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A bibliometric and visualization analysis on the association between chronic exposure to fine particulate matter and cancer risk.

As one of the major pollutants in ambient air pollution, fine particulate matter (PM To investigate its association with the commonly observed PM-related cancer, a bibliometric study was performed on related publications from 2012 to 2021 from a macroscopic perspective with the help of the Web of Science database and scientometric software VOSviewer, CiteSpace V, HistCite, and Biblioshiny. The results indicated that of the 1,948 enrolled documents, scientific productions increased steadily and peaked in 2020 with 348 publications. The most prolific authors, journals, organizations, and countries were Raaschou-Nielsen O, The toxic mechanism of carcinogenicity was explained and is worthy of further investigation. China and the US collaborated most closely, and it is hoped the two countries can strengthen their collaboration to combat air pollution. There is also a need to identify the components of PM

Disparities in inflammation between non-Hispanic black and white individuals with lung cancer in the Greater Chicago Metropolitan area.

Lung cancer incidence and mortality rates are higher in Non-Hispanic Black (NHB) compared to Non-Hispanic White (NHW) individuals in the Chicago metropolitan area, which may be related to exposure to chronic stress which may increase inflammation. We investigated disparities in inflammation as measured by neutrophil to lymphocyte ratio (NLR) in individuals with lung cancer by race and by neighborhood concentrated disadvantage index (CDI). This retrospective, cross-sectional study included 263 NHB and NHW adults with lung cancer. We analyzed NLR as a continuous and categorical variable to determine degree and prevalence of inflammation. We used Mann Whitney U, t-tests, Chi square tests, linear and logistic regression models as appropriate. More than 60% of subjects had inflammation (NLR ≥ 3) at lung cancer diagnosis. The degree of inflammation was significantly lower in NHB (NLR 5.50 - 7.45) compared to NHW individuals (NLR 6.53 - 6.53 p0.01) but did not differ by neighborhood CDI. The prevalence of inflammation (NLR ≥ 3) was significantly lower in NHB (55.07%) compared to NHW individuals (71.20% p<0.01) and in those from the most disadvantaged (54.07%) compared to the least disadvantaged (71.88% p<0.01) neighborhoods. At lung cancer diagnosis, there is a lower degree and prevalence of inflammation in NHB compared to NHW individuals, and lower prevalence in those residing in the most disadvantaged neighborhoods. Further research is needed to determine mechanisms of inflammation that may be contributing to lung cancer disparities as well as whether NLR is an appropriate biomarker when examining racial differences in inflammation.

Downregulation of T-cell cytotoxic marker IL18R1 promotes cancer proliferation and migration and is associated with dismal prognosis and immunity in lung squamous cell carcinoma.

Immunotherapy can improve the survival of patients with advanced lung squamous cell carcinoma (LUSC). T cytotoxic cells are one of the main members of the immune microenvironment. Herein, we aimed to identify the roles of T-cell cytotoxic markers interleukin 18 (IL18) receptor 1 (IL18R1) in the LUSC progression using bioinformatics, clinical tissue specimen, and cell experiment. We assessed the association between the IL18R1 expression and immune infiltration and IL18R1-related competing RNA network. The IL18R1 expression was downregulated in the LUSC tissues. The IL18R1 expression downregulation was associated with diagnosis and short overall survival and disease-specific survival, and it was also an independent risk factor for dismal survival time in LUSC. IL18R1-related nomograms predicted the survival time of patients with LUSC. IL18R1 overexpression inhibited the proliferation, migration, and invasion of LUSC cells. The IL18R1 expression was significantly associated with the microenvironment (stromal, immune, and estimate scores), immune cells (such as the T cells, cytotoxic cells, CD8 T cells), and immune cell markers (such as the CD8A, PD-1, and CTLA4) in LUSC. AC091563.1 and RBPMS-AS1 downregulation was positively associated with the IL18R1 expression, negatively associated with the miR-128-3p expression, and associated with short disease-specific survival and progression in LUSC. In conclusion, IL18R1 was significantly downregulated and associated with the prognosis and immune microenvironment. IL18R1 overexpression inhibits the growth and migration of cancer cells in LUSC. Furthermore, AC091563.1 and RBPMS-AS1 might compete with IL18R1 to bind miR-128-3p for participating in LUSC progression. These results showed that IL18R1 is a biomarker for evaluating the prognosis of patients with LUSC.

Combining PD-1 or PD-L1 inhibitors with chemotherapy is a good strategy for the treatment of extensive small cell lung cancer A retrospective analysis of clinical studies.

To provide an updated systematic review and meta-analysis of published randomized controlled trials (RCTs) of the efficacy and safety of programmed cell death 1 (PD-1)programmed cell death ligand 1 (PD-L1) inhibitors combined with chemotherapy versus chemotherapy alone in the treatment of extensive-stage small-cell lung cancer (ES-SCLC). PubMed, Web of Science, Embase, Clinicaltrials and the Cochrane Library were systematically searched to extract RCTs concerning the efficacy and safety of PD-1PD-L1 inhibitors combined with chemotherapy versus chemotherapy alone in the treatment of ES-SCLC from the time of database inception to October 31, 2022. The literature was independently selected, information was extracted and the risk of bias of the RCTs was evaluated according to the inclusion and exclusion criteria. Stata14.0 was used for the meta-analysis. Six studies involving 2,600 patients were included in the analysis. The results of the meta-analysis showed that the combination of PD-1PD-L1 inhibitors significantly improved the OS (HR 0.73, 95% CI 0.66-0.80 PD-1PD-L1 inhibitors combination chemotherapy significantly improves PFS and OS in ES-SCLC patients without increasing the overall incidence of TRAEs.

Autoimmunity in monogenic combined immune deficiencies with associated or syndromic features.

Combined immune deficiencies (CIDs) with associated or syndromic features are a highly heterogeneous subgroup of inherited immune disorders. These patients represent specific clinical complications with an increased risk of autoimmune conditions. We analyzed data of monogenic patients with syndromic CIDs adopted from the Iranian inborn errors of immunity registry up to January 2022. A comprehensive comparison in terms of demographic, clinical, and immunological features was performed between patients with and without autoimmunity and also among four mutation groups with the most registered cases including A total of 137 patients with monogenic syndromic CIDs were included. Most commonly mutated genes were the About 18% of patients with monogenic syndromic CIDs developed autoimmunity, mainly in the form of hematological immune diseases. Autoimmunity could be an early-onset involvement with a potential diagnostic impact on suspicious cases of syndromic CIDs.

The role of PD-1PD-L1 axis in idiopathic pulmonary fibrosis Friend or foe

Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease with a bleak prognosis. Mounting evidence suggests that IPF shares bio-molecular similarities with lung cancer. Given the deep understanding of the programmed cell death-1 (PD-1)programmed death-ligand 1 (PD-L1) pathway in cancer immunity and the successful application of immune checkpoint inhibitors (ICIs) in lung cancer, recent studies have noticed the role of the PD-1PD-L1 axis in IPF. However, the conclusions are ambiguous, and the latent mechanisms remain unclear. In this review, we will summarize the role of the PD-1PD-L1 axis in IPF based on current murine models and clinical studies. We found that the PD-1PD-L1 pathway plays a more predominant profibrotic role than its immunomodulatory role in IPF by interacting with multiple cell types and pathways. Most preclinical studies also indicated that blockade of the PD-1PD-L1 pathway could attenuate the severity of pulmonary fibrosis in mice models. This review will bring significant insights into understanding the role of the PD-1PD-L1 pathway in IPF and identifying new therapeutic targets.

