PubMed, CBM, Embase, CNKI, and WanFang Data were searched to collect randomized controlled trials about endostar combined with cisplatin for NSCLC with malignant pleural effusion from inception to April 2022. Two reviewers independently screened the literature, extracted data, and assessed the risk of bias in included studies. Finally, the meta-analysis was made by using RevMan 5.4.1 software. A total of 11 randomized controlled trials involving 814 patients were finally included. The results of the meta-analysis showed that The overall response rate and the improvement rate of quality of life in the endostar combined with cisplatin group were higher than that of the cisplatin alone group (relative risk 1.58, 95% confidence interval 1.42-1.76, P < .00001 relative risk 1.63, 95% confidence interval 1.38-1.93, P < .00001, respectively). Meanwhile, there were no significant differences between the 2 groups in the incidence of gastrointestinal reaction, the incidence of leucopenia, the incidence of thrombocytopenia, and the incidence of hypodynamia (all P values > .05). Compared with cisplatin, intrapleural injection of endostar combined with cisplatin could improve the overall response rate and the quality of life of NSCLC patients with malignant pleural effusion. Due to the limited quality and quantity of included studies, more high-quality studies are needed to verify the above conclusion.

A pan-cancer analysis of the oncogenic role of polypyrimidine tract binding protein 1 (PTBP1) in human tumors.

Polypyrimidine tract-binding protein 1 (PTBP1) is an RNA-binding protein that regulates several posttranscriptional events and is closely related to the development of multiple tumors. However, little is known about PTBP1. Thus, we carried out a systematic pan-cancer analysis to explore the relationship between PTBP1 and cancer. We used The Cancer Genome Atlas, Gene Expression Omnibus, and Human Protein Atlas datasets, as well as several bioinformatics tools, to explore the role of PTBP1 in 33 tumor types. The expression of PTBP1 in most tumor tissues was higher than that in normal tissues. Survival analysis indicated that overexpression of PTBP1 generally predicted poor overall survival in patients with tumors such as adrenocortical carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, and skin cutaneous melanoma. In addition, we compared the phosphorylation and immune infiltration of PTBP1 in cancer-associated fibroblasts between normal and primary tumor tissues and explored the putative functional mechanism of tumorigenesis mediated by PTBP1. These results provide clues to better understand PTBP1 from the perspective of bioinformatics and highlight its importance in various human cancers.

Characterization of multiple interactions between the envelope E protein of SARS-CoV-2 and human BRD4.

The SARS-CoV-2 envelope (E) protein hijacks human BRD4 (bromodomain and extra-terminal domain protein 4). Here, we describe a protocol to characterize the interaction of the acetylated E protein with BRD4 in vivo. We detail steps to use NMR spectroscopy to map the binding interface and include steps to monitor the effect of BRD4 inhibitors in SARS-CoV-2-infected human lung bronchial epithelial cells. This approach could be applied to study interactions involving other viral and human proteins. For complete details on the use and execution of this protocol, please refer to Vann et al. (2022).

Relationship between asporin and extracellular matrix behavior A literature review.

Asporin (ASPN), as a member of the small leucine-rich repeat proteoglycan family, is a type of protein that is found in the extracellular matrix. Collagen deposition or transformation is involved in a variety of pathological processes. ASPN is identified in cancerous tissue, pathological cardiac tissue, articular cartilage, keloid, and fibrotic lung tissue, and it has a role in the development of cancer, cardiovascular, bone and joint, keloid, and pulmonary fibrosis by interfering with collagen metabolism. This review article summarizes the data on ASPN expressions in mouse and human and highlights that overexpress of ASPN might play a role in a variety of diseases. Although our knowledge of ASPN is currently limited, these instances may help us better understand how it interacts with diseases.

Metagenomic next-generation sequencing as an unconventional approach to warn of tumor cells in a patients with non-mucinous pneumonic-type lung adenocarcinoma Case report.