Transcriptomic FHIT

In recent decades, the development of immunotherapy and targeted therapies has considerably improved the outcome of non-small cell lung cancer (NSCLC) patients. Despite these impressive clinical benefits, new biomarkers are needed for an accurate stratification of NSCLC patients and a more personalized management. We recently showed that the tumor suppressor fragile histidine triad (FHIT), frequently lost in NSCLC, controls HER2 receptor activity in lung tumor cells and that tumor cells from NSCLC patients harboring a FHIT We performed RNA sequencing analysis on tumor cells isolated from NSCLC (n12) according to FHITpHER2 status and a functional analysis of differentially regulated genes. We also investigated the FHIT We showed that up-regulated genes in FHIT These data suggest that ICI might not be a relevant option for NSCLC patients with FHIT

Combination of immune checkpoint inhibitors with radiation therapy in cancer A hammer breaking the wall of resistance.

Immuno-oncology is an emerging field in the treatment of oncological diseases, that is based on recruitment of the host immune system to attack the tumor. Radiation exposure may help to unlock the potential of the immune activating agents by enhancing the antigen release and presentation, attraction of immunocompetent cells to the inflammation site, and eliminating the tumor cells by phagocytosis, thereby leading to an overall enhancement of the immune response. Numerous preclinical studies in mouse models of glioma, murine melanoma, extracranial cancer, or colorectal cancer have contributed to determination of the optimal radiotherapy fractionation, as well as the radio- and immunotherapy sequencing strategies for maximizing the antitumor activity of the treatment regimen. At the same time, efficacy of combined radio- and immunotherapy has been actively investigated in clinical trials of metastatic melanoma, non-small-cell lung cancer and renal cell carcinoma. The present review summarizes the current advancements and challenges related to the aforementioned treatment approach.

Protective Behavioural Mechanisms Against Cannabis Use Among Adolescents in Cannabis-Growing Settings of South Africa Insights Into Adolescent Cannabis Use Prevention.

We aimed to explore the behavioural protective mechanisms against cannabis use among adolescents living in South African illicit cannabis-growing communities, based on the Self Determination Theory (SDT). Exploratory qualitative design techniques were followed in conducting the study. The snowball sampling technique was used to recruit thirty (30) non-cannabis smoking adolescents from 2 purposively selected communities and grouped into 4 focus groups and interviewed. A semi-structured focus group interview guide was used to moderate the discussions. Data were analysed inductively, using the ATLAS. ti software. Nine behavioural coping mechanisms, grouped under intrinsic and extrinsic protective behavioural mechanisms, protected participants from using cannabis. Intrinsically, participants determination not to engage in bad behaviours, focus on their academic work during their free periods, their non-financial dependence on cannabis-using peers, self-preservation to ensure good marriages, and religious beliefs on substance abuse motivated them to not use cannabis. On the other hand, the concept of

The value of the Advanced Lung Cancer Inflammation Index (ALI) in assessing the prognosis of patients with hepatocellular carcinoma treated with camrelizumab a retrospective cohort study.

The Advanced Lung Cancer Inflammation Index (ALI) is considered a useful prognostic biomarker for clinical outcome in patients with malignancy. However, the prognostic value of ALI in patients with advanced hepatocellular carcinoma (HCC) is unclear. In this study we assessed the prognostic value of the ALI in patients with HCC treated with camrelizumab. This retrospective study analyzed patients with advanced hepatocellular carcinoma treated with the ICI, camrelizumab alone or in combination at Henan Cancer Hospital from January 2017 to January 2020. Sixty-five patients were finally screened for at least 2 years of follow-up according to the inclusion criteria, with no significant differences in patient baseline data. The receiver operating characteristic (ROC) curve was used to determine the optimal cut-off point for the ALI which was compared to other clinical indicators for predicting survival. A Kaplan-Meier analysis and Cox proportional analysis were conducted to examine the association between the ALI and patient prognosis. The median overall survival (OS) for the overall group of patients was 383 days, the area under the curve for ALI was 0.815 and the optimal cut-off value for predicting OS was 34.65. The median OS for patients with an ALI score ≤34.65 was 336 days and that for patients with an ALI score >34.65 was 524 days. The univariate analysis showed that the Eastern Cooperative Oncology Group (ECOG) score, aspartate aminotransferase (AST) level, and the ALI score predicted OS. The multivariate analysis showed that the ALI score was an independent prognostic factor of OS in patients with advanced HCC who had been treated with immunotherapy hazard ratio (HR) 0.285, 95% confidence interval (CI) 0.097-0.833, P0.022. A nomogram that included ALI performed well relative to the prediction of prognosis after immunotherapy for patients with advanced liver cancer. The ALI may be a new prognostic marker in patients with advanced HCC undergoing immunotherapy.

Incidence rate of chronic pain after 1.5-2 years of thoracotomy between paravertebral block versus epidural block a cohort study.

Paravertebral block and epidural block are frequently employed for post-thoracotomy pain relief. It is not clear which postoperative analgesia method is effective for the chronic pain after the postoperative long term progress. Our hypothesis was that paravertebral block would be more effective than epidural block for chronic pain 1.5-2 years after thoracotomy. A cohort study investigating postoperative pain was performed in lung cancer patients undergoing thoracotomy between the ages of 20-80 year-old, employed for another randomized controlled trial. In previously study, the patients were randomly allocated into either the epidural block or paravertebral block group (

Large lung mass lesion with spontaneous regression in a patient with IgG4-related lung disease.

IgG4-related lung disease (IgG4-RLD) may present with a variety of radiological findings, but large lung mass lesion are rare. Although steroid therapy is strongly recommended for IgG4-RLD with or without symptoms, respirologists should be aware that some patients may not need steroid therapy.

Plasma tumor mutation burden is associated with clinical benefit in patients with non-small cell lung cancer treated with anti-programmed death-1 monotherapy.

The clinical utility of plasma tumor mutational burden (pTMB) requires further validation. Herein, the pTMB and genetic alterations were investigated as predictive biomarkers for anti-PD-1 monotherapy outcome in metastatic non-small cell lung cancer (NSCLC). The GuardantOMNI panel (Guardant Health) was used to identify pTMB and genetic alterations. Data from 99 patients with metastatic NSCLC treated with pembrolizumab or nivolumab in first-, second-, or third-line settings between June 2016 and December 2020 were collected. Associations between pTMB and clinical benefit rate (CBR, stable disease ⩾6 months or partial response), progression-free survival (PFS), and overall survival (OS) were assessed. Median pTMB in 84 patients was 10.8 mutationsmegabase (mutMb). Histological analyses revealed that 61 and 36% of the patients had adenocarcinomas and squamous NSCLC, respectively. Most patients were treated with nivolumab (74%) and most anti-PD-1 agents were administered as second-line treatment (70%). The median follow-up duration was of 10.9 months (range, 0.2-40.7). Patients with high pTMB (⩾19 mutMb) had a higher CBR (69%) compared with low pTMB patients (33% High pTMB (⩾19 mutMb) is significantly associated with CBR in patients with NSCLC treated with anti-PD-1 agents.

Combatting acquired resistance to osimertinib in EGFR-mutant lung cancer.

The discovery of activating mutations in epidermal growth factor receptor (EGFR) in non-small-cell lung cancer transformed the care and prognosis of patients and heralded the era of personalized medicine in thoracic oncology. Osimertinib, a third-generation EGFR inhibitor, has been established as the preferred EGFR inhibitor for newly diagnosed patients which urged the need to develop treatment options for patients progressing on first-line osimertinib. However, acquired resistance invariably emerges and numerous efforts have been attempted to delay or overcome acquired resistance. In this article, we thoroughly reviewed the current understanding of osimertinib resistance mechanisms and explored the established and emerging treatment options. Newer treatment strategies targeting EGFR-dependent or -independent resistance mechanisms, novel approaches using bispecific antibodies and antibody-drug conjugates will be discussed. Moreover, what to do with brain only progression, and how to incorporate immunotherapy in EGFR-mutant lung cancer will be discussed. Lastly, future perspectives on the ongoing clinical trials and combination of front-line therapy will be introduced.

αCT1 peptide sensitizes glioma cells to temozolomide in a glioblastoma organoid platform.

Glioblastoma (GBM) is the most common form of brain cancer. Even with aggressive treatment, tumor recurrence is almost universal and patient prognosis is poor because many GBM cell subpopulations, especially the mesenchymal and glioma stem cell populations, are resistant to temozolomide (TMZ), the most commonly used chemotherapeutic in GBM. For this reason, there is an urgent need for the development of new therapies that can more effectively treat GBM. Several recent studies have indicated that high expression of connexin 43 (Cx43) in GBM is associated with poor patient outcomes. It has been hypothesized that inhibition of the Cx43 hemichannels could prevent TMZ efflux and sensitize otherwise resistance cells to the treatment. In this study, we use a three-dimensional organoid model of GBM to demonstrate that combinatorial treatment with TMZ and αCT1, a Cx43 mimetic peptide, significantly improves treatment efficacy in certain populations of GBM. Confocal imaging was used to visualize changes in Cx43 expression in response to combinatorial treatment. These results indicate that Cx43 inhibition should be pursued further as an improved treatment for GBM.

Quantifying causal effects from observed data using quasi-intervention.

Causal inference is a crucial element within medical decision-making. There have been many methods for investigating potential causal relationships between disease and treatment options developed in recent years, which can be categorized into two main types observational studies and experimental studies. However, due to the nature of experimental studies, financial resources, human resources, and patients ethical considerations, researchers cannot fully control the exposure of the research participants. Furthermore, most existing observational research designs are limited to determining causal relationships and cannot handle observational data, let alone determine the dosages needed for medical research. This paper presents a new experimental strategy called quasi-intervention for quantifying the causal effect between disease and treatment options in observed data by using a causal inference method, which converts the potential effect of different treatment options on disease into computing differences in the conditional probability. We evaluated the accuracy of the quasi-intervention by quantifying the impact of adjusting Chinese patients neutrophil-to-lymphocyte ratio (NLR) on their overall survival (OS) (169 lung cancer patients and 79 controls).The results agree with the literature in this study, consisting of nine papers on cohort studies on the NLR and the prognosis of lung cancer patients, proving that our method is correct. Taken together, the results imply that quasi-intervention is a promising method for quantifying the causal effect between disease and treatment options without clinical trials, and it could improve confidence about treatment options efficacy and safety.

Exhaled phospholipid transfer protein and hepatocyte growth factor receptor in lung adenocarcinoma.

Screening decreases mortality among lung cancer patients but is not widely implemented, thus there is an unmet need for an easily accessible non-invasive method to enable early diagnosis. Particles in exhaled air offer a promising such diagnostic tool. We investigated the validity of a particles in exhaled air device (PExA) to measure the particle flow rate (PFR) and collect exhaled breath particles (EBP) to diagnose primary lung adenocarcinoma (LUAD). Seventeen patients listed for resection of LUAD stages IA-IIIA and 18 non-cancer surgical control patients were enrolled. EBP were collected before and after surgery for LUAD, and once for controls. Proteomic analysis was carried out using a proximity extension assay technology. Results were validated in both plasma from the same cohort and with microarray data from healthy lung tissue and LUAD tissue in the GSE10072 dataset. Of the 92 proteins analyzed, levels of five proteins in EBP were significantly higher in the LUAD patients compared to controls. Levels of phospholipid transfer protein (PLTP) and hepatocyte growth factor receptor (MET) decreased in LUAD patients after surgery compared to control patients. PFR was significantly higher in the LUAD cohort at all timepoints compared to the control group. MET in plasma correlated significantly with MET in EBP. Collection of EBP and measuring of PFR has never been performed in patients with LUAD. In the present study PFR alone could distinguish between LUAD and patients without LUAD. PLTP and MET were identified as potential biomarkers to evaluate successful tumor excision.

A prospective observational study for a Federated Artificial Intelligence solution for moniToring mental Health status after cancer treatment (FAITH) study protocol.

Depression is a common condition among cancer patients, across several points in the disease trajectory. Although presenting higher prevalence rates than the general population, it is often not reported or remains unnoticed. Moreover, somatic symptoms of depression are common in the oncological context and should not be dismissed as a general symptom of cancer. It becomes even more challenging to track psychological distress in the period after the treatment, where connection with the healthcare system typically becomes sporadic. The main goal of the FAITH project is to remotely identify and predict depressive symptoms in cancer survivors, based on a federated machine learning (ML) approach, towards optimization of privacy. FAITH will remotely analyse depression markers, predicting their negative trends. These markers will be treated in distinct categories, namely nutrition, sleep, activity and voice, assessed in part through wearable technologies. The study will include 300 patients who have had a previous diagnosis of breast or lung cancer and will be recruited 1 to 5 years after the end of primary cancer. The study will be organized as a 12-month longitudinal prospective observational cohort study, with monthly assessments to evaluate depression symptoms and quality of life among cancer survivors. The primary endpoint is the severity of depressive symptoms as measured by the Hamilton Depression Rating Scale (Ham-D) at months 3, 6, 9 and 12. Secondary outcomes include self-reported anxiety and depression symptoms (HADS scale), and perceived quality of life (EORTC questionnaires), at baseline and monthly. Based on the predictive models gathered during the study, FAITH will also aim at further developing a conceptual federated learning framework, enabling to build machine learning models for the prediction and monitoring of depression without direct access to users personal data. Improvements in the objectivity of psychiatric assessment are necessary. Wearable technologies can provide potential indicators of depression and anxiety and be used for biofeedback. If the FAITH application is effective, it will provide healthcare systems with a novel and innovative method to screen depressive symptoms in oncological settings. Trial ID ISRCTN10423782 . Date registered 21032022.