Pneumonic-type lung cancer (PTLC) is a special type of lung cancer with cough and expectoration as the main clinical symptoms and inflammatory signals as the main imaging manifestations. PTLC can be easily misdiagnosed as pneumonia, and the diagnosis and treatment are always delayed. Metagenomic next-generation sequencing (mNGS), as an emerging and effective method to identify occult pathogens, has been gradually adopted by clinicians. A 58-year-old woman with recurrent cough and expectoration was admitted to hospital on January 12th, 2022. She reported that she was diagnosed with pneumonia half a month ago, after treatment with expectorant and antibiotics for 5 days, the symptoms were relieved. However, the symptoms worsened again 10 days after stopping the drugs. On the current presentation, she denied exposure to patients with infection of COVID-19, smoking history, night sweats, weight loss, rash, joint pain, fever, and shortness of breath. The patient was diagnosed with non-mucinous pneumonic-type lung adenocarcinoma according to the clinical symptoms, changes of CT scans after treatment and cytopathology examinations. The patient was initially diagnosed with pulmonary infection according to computerized tomography (CT) scan. Expectorant and antibiotics used. However, the symptoms worsened again 10 days after stopping the drugs. On her return visit, the CT scan did not showed obvious consolidation absorption and was similar to the previous imaging findings. mNGS was performed to detect the occult pathogens. None pathogen was detected, however, 39 copy number variations were found in Human Chromosomal Instability Analysis of mNGS indicating the presence of tumor cells. The cytopathology findings confirmed the presence of lung adenocarcinoma (non-mucinous adenocarcinoma). She was treated with targeted antitumor drugs, and the CT scan after 20 days of targeted antitumor therapy showed obvious absorption of the lesions. mNGS may have potential value to screen tumor cells in bronchoalveolar lavage fluid of patients with PTLC, especially in the patients whose samples in bronchioli cannot be collected using existing sampling tools.

A randomized controlled study of a combination of internal and external treatments for albumin paclitaxel-related peripheral neurotoxicity A randomized controlled A study protocol.

Albumin-bound paclitaxel (nab-PTX), a novel paclitaxel preparation, has been found to successfully blocks tumor progression in breast and lung cancer. However, at the same time of as clinical application, neurotoxicity caused by nab-PTX has become the main factor limiting the clinical application of nab-PTX, which seriously affects the quality of life of patients and increases their psychological or financial burden. In clinical applications, JHGWD combined with bloodletting therapy at the end of the extremities has a positive effect on neurotoxic symptoms such as numbness, pain, and weakness of the hands and feet caused by nab-PTX. In a single-arm experiment, it was also found that the immediate effective rate of exsanguination therapy was as high as 70%, and when combined with oral Chinese medicine treatment, it further improved the efficacy. Therefore, a randomized controlled trial (RCT) was designed to further evaluate the efficacy and safety of this treatment. This RCT will be conducted at the Shanxi Provincial Hospital of Traditional Chinese Medicine. A total of 120 patients with Nab-PTX chemotherapy-induced neurotoxicity will be recruited. Treatment groups will be categorized into herbs alone group, bloodletting treatment alone group, and herbs combined with bloodletting group. Blank control was used. The primary outcome will be the EORTC QLQ-CIPN20 scale of the included patients, and the secondary outcomes will include EMG, peripheral neurotoxicity symptom score, NCI-CTCAE5.0 peripheral neurotoxicity grade, and WHO anti-tumor drug peripheral neurotoxicity grade. Adverse reactions will be recorded throughout the process. All data in this RCT will be analyzed by SPSS 26.0 software. The results of this RCT will contribute to treating PIPN, relieving the neurotoxic symptoms, and improving the quality of life of patients. Finally, the RCT results will be published in a relevant academic journal on completion of the trial. ChiCTR2200060217(May22,2022).

Expression of KAI1 and AGR2 in lung adenocarcinoma and their clinicopathological significance.