A Novel Deep Learning Model Based on Multi-Scale and Multi-View for Detection of Pulmonary Nodules.

Lung cancer manifests as pulmonary nodules in the early stage. Thus, the early and accurate detection of these nodules is crucial for improving the survival rate of patients. We propose a novel two-stage model for lung nodule detection. In the candidate nodule detection stage, a deep learning model based on 3D context information roughly segments the nodules detects the preprocessed image and obtain candidate nodules. In this model, 3D image blocks are input into the constructed model, and it learns the contextual information between the various slices in the 3D image block. The parameters of our model are equivalent to those of a 2D convolutional neural network (CNN), but the model could effectively learn the 3D context information of the nodules. In the false-positive reduction stage, we propose a multi-scale shared convolutional structure model. Our lung detection model has no significant increase in parameters and computation in both stages of multi-scale and multi-view detection. The proposed model was evaluated by using 888 computed tomography (CT) scans from the LIDC-IDRI dataset and achieved a competition performance metric (CPM) score of 0.957. The average detection sensitivity per scan was 0.9711.0 FP. Furthermore, an average detection sensitivity of 0.9331.0 FP per scan was achieved based on data from Shanghai Pulmonary Hospital. Our model exhibited a higher detection sensitivity, a lower false-positive rate, and better generalization than current lung nodule detection methods. The method has fewer parameters and less computational complexity, which provides more possibilities for the clinical application of this method.

Cancer statistics in Chinese older people, 2022 current burden, time trends, and comparisons with the US, Japan, and the Republic of Korea.

Largely due to population ageing, the cancer burden from older people has been rising, which imposed considerable pressure on current Chinese healthcare system. We provide comprehensive information about cancer burden of Chinese older people based on the most recent data from National Central Cancer Registry of China. The logarithmic linear regression was used to project the current cancer burden in 2022, and Joinpoint regression was used for temporal trend analysis from 2000 to 2017. We also estimated cancer statistics of older people in the US, Japan and the Republic of Korea for comparisons. It is estimated that 2.79 million cases and 1.94 million deaths occur for Chinese older people, representing 55.8% and 68.2% of cases and deaths in all population in 2022. The overall cancer incidence rate gradually increased among older women, while the mortality rates declined for both sexes. Notably, approximately 10.0% of all cases and 17.7% of all deaths are from people aged over 80 years, and cancer incidence and mortality in this age group showed upward trends for women. Lung cancer and digestive cancers are the leading cancer types for Chinese older people. Compared with other countries, China has lower incidence rates but higher mortality rates for older people. The rapidly growing burden of prostate cancer, breast cancer, colorectal cancer, and declines in esophageal cancer, stomach cancer, and liver cancer among older people indicate the cancer pattern in China is being in a transition stage to that in developed countries. Our findings imply that it should be the national health priority to meet the growing demands for cancer diagnosis, treatment and care services from the older people as the rapid population ageing in next few decades.

Recurrent germline variant in ATM associated with familial myeloproliferative neoplasms.

Genetic predisposition (familial risk) in the myeloproliferative neoplasms (MPNs) is more common than the risk observed in most other cancers, including breast, prostate, and colon. Up to 10% of MPNs are considered to be familial. Recent genome-wide association studies have identified genomic loci associated with an MPN diagnosis. However, the identification of variants with functional contributions to the development of MPN remains limited. In this study, we have included 630 MPN patients and whole genome sequencing was performed in 64 individuals with familial MPN to uncover recurrent germline predisposition variants. Both targeted and unbiased filtering of single nucleotide variants (SNVs) was performed, with a comparison to 218 individuals with MPN unselected for familial status. This approach identified an ATM L2307F SNV occurring in nearly 8% of individuals with familial MPN. Structural protein modeling of this variant suggested stabilization of inactive ATM dimer, and alteration of the endogenous ATM locus in a human myeloid cell line resulted in decreased phosphorylation of the downstream tumor suppressor CHEK2. These results implicate ATM, and the DNA-damage response pathway, in predisposition to MPN.

Analysis of prognostic model based on immunotherapy related genes in lung adenocarcinoma.

Lung cancer is one of the most common malignant tumors, and ranks high in the list of mortality due to cancers. Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer. Despite progress in the diagnosis and treatment of lung cancer, the prognosis of these patients remains dismal. Therefore, it is crucial to identify the predictors and treatment targets of lung cancer to provide appropriate treatments and improve patient prognosis. In this study, the gene modules related to immunotherapy were screened by weighted gene co-expression network analysis (WGCNA). Using unsupervised clustering, patients in The Cancer Genome Atlas (TCGA) were divided into three clusters based on the gene expression. Next, gene clustering was performed on the prognosis-related differential genes, and a six-gene prognosis model (comprising PLK1, HMMR, ANLN, SLC2A1, SFTPB, and CYP4B1) was constructed using least absolute shrinkage and selection operator (LASSO) analysis. Patients with LUAD were divided into two groups high-risk and low-risk. Significant differences were found in the survival, immune cell infiltration, Tumor mutational burden (TMB), immune checkpoints, and immune microenvironment between the high- and low-risk groups. Finally, the accuracy of the prognostic model was verified in the Gene Expression Omnibus (GEO) dataset in patients with LUAD (GSE30219, GSE31210, GSE50081, GSE72094).

Characterization and in vitro anticancer potential of exopolysaccharide extracted from a freshwater diatom Nitzschia palea (Kütz.) W.Sm. 1856.

Diatoms are photoautotrophic microalgae classified under class Bacillariophyceae, engulfed by hard silicate frustules, which give mechanical support and protection from bacterial infections. They exude polysaccharides extracellularly that help them with their gliding motion (locomotion). However, the bioactivity of such compounds was least explored from freshwater diatoms. In the present study, a single species of pennate diatom identified as Nitzschia palea was isolated and molecularly characterized by 18S rRNA smaller subunit gene (partial) sequencing and submitted to GenBank NCBI and accession number retrieved as ON360983. Based on logarithmic growth curve analysis, the exponential phase was obtained from 3rd to 4th day of diatom culture. The exopolysaccharide was extracted by the hot-water extraction method, and characterized by FT-IR. The total yield of exopolysaccharide from Nitzschia palea was estimated as 1.56 mg in 100 mL of culture after 7 days of incubation. The estimated carbohydrate content was 51.35 µg100 µL. The monosaccharide constituents were determined by acid hydrolysis of exopolysaccharide, silylation (derivatization), followed by GC-MS analysis and tabulated. The extracted exopolysaccharide was evaluated for its anti-cancer potential against the Human Adenocarcinoma lung cancer cell line (A549) and the estimated IC

Tumor immune microenvironment and immunotherapy efficacy in BRAF mutation non-small-cell lung cancer.

Previous small-size studies reported BRAF-mutated NSCLC patients have comparable sensitivity to immune checkpoint inhibitors (ICIs). However, how BRAF mutation affects the tumor immune microenvironment (TIME) is unknown. We performed Nanostring-panel RNA sequencing to evaluate TIME in 57 BRAF mutated and wild-type (WT) NSCLC specimens (cohort A). The efficacy of ICI monotherapy or combined therapies was determined in 417 patients with WT and BRAF mutated NSCLC (cohort B). We found that BRAF-mutant tumors had similar ratios of CD8 T cells to Tregs, the balance of cytotoxicity gene expression signatures and immune suppressive features, and similar ICI-response-related biomarkers to WT NSCLC. A similar TIME pattern was observed between the BRAF V600E and Non-V600E subgroups of NSCLC. The further retrospective study confirmed that treatment with ICI monotherapy or combined therapies resulted in similar overall survival (OS) (HR 0.85 95% CI, 0.56 to 1.30 p 0.47) and progress-free survival (PFS) (HR 1.02 95% CI, 0.72 to 1.44 p 0.91) of patients with WT (n 358) and BRAF mutant (n 59) NSCLC. Similarly, both patients with BRAF V600E or Non-V600E NSCLC had similar responses to immunotherapy. Our findings support that BRAF mutation did not modulate TIME in NSCLC and therapeutic responses to ICIs. Patients with NSCLC harboring BRAF mutation should not be denied treatment with ICIs.

Targeting SPHK1S1PR3-regulated S-1-P metabolic disorder triggers autophagic cell death in pulmonary lymphangiomyomatosis (LAM).

Lymphangioleiomyomatosis (LAM), a progressive pulmonary disease exclusively affecting females, is caused by defects or mutations in the coding gene tuberous sclerosis complex 1 (TSC1) or TSC2, causing the mammalian target of rapamycin complex 1 (mTORC1) activation and autophagy inhibition. Clinically, rapamycin shows limited cytocidal effects, and LAM recurs after drug withdrawal. In this study, we demonstrated that TSC2 negatively regulated the sphingolipid metabolism pathway and the expressions of sphingosine kinase 1 (SPHK1) and sphingosine-1-phosphate receptor 3 (S1PR3) were significantly elevated in LAM patient-derived TSC2-deficient cells compared to TSC2-addback cells, insensitive to rapamycin treatment and estrogen stimulation. Knockdown of SPHK1 showed reduced viability, migration and invasion in TSC2-deficient cells. Selective SPHK1 antagonist PF543 potently suppressed the viability of TSC2-deficient cells and induced autophagy-mediated cell death. Meanwhile, the cognate receptor S1PR3 was identified to mediating the tumorigenic effects of sphingosine-1-phosphate (S1P). Treatment with TY52156, a selective antagonist for S1PR3, or genetic silencing using S1PR3-siRNA suppressed the viability of TSC2-deficient cells. Both SPHK1 and S1PR3 inhibitors markedly exhibited antitumor effect in a xenograft model of TSC2-null cells, restored autophagy level, and triggered cell death. Together, we identified novel rapamycin-insensitive sphingosine metabolic signatures in TSC2-null LAM cells. Therapeutic targeting of aberrant SPHK1S1PS1PR3 signaling may have potent therapeutic benefit for patients with TSCLAM or other hyperactive mTOR neoplasms with autophagy inhibition.

Detection of new phytochemical compounds from

SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination.

Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R 0.05, p 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity. This study has been supported by ISARIC4C and PHOSP-COVID consortia. ISARIC4C is supported by grants from the National Institute for Health and Care Research and the Medical Research Council. Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research. The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research. The funders were not involved in the study design, interpretation of data or the writing of this manuscript.

Primary intraosseous alveolar soft part sarcoma Report of two cases with radiologic-pathologic correlation.

Alveolar soft part sarcoma (ASPS) accounts for less than 1 % of all soft tissue sarcomas. ASPS presents a poor prognosis and develops frequent metastases, especially in the lungs, brain and bones. Current therapies, such as surgery, radiotherapy and chemotherapy, are not fully effective and other alternative treatments are currently being studied. ASPS is predominantly found in the deep soft tissues of the lower extremities. To our knowledge, only thirteen primary intraosseous ASPS have been reported in the literature. In this study, we report two new cases of this exceedingly rare entity. Both cases already had multiple metastases since diagnosis one of them represents the first case of a primary bone ASPS in the ulna and is also the primary intraosseous ASPS with the longest reported case of survival, after having maintained long periods of stabilization despite not having received any systemic treatment.

Serial 7-Day Electrocardiogram Patch Screening for AF in High-Risk Older Women by the CHARGE-AF Score.

Asymptomatic atrial fibrillation (AF) is associated with an increased risk of stroke. The yield of serial electrocardiographic (ECG) screening for AF is unknown. The aim of this study was to determine the frequency of AF detected by serial, 7-day ECG patch screenings in older women identified as having an elevated risk of AF according to the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology)-AF clinical prediction score. Postmenopausal women with a 5-year predicted risk of new-onset AF ≥5% according to CHARGE-AF were recruited from the ongoing WHISH (Womens Health Initiative Strong and Healthy) randomized trial of a physical activity intervention. Participants with AF at baseline by self-report or medical records review were excluded. Screening with 7-day ECG patch monitors was performed at baseline, 6 months, and 12 months from study enrollment. On baseline monitoring, 2.5% of the cohort had AF detected, increasing to 3.7% by 6 months and 4.9% cumulatively by 12 months. Yield of patch screening was higher among participants with a higher (≥10%) CHARGE-AF score 4.2% had AF detected at baseline, 5.9% at 6 months, and 7.2% at 12 months. Most participants with patch-identified AF never had a clinical diagnosis of AF (36 of 46 78%). Older women with an elevated CHARGE-AF score had a high prevalence of AF on 7-day ECG patch screening. Serial screening over 12 months substantially increased the detection of AF. These data can be useful in helping identify high-risk participants for enrollment in future studies of the management of asymptomatic AF.(Womens Health Initiative Silent Atrial Fibrillation Recording Study WHISH STAR NCT05366803.).

Interleukin-10 induces expression of CD39 on CD8T cells to potentiate anti-PD1 efficacy in EGFR-mutated non-small cell lung cancer.

Anti-PD-1(L1) therapies are less efficacious in patients with The characteristics of T cells in Our study suggested that owing to low level of IL-10 to induce the expression of CD39 on CD8

Sensitivity and complications of thoracentesis and thoracoscopy a meta-analysis.