Anticancer 1 (KAI1, tumor metastasis suppressor gene) and Anterior gradient-2 (AGR2, considered a valuable prognostic factor for some cancers) are associated with metastasis and prognosis of various types of human cancers. Nevertheless, the relationship between KAI1 and AGR2 in lung adenocarcinoma (LUAD) remains unclear. In this research, we analyzed the correlations between KAI1 and AGR2 in LUAD, and explored their correlations with clinicopathological parameters and overall survival time (OS) in patients with LUAD. Immunohistochemical staining was used to detect KAI1 and AGR2 expression in 132 cases of LUAD samples. At the same time, all clinicopathological parameters and postoperative survival information were collected. AGR2 positive rate was significantly increased and KAI1 positive rate was significantly decreased in LUAD and control tissues. KAI1 positive rates were negatively correlated with tumor stage, LNM stage and TNM stage, and KAI1 subgroup positive expression of OS was significantly higher than negative KAI1 subgroup. The positive rate of AGR2 was positively correlated with tumor grade, LNM stage and TNM stage, and negatively correlated with patients OS. Active expression of AGR2 and KAI1, tumor stage, and LNM stage in multivariate analyses may be independent prognostic factors for OS in LUAD patients. KAI1 and AGR2 may be potential biomarkers for prognosis and metastasis, and they are also promising therapeutic targets for LUAD patients.

The clinicopathological and prognostic significance of mTOR and p-mTOR expression in patients with non-small cell lung cancer A meta-analysis.

The mammalian target of rapamycin (mTOR) has a crucial role in carcinogenesis, angiogenesis, cellular proliferation, and metastasis however, its significance in non-small cell lung cancer (NSCLC) remains contentious. Consequently, this study aims to assess the clinicopathological and prognostic importance of mTORp-mTOR expression in NSCLC. Literature retrieval was undertaken by searching English databases PubMed, EMBASE, Web of Science, and Cochrane Library as well as Chinese databases CNKI, Wan Fang, and VIP for full-text publications that satisfied our eligibility criteria up to November 2021. STATA 12.0 was used to conduct statistical analysis (STATA Corporation, College Station, TX). This meta-analysis includes a total of 4683 patients from 28 primary publications. mTORp-mTOR expression was associated with sex (OR 0.608, 95% CI 0.442-0.836), lymph node metastasis (OR 2.084, 95% CI 1.437-3.182), and CEA (OR 1.584, 95% CI 1.135-2.209), but not with age, histological type, depth of tumor invasion, distant metastasis, TNM stage, differentiation degree, tumor size, or smoking. In addition, the expression of mTORp-mTOR is related to shorter overall survival in NSCLC patients (HR 1.415, 95% CI 1.051-1.905). Positive mTORp-mTOR expression was substantially correlated with unfavorable conditions on the sex, lymph node metastases, and CEA levels. mTORp-mTOR may indicate a bad prognosis for NSCLC. The current findings must be confirmed and changed by other high-quality research employing a multivariate analysis on bigger sample size.

Telehealth Use Following COVID-19 Within Patient-Sharing Physician Networks at a Rural Comprehensive Cancer Center Cross-sectional Analysis.

In response to the COVID-19 pandemic, cancer centers rapidly adopted telehealth to deliver care remotely. Telehealth will likely remain a model of care for years to come and may not only affect the way oncologists deliver care to their own patients but also the physicians with whom they share patients. This study aimed to examine oncologist characteristics associated with telehealth use and compare patient-sharing networks before and after the COVID-19 pandemic in a rural catchment area with a particular focus on the ties between physicians at the comprehensive cancer center and regional facilities. In this retrospective observational study, we obtained deidentified electronic health record data for individuals diagnosed with breast, colorectal, or lung cancer at Dartmouth Health in New Hampshire from 2018-2020. Hierarchical logistic regression was used to identify physician factors associated with telehealth encounters post COVID-19. Patient-sharing networks for each cancer type before and post COVID-19 were characterized with global network measures. Exponential-family random graph models were performed to estimate homophily terms for the likelihood of ties existing between physicians colocated at the hub comprehensive cancer center. Of the 12,559 encounters between patients and oncologists post COVID-19, 1228 (9.8%) were via telehealth. Patient encounters with breast oncologists who practiced at the hub hospital were over twice as likely to occur via telehealth compared to encounters with oncologists who practiced in regional facilities (odds ratio 2.2, 95% CI 1.17-4.15 P.01). Patient encounters with oncologists who practiced in multiple locations were less likely to occur via telehealth, and this association was statistically significant for lung cancer care (odds ratio 0.26, 95% CI 0.09-0.76 P.01). We observed an increase in ties between oncologists at the hub hospital and oncologists at regional facilities in the lung cancer network post COVID-19 compared to before COVID-19 (93318, 29.3%, vs 79370, 21.6%, respectively), which was also reflected in the lower homophily coefficients post COVID-19 compared to before COVID-19 for physicians being colocated at the hub hospital (estimate 1.92, 95% CI 1.46-2.51, vs 2.45, 95% CI 1.98-3.02). There were no significant differences observed in breast cancer or colorectal cancer networks. Telehealth use and associated changes to patient-sharing patterns associated with telehealth varied by cancer type, suggesting disparate approaches for integrating telehealth across clinical groups within this health system. The limited changes to the patient-sharing patterns between oncologists at the hub hospital and regional facilities suggest that telehealth was less likely to create new referral patterns between these types of facilities and rather replace care that would otherwise have been delivered in person. However, this study was limited to the 2 years immediately following the initial outbreak of COVID-19, and longer-term follow-up may uncover delayed effects that were not observed in this study period.

A bioengineered probiotic for the oral delivery of a peptide Kv1.3 channel blocker to treat rheumatoid arthritis.

Engineered microbes for the delivery of biologics are a promising avenue for the treatment of various conditions such as chronic inflammatory disorders and metabolic disease. In this study, we developed a genetically engineered probiotic delivery system that delivers a peptide to the intestinal tract with high efficacy. We constructed an inducible system in the probiotic

Tumor dynamic model-based decision support for Phase IbII combination studies A retrospective assessment based on resampling of the Phase III study IMpower150.

Model-based tumor growth inhibition (TGI) metrics are increasingly incorporated into gono-go decisions in early clinical studies. To apply this methodology to new investigational combinations requires independent evaluation of TGI metrics in recently completed Phase III trials of effective immunotherapy. Data were extracted from IMpower150, a positive, randomized, Phase III study of first-line therapy in 1202 patients with non-small cell lung cancer. We resampled baseline characteristics and longitudinal sum of longest diameters of tumor lesions of patients from both arms, atezolizumabbevacizumabchemotherapy (ABCP) vs. BCP, to mimic Phase IbII studies of 15-40 patientsarm with 6-24 weeks follow-up. TGI metrics were estimated using a bi-exponential TGI model. Effect sizes were calculated as TGI metrics geometric mean ratio (GMR), objective response rate (ORR) difference (d), and progression-free survival (PFS) hazard ratio (HR) between arms. Correct and incorrect go decisions were evaluated as the probability to achieve desired effect sizes in ABCP vs. BCP and BCP vs. BCP, respectively, across 500 replicated subsamples for each design. For 40 patients24 weeks follow-up, correct go decisions based on probability tumor growth rate KG GMR<0.90, dORR>0.10 and PFS HR<0.70 were 83%, 69%, and 58% with incorrect go decision rates of 4%, 12% and 11%, respectively. For other designs, the ranking did not change with TGI metrics consistently over-performing RECIST endpoints. The predicted OS HR was around 0.80 in most of the scenarios investigated. Model-based estimate of KG GMR is an exploratory endpoint that informs early clinical decisions for combination studies.

IL-6 mediates suppression of T and NK cells function in EMT-associated TKI-resistant EGFR mutant NSCLC<.

Advanced non-small cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations are initially responsive to tyrosine kinase inhibitors (TKIs). However, therapeutic resistance eventually emerges, often via secondary EGFR mutations or EGFR-independent mechanisms such as EMT. Treatment options after EGFR-TKI resistance are limited as anti-PD-1PD-L1 inhibitors typically display minimal benefit. Given that IL-6 is associated with worse outcomes in NSCLC patients, we investigate if IL-6 in part contributes to this immunosuppressed phenotype. We utilized a syngeneic genetically engineered mouse model (GEMM) of EGFR mutant NSCLC to investigate the effects of IL-6 on the tumor microenvironment and the combined efficacy of IL-6 inhibition and anti-PD1 therapy. Corresponding in vitro studies used EGFR mutant human cell lines and clinical specimens. We identified that EGFR mutant tumors which have oncogene-independent acquired resistance to EGFR-TKIs were more mesenchymal and had markedly enhanced IL-6 secretion. In EGFR mutant GEMMs, IL-6 depletion enhanced activation of infiltrating NK and T cell subpopulations and decreased immunosuppressive T-regulatory and Th17 cell populations. Inhibition of IL-6 increased NK and T cell -mediated killing of human osimertinib-resistant EGFR mutant NSCLC tumor cells in cell culture. IL-6 blockade sensitized EGFR mutant GEMM tumors to PD-1 inhibitors through an increase in tumor-infiltrating IFNγ CD8 T cells. These data indicate that IL-6 is upregulated in EGFR mutant NSCLC tumors with acquired EGFR-TKI resistance and suppressed T and NK cell function. IL-6 blockade enhanced antitumor immunity and efficacy of anti-PD1 therapy warranting future clinical combinatorial investigations.