Thoracentesis and thoracoscopy are used to diagnose malignant pleural effusions (MPE). Data on how sensitivity varies with tumour type is limited. Systematic review using PubMed was performed through August 2020 to determine the sensitivity of thoracentesis and thoracoscopy for MPE secondary to malignancy, by cancer type, and complication rates. Tests to identify sources of heterogeneity were performed. Study quality was assessed using Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 and National Institutes of Health quality assessment tools. Publication bias was tested using funnel plots. Meta-analyses for sensitivity of thoracentesis for MPE secondary to malignancy, mesothelioma and lung and breast cancer included 29, eight, 12 and nine studies, respectively. Pooled sensitivities were 0.643 (95% CI 0.592-0.692), 0.451 (95% CI 0.249-0.661), 0.738 (95% CI 0.659-0.836) and 0.820 (95% CI 0.700-0.917), respectively. For sensitivity of thoracoscopy for MPE secondary to malignancy and mesothelioma, 41 and 15 studies were included, respectively. Pooled sensitivities were 0.929 (95% CI 0.905-0.95) and 0.915 (95% CI 0.871-0.952), respectively. Pooled complication rates of thoracentesis and thoracoscopy were 0.041 (95% CI 0.025-0.051) and 0.040 (95% CI 0.029-0.052), respectively. Heterogeneity was significant for all meta-analyses. Funnel plots were asymmetric. Sensitivity of thoracentesis varied significantly per cancer type. Pooled complication rates were low. Awareness of how sensitivity of thoracentesis changes across cancers can improve decision-making when MPE is suspected.

An update on lorlatinib a novel first line treatment for

Anaplastic lymphoma kinase ( This review summarizes the mechanism of action, efficacy, and safety of lorlatinib in Lorlatinib has shown good efficacy and safety in

Differential diagnosis of bone marrow failure syndromes guided by machine learning.

The choice to postpone treatment while awaiting genetic testing can result in significant delay in definitive therapies in severely pancytopenic patients. Conversely, inherited bone marrow failure (BMF) misdiagnosis can expose patients to ineffectual and expensive therapies, toxic transplant conditioning regimens, and inappropriate use of an affected family member as a stem cell donor. To predict the likelihood of patients having acquired or inherited BMF, we developed a two-step data-driven machine-learning model using 25 clinical and laboratory variables typically recorded at the initial clinical encounter. For models development, patients were labeled as having acquired or inherited BMF depending on their genomic data. Datasets were unbiasedly clustered and an ensemble model was trained with cases from the largest cluster of the training cohort (n359) and validated with an independent cohort (n127). Cluster A, the largest group, was mostly immune or inherited aplastic anemia, whereas Cluster B was composed of underrepresented BMF phenotypes, and not included in the next step of data modeling due to small sample size. The ensemble model Cluster A-specific was accurate (89%) to predict BMF etiology, correctly predicting inherited and likely immune BMF in 79% and 92% of cases, respectively. Our model represents a practical guide for BMF diagnosis and highlights the importance of clinical and laboratory variables in the initial evaluation, particularly telomere length. Our tool can be potentially used by general hematologists and health care providers not specialized in BMF, and in under-resourced centers, to prioritize patients for genetic testing or for expeditious treatment.

A monoclonal antibody targeting nonjunctional claudin-1 inhibits fibrosis in patient-derived models by modulating cell plasticity.

Tissue fibrosis is a key driver of end-stage organ failure and cancer, overall accounting for up to 45% of deaths in developed countries. There is a large unmet medical need for antifibrotic therapies. Claudin-1 (CLDN1) is a member of the tight junction protein family. Although the role of CLDN1 incorporated in tight junctions is well established, the function of nonjunctional CLDN1 (njCLDN1) is largely unknown. Using highly specific monoclonal antibodies targeting a conformation-dependent epitope of exposed njCLDN1, we show in patient-derived liver three-dimensional fibrosis and human liver chimeric mouse models that CLDN1 is a mediator and target for liver fibrosis. Targeting CLDN1 reverted inflammation-induced hepatocyte profibrogenic signaling and cell fate and suppressed the myofibroblast differentiation of hepatic stellate cells. Safety studies of a fully humanized antibody in nonhuman primates did not reveal any serious adverse events even at high steady-state concentrations. Our results provide preclinical proof of concept for CLDN1-specific monoclonal antibodies for the treatment of advanced liver fibrosis and cancer prevention. Antifibrotic effects in lung and kidney fibrosis models further indicate a role of CLDN1 as a therapeutic target for tissue fibrosis across organs. In conclusion, our data pave the way for further therapeutic exploration of CLDN1-targeting therapies for fibrotic diseases in patients.

Impact of early detection on cancer curability A modified Delphi panel study.

Expert consensus on the potential benefits of early cancer detection does not exist for most cancer types. We convened 10 practicing oncologists using a RANDUCLA modified Delphi panel to evaluate which of 20 solid tumors, representing >40 American Joint Committee on Cancer (AJCC)-identified cancer types and 80% of total cancer incidence, would receive potential clinical benefits from early detection. Pre-meeting, experts estimated how long cancers take to progress and rated the current curability and benefit (improvement in curability) of an annual hypothetical multi-cancer screening blood test. Post-meeting, experts rerated all questions. Cancers had varying estimates of the potential benefit of early cancer detection depending on estimates of their curability and progression by stage. Cancers rated as progressing quickly and being curable in earlier stages (stomach, esophagus, lung, urothelial tract, melanoma, ovary, sarcoma, bladder, cervix, breast, colonrectum, kidney, uterus, anus, head and neck) were estimated to be most likely to benefit from a hypothetical screening blood test. Cancer types rated as progressing quickly but having comparatively lower cure rates in earlier stages (liverintrahepatic bile duct, gallbladder, pancreas) were estimated to have medium likelihood of benefit from a hypothetical screening blood test. Cancer types rated as progressing more slowly and having higher curability regardless of stage (prostate, thyroid) were estimated to have limited likelihood of benefit from a hypothetical screening blood test. The panel concluded most solid tumors have a likelihood of benefit from early detection. Even among difficult-to-treat cancers (e.g., pancreas, liverintrahepatic bile duct, gallbladder), early-stage detection was believed to be beneficial. Based on the panel consensus, broad coverage of cancers by screening blood tests would deliver the greatest potential benefits to patients.

Robot-assisted segmentectomy for small lung cancer using a radiofrequency identification marker.

Owing to the prevalence of robot-assisted thoracoscopic surgery and the increase in the number of small lung cancer cases, robot-assisted thoracoscopic segmentectomy cases have also been increasing. For small lung cancers, such as ground-glass opacity lesions, identifying the location and securing a sufficient free margin from the main tumor can be difficult. We have already developed and reported the clinical application of a new marking system, a radiofrequency identification marker. In the current study, we applied this technique to robot-assisted thoracoscopic segmentectomies. Concomitant with other devices, we believe that robot-assisted thoracoscopic surgery has a great advantage in segmentectomy.

Early Prediction of Radiation-Induced Pulmonary Fibrosis Using Gastrin-Releasing Peptide Receptor-Targeted PET Imaging.

Early diagnosis of radiation-induced pulmonary fibrosis (RIPF) in lung cancer patients after radiation therapy is important. A gastrin-releasing peptide receptor (GRPR) mediates the inflammation and fibrosis after irradiation in mice lungs. Previously, our group synthesized a GRPR-targeted positron emission tomography (PET) imaging probe,

Development and Validation of a Nomogram for Predicting the 1-, 3-, and 5-year Survival in Patients with Acinar-predominant Lung Adenocarcinoma.