lncRNA-disease association prediction based on the weight matrix and projection score.

With the development of medical science, long noncoding RNA (lncRNA), originally considered as a noise gene, has been found to participate in a variety of biological activities. Several recent studies have shown the involvement of lncRNA in various human diseases, such as gastric cancer, prostate cancer, lung cancer, and so forth. However, obtaining lncRNA-disease relationship only through biological experiments not only costs manpower and material resources but also gains little. Therefore, developing effective computational models for predicting lncRNA-disease association relationship is extremely important. This study aimed to propose an lncRNA-disease association prediction model based on the weight matrix and projection score (LDAP-WMPS). The model used the relatively perfect lncRNA-miRNA relationship data and miRNA-disease relationship data to predict the lncRNA-disease relationship. The integrated lncRNA similarity matrix and the integrated disease similarity matrix were established by fusing various methods to calculate the similarity between lncRNA and disease. This study improved the existing weight algorithm, applied it to the lncRNA-miRNA-disease triple network, and thus proposed a new lncRNA-disease weight matrix calculation method. Combined with the improved projection algorithm, the lncRNA-miRNA relationship and miRNA-disease relationship were used to predict the lncRNA-disease relationship. The simulation results showed that under the Leave-One-Out-Cross-Validation framework, the area under the receiver operating characteristic curve of LDAP-WMPS could reach 0.8822, which was better than the latest result. Taking adenocarcinoma and colorectal cancer as examples, the LDAP-WMPS model was found to effectively infer the lncRNA-disease relationship. The simulation results showed good prediction performance of the LDAP-WMPS model, which was an important supplement to the research of lncRNA-disease association prediction without lncRNA-disease relationship data.

Dual Nicotinamide Phosphoribosyltransferase (NAMPT) and Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors for the Treatment of Drug-Resistant Nonsmall-Cell Lung Cancer.

Depleting NAD

Brachytherapy and osteoradionecrosis in patients with base of tongue cancer.

Base of tongue cancer incidence and patient survival is increasing why treatment sequelae becomes exceedingly important. Osteoradionecrosis (ORN) is a late adverse effect of radiotherapy and brachytherapy (BT) could be a risk factor. Brachytherapy is used in three out of six health care regions in Sweden. Investigate if patients treated in regions using BT show an increased risk for ORN and whether brachytherapy has any impact on overall survival. We used data from the Swedish Head and Neck Cancer Register between 2008-2014. Due to the nonrandomized nature of the study and possible selection bias we compared the risk for ORN in brachy vs non-brachy regions. Fifty out of 505 patients (9.9%) developed ORN eight of these were treated in nonbrachy regions (16%), while 42 (84%) were treated in brachy regions. Neither age, sex, TNM-classificationstage, p16, smoking, neck dissection, or chemotherapy differed between ORN and no-ORN patients. The risk for ORN was significantly higher for patients treated in brachy regions compared to non-brachy regions (HR 2,63, Brachytherapy ought to be used cautiously for selected patients or within prospective randomized studies.

Association Between Rheumatic Autoantibodies and Immune-Related Adverse Events.