This study aimed to develop a nomogram to predict the overall survival (OS) of patients with acinar-predominant adenocarcinoma (APA). Data from patients with APA obtained from the Surveillance, Epidemiology, and End Results (SEER) database between 2008 and 2016 were used. Significant prognostic factors were incorporated to construct a nomogram for predicting the 1-, 3-, and 5-year OS in these patients. The discrimination and calibration abilities of the nomogram were assessed using a C-index and calibration curves, respectively. A total of 2242 patients with APA were randomly divided into a training cohort (n1576) and validation cohort (n666). The independent prognostic factors for OS incorporated into the nomogram included marital status, age, gender, differentiation grade, T stage, N stage, and M stage. The nomogram showed good prediction capability, as indicated by the C-index 0.713, 95% confidence interval (CI) 0.705-0.721 in the training cohort, and 0.662, 95% CI 0.649-0.775 in the validation cohort. The calibration curves demonstrated that the 1-, 3-, and 5-year OS probabilities were consistent between the observed and predicted outcome frequencies. Patients were divided into the high-risk and low-risk groups with the former showing significantly worse survival than the latter (P<0.001). Using the SEER database, a nomogram was established to predict the 1-, 3-, and 5-year OS of patients with APA and was superior to the tumor size, lymph node, and metastasis staging system in terms of evaluating long-term prognosis.

Approaches and outcomes of Robotic-Assisted Thoracic Surgery (RATS) for lung cancer a narrative review.

Robotic-Assisted Thoracic Surgery (RATS) is considered one of the main issues of present thoracic surgery. RATS is a minimally invasive surgical technique allowing enhanced view, accurate and complex movements, and high ergonomics for the surgeon. Despite these advantages, its application in lung procedures has been limited, mainly by its costs. Since now many different approaches have been proposed and the experience in RATS for lungs ranges from wedge resection to pneumonectomy and is mainly related to lung cancer. The present narrative review explores main approaches and outcomes of RATS lobectomy for lung cancer. A non-systematic review of literature was conducted using the PubMed search engine. An overview of lung robotic surgery is given, and main approaches of robotic lobectomy for lung cancer are exposed. Initial experiences of biportal and uniportal RATS are also described. So far, retrospective analysis reported satisfactory robotic operative outcomes, and comparison with VATS might suggest a more accurate lymphadenectomy. Some Authors might even suggest better perioperative outcomes too. From an oncological standpoint, no definitive prospective study has yet been published but several retrospective analyses report oncological outcomes comparable to those of VATS and open surgery. Literature suggests that RATS for lung procedures is safe and effective and should be considered as a valid additional surgical option.

Effectiveness of healthy lifestyle-based interventions in lung cancer survivors a systematic review and meta-analysis.

To assess the effectiveness of healthy lifestyle-based interventions in lung cancer survivors. We performed a literature search using PubMed, Web of Science, and Science Direct (last search March 2022). Quality assessment and risk of bias were assessed using the Downs and Black scale and the Cochrane tool. A systematic review and meta-analysis of randomized controlled trials were performed. We included controlled trials testing the effect of healthy lifestyle-based interventions in lung cancer survivors versus a control intervention where lung cancer patients had no treatment, were receiving the usual care, or had not an active role in the intervention. The data were pooled and a meta-analysis was completed for quality of life, psychological distress, and cancer-related symptoms. We selected 14 studies, which included 1519 patients with lung cancer. The treatment status of these patients was heterogeneous. Healthy lifestyle programs were applied isolated or in combination with usual care in most of the studies. The components of the healthy lifestyle programs were also heterogeneous. Results showed significant differences in favor of healthy lifestyle-based interventions in comparison to the control group for quality of life (p 0.01), psychological distress (p 0.05), and cancer-related symptoms (p 0.03). The findings indicated a beneficial effect of healthy lifestyle-based interventions for improving quality of life, psychological distress, and cancer-related symptoms in lung cancer patients. However, this review could not show any conclusion about the better treatment moment to apply healthy lifestyle-based interventions. PROSPERO Identifier CRD42021292152. 19122021.

Comprehensive analysis of roles of atrial-fibrillation-related genes in lung adenocarcinoma using bioinformatic methods.

Atrial fibrillation (AF) is the most common tachyarrhythmia in the world. Lung cancer is the leading cause of cancer deaths in 93 countries. Previous studies demonstrated that the prevalence of AF was higher in patients with lung cancer. However, research on the associations between AF and lung cancer is still rare. In the present study, we first identified AF-related genes using weighted gene correlation network analysis. We then analyzed the expression profiles, prognosis, immune infiltration, and methylation characteristics of these genes in LUAD patients using bioinformatics analysis. We found several AF-related genes, including CBX3, BUB1, DSC2, P4HA1, and CYP4Z1, which differently expressed between tumor and normal tissues. Survival analysis demonstrated that CYP4Z1 was positively correlated with overall survival in LUAD patients, while CBX3, BUB1, DSC2, and P4HA1 were negatively correlated. Moreover, we found that the methylation level of DSC2 in normal lung tissues was significantly higher than that in tumor tissues, and six methylation sites in the DNA sequences of DSC2 were identified negatively correlated with its expression levels. Immune infiltration analysis suggested that levels of immune cell infiltration were related to gene expression levels in varying degrees. We identified AF-related genes and found these genes were correlated with prognosis, immune infiltration, and methylation levels in lung cancer patients. We also constructed a risk signature based on these genes in LUAD patients. We hoped that the current study could provide a novel insight into roles of AF-related genes in lung cancer patients.

Machine learning driven drug repurposing strategy for identification of potential RET inhibitors against non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) remains the leading cause of mortality and morbidity worldwide accounting about 85% of total lung cancer cases. The receptor REarranged during Transfection (RET) plays an important role by ligand independent activation of kinase domain resulting in carcinogenesis. Presently, the treatment for RET driven NSCLC is limited to multiple kinase inhibitors. This situation necessitates the discovery of novel and potent RET specific inhibitors. Thus, we employed high throughput screening strategy to repurpose FDA approved compounds from DrugBank comprising of 2509 molecules. It is worth noting that the initial screening is accomplished with the aid of in-house machine learning model built using IC

Encapsulation of Gold-Based Anticancer Agents in Protease-Degradable Peptide Nanofilaments Enhances Their Potency.

We investigated the use of amphiphilic, protease-cleavable peptides as encapsulation moieties for hydrophobic metallodrugs, in order to enhance their bioavailability and consequent activity. Two hydrophobic, gold-containing anticancer agents varying in aromatic ligand distribution (Au(I)-N-heterocyclic carbene compounds

Increased levels of N6-methyladenosine in peripheral blood RNA a perspective diagnostic biomarker and therapeutic target for non-small cell lung cancer.

Due to lack of effective biomarkers for non-small cell lung cancer (NSCLC), many patients are diagnosed at an advanced stage, which leads to poor prognosis. Dysregulation of N6-methyladenosine (m Peripheral blood samples from 152 NSCLC patients and 64 normal controls (NCs) were applied to assess the m Robust elevation of m These findings unraveled that m

Sphingosine Kinase 2 in Stromal Fibroblasts Creates a Hospitable Tumor Microenvironment in Breast Cancer.