Side effects of immune checkpoint inhibitors (ICIs), called immune-related adverse events (irAEs), closely resemble primary autoimmune or rheumatic diseases. We aimed to understand the clinical utility of rheumatic autoantibodies (rhAbs) for diagnosing irAEs. Patients without pre-existing autoimmune disease (pAID) who had cancer treated with ICI(s) treatment from 112011 to 12212020 and a rhAb checked were retrospectively identified. Logistic regression assessed associations between autoantibodies and irAEs, cancer outcome, and survival. Specificity, sensitivity, and positivenegative predictive values (PPV, NPV) were estimated for key rhAbs and ICI-arthritis. Kaplan-Meier analyzed objective response rate (ORR) and overall survival (OS). A total of 2662 patients were treated with≥1 ICIs. One hundred and thirty-five without pAID had ≥ 1 rhAb tested. Of which 70135(52%) were female median age at cancer diagnosis was 62 years with most common cancers melanoma (23%) or non-small cell lung cancer (21%), 96135 (75%) were anti-PD1PDL1 treated. Eighty had a rhAb ordered before ICI, 96 after ICI, and 12 before and after. Eighty-two (61%) experienced an irAE, 33 (24%) with rheumatic-irAE. Pre-ICI RF showed significant association with rheumatic-irAEs (OR 25, 95% CI, 1.52-410.86, P .024). Pre- and post-ICI RF yielded high specificity for ICI-arthritis (93% and 78%), as did pre- and post-ICI CCP (100% and 91%). Pre-ICI RF carried 93% NPV and pre-ICI CCP had 89% PPV for ICI-arthritis. No variables were significantly correlated with ORR. Any-type irAE, rheumatic-irAE and ICI-arthritis were all associated with better OS (P .000, P .028, P .019). Pre-ICI RF was associated with higher odds of rheumatic-irAEs. IrAEs had better OS therefore, clinical contextualization for rhAbs is critical to prevent unnecessary withholding of lifesaving ICI for fear of irAEs.

Contemporary Outcomes for the Curative Treatment of Colorectal Cancer Pulmonary Metastases.

Treatment of pulmonary metastases (PM) from colorectal cancer (CRC) is the standard of care by several guidelines from Europe and the USA, but the validity of this strategy has been recently questioned, and the available evidence supporting this strategy is weak. We report the outcomes of a curative intent strategy in a very recent and homogenous series of patients. We did a retrospective review of all curative intent surgical or ablative treatment of PM from CRC performed consecutively in 3 French institutions from January 2015 to December 2019. Demographics, clinicopathological, and molecular characteristics were evaluated. Cox regression models were used to identify prognostic factors related to local recurrence and disease-free survival. Records from 152 patients were reviewed. One-hundred thirty-five patients (88%) had surgical metastasectomy. Median age was 67 years. Most of the patients had a single lesion (66%), and 16% had synchronous PM. Eighty-one patients (53%) experienced recurrence, and the thorax was the most common site of recurrence. Median disease-free survival and overall survival were 35 months and 78 months after PM treatment. At the end of the study, only 17% of the patients died. Pulmonary tumor burden was correlated with disease-free survival in univariate analysis, but multivariate analysis did not find any prognostic factor independently associated with local recurrence or survival. Our finds corroborate existing recommendation for the invasive treatment of PM from CRC in selected patients.

Dual-layer spectral detector CT (SDCT) can improve the detection of mixed ground-glass lung nodules.

Mixed ground-glass lung nodules are a high-risk factor for lung adenocarcinoma. This study aimed to analyze the value of SDCT electron density imaging in the detection of mixed ground-glass lung nodules (GGNs). 150 patients with GGNs confirmed by chest SDCT and surgical pathology were retrospectively analyzed. GGNs were screened by two senior radiologists by the double-blind method based on conventional CT and SDCT electron density images. Average CT values and electron density (ED) values of GGNs were measured for all, solid and ground-glass. Thirty pGGN cases determined by conventional CT were found to be mGGN on electron density images, including 23 in the invasive adenocarcinoma group (detection rate of 35.38%), which was significantly higher than that of the PGL group (14.89%, P < 0.05). In electron density images, average CT values and ED values in the PGL and invasive adenocarcinoma groups with pGGNs were no difference. The average CT value and ED value were significantly higher in the mGGN invasive adenocarcinoma group compared with the PGL group (P < 0.05). Meanwhile, ROC curve analysis of average CT value and ED value revealed AUC values for mGGN infiltration of 0.759 and 0.752. SDCT can improve GGN visualization and increase the detection rate of mGGN compared with conventional CT. Attention should be paid to invasive adenocarcinoma for lung GGNs detected as mGGNs with high average CT value or ED value.