Reciprocal interactions between breast cancer cells and the tumor microenvironment (TME) are important for cancer progression and metastasis. We report here that the deletion or inhibition of sphingosine kinase 2 (SphK2), which produces sphingosine-1-phosphate (S1P), markedly suppresses syngeneic breast tumor growth and lung metastasis in mice by creating a hostile microenvironment for tumor growth and invasion. SphK2 deficiency decreased S1P and concomitantly increased ceramides, including C16-ceramide, in stromal fibroblasts. Ceramide accumulation suppressed activation of cancer-associated fibroblasts (CAF) by upregulating stromal p53, which restrained production of tumor-promoting factors to reprogram the TME and to restrict breast cancer establishment. Ablation of p53 in SphK2-deficient fibroblasts reversed these effects, enabled CAF activation and promoted tumor growth and invasion. These data uncovered a novel role of SphK2 in regulating non-cell-autonomous functions of p53 in stromal fibroblasts and their transition to tumor-promoting CAFs, paving the way for the development of a strategy to target the TME and to enhance therapeutic efficacy. Sphingosine kinase 2 (SphK2) facilitates the activation of stromal fibroblasts to tumor-promoting cancer-associated fibroblasts by suppressing host p53 activity, revealing SphK2 as a potential target to reprogram the TME.

Frontline Promise for Adagrasib-Pembrolizumab Combination.

Two trials offer early evidence that adagrasib plus pembrolizumab is a safe and effective regimen for patients with newly diagnosed non-small cell lung cancer harboring a KRASG12C mutation. The overall response rate in one trial was 49%, and in the other it was 57%. The drug combination showed lower levels of liver toxicity than other combinations of checkpoint inhibitors and targeted therapies.

Towards the characterization of the tumor microenvironment through dictionary learning-based interpretable classification of multiplexed immunofluorescence images.

Persisting Gaps in Optimal Care of Stage III Non-small Cell Lung Cancer An Australian Patterns of Care Analysis.

Wide variation exists globally in the treatment and outcomes of stage III patients with non-small cell lung cancer (NSCLC). We conducted an up-to-date patterns of care analysis in the state of Victoria, Australia, with a particular focus on the proportion of patients receiving treatment with radical intent, treatment trends over time, and survival. Stage III patients with NSCLC were identified in the Victorian Lung Cancer Registry and categorized by treatment received and treatment intent. Logistic regression was used to explore factors predictive of receipt of radical treatment and the treatment trends over time. Cox regression was used to explore variables associated with overall survival (OS). Covariates evaluated included age, sex, ECOG performance status, smoking status, year of diagnosis, Australian born, Aboriginal or Torres Strait Islander status, socioeconomic status, rurality, publicprivate status of notifying institution, and multidisciplinary meeting discussion. A total of 1396 patients were diagnosed between 2012 and 2019 and received treatment with radical intent 67%, palliative intent 23%, unknown intent 5% and no treatment 5%. Radical intent treatment was less likely if patients were >75 years, ECOG ≥1, had T3-4 or N3 disease or resided rurally. Surgery use decreased over time, while concurrent chemoradiotherapy and immunotherapy use increased. Median OS was 38.0, 11.1, and 4.4 months following radical treatment, palliative treatment or no treatment, respectively. Almost a third of stage III patients with NSCLC still do not receive radical treatment. Strategies to facilitate radical treatment and better support decision making between increasing multimodality options are required.

Uncertainty-driven determination of target measurement times for indirect tracking validation in adaptive radiotherapy.

The miRNA-24, miRNA-21 expressions and matrix metalloproteinase-7 level in exhaled breath condensate of children with primary spontaneous pneumothorax.

Bullous lung diseases may cause primary spontaneous pneumothorax (PSP) in children. The microRNAs (miRNAs) are non-coding RNAs that participate in regulation of inflammation and cancer. We hypothesized that children with bullous lung disease and PSP may have altered miRNA expressions in their exhaled breath condensates (EBCs). Therefore, a prospective study was performed to evaluate the miRNA-24 and 21 expression, and the matrix metalloproteinase-7 (MMP-7) levels in EBC of children with PSP. Children with PSP were evaluated for age, gender, clinical features and results of surgical treatment. EBC samples (500-1000 ml) were collected to evaluate the miRNA-21, 24 expressions, and MMP-7, and tissue-inhibitor-MMP-1 (TIMP-1) levels. miRNA expressions and MMP levels of patients were compared with healthy controls (control group (CG),

A novel manganese dioxide-based drug delivery strategy

Cisplatin (CDDP) is one of the most frequently used chemotherapeutic drugs due to its broad-spectrum and potent antitumor activity. Unfortunately, inactivation due to glutathione (GSH) substances and insufficient cellular uptake of CDDP greatly hinder its clinical applications. Herein, manganese dioxide (MnO

EIF4A3 stabilizes the expression of lncRNA AGAP2-AS1 to activate cancer-associated fibroblasts via MyD88NF-κb signaling.

Lung cancer (LC) is a fatal malignancy and often accompanied with converting normal fibroblasts to cancer-associated fibroblasts (CAFs). Exosomal lncRNA AGAP2-AS1 has been elucidated to be a potent prognostic factor for LC, while its role in activating CAFs is largely unknown. We first extracted exosomes from LC patients and co-cultured them with MRC5 cells to observe the state of MRC5 cells, detect AGAP2-AS1 using real-time quantitative polymerase chain reaction, and then analyze the interaction between EIF4A3 and AGAP2-AS1 using RNA pull down experiments. CCK-8 assay was used to detect cell proliferation. Transwell experiments demonstrated the regulation of MRC5 cells and, finally, the role of MyD88NF-κB in the downstream mechanism of EIF4A3AGAP2-AS1 was explored by RNA interference technology and pyrrolidinedithiocarbamic acid inhibition. We demonstrated that exosomes from the LC patients (cancer-exo) notably increased the metastatic ability of MRC-5 cells, promoting the expressions of the CAF biomarkers and lncRNA AGAP2-AS1. Overexpression of lncRNA AGAP2-AS1 prominently activated MRC-5 cells. Moreover, EIF4A3 was upregulated in the cancer-exo-treated MRC-5 cells, and EIF4A3 was verified to bind with lncRNA AGAP2-AS1 to improve its stability. The MyD88NF-κB signaling pathway was subsequently proved to be positively regulated by lncRNA AGAP2-AS1, and the promotive role of lncRNA AGAP2-AS1 in LC and activating CAFs was confirmed in vivo. The positive feedback of EIF4A3AGAP2-AS1MyD88NF-κB signaling pathway contributed to the activation of CAFs and exacerbated LC in turn, revealing a novel regulatory axis underlying LC.

Type I and Ir pleuropulmonary blastoma (PPB) A report from the International PPBDICER1 Registry.

Pleuropulmonary blastoma (PPB) is the most common lung cancer of infancy and early childhood. Type I PPB is a purely cystic lesion that has a microscopic population of primitive small cells with or without rhabdomyoblastic features and may progress to type II or III PPB, whereas type Ir lacks primitive small cells. Children with suspected PPB were enrolled in the International PPBDICER1 Registry. Pathology was centrally reviewed, and follow-up was ascertained annually. Between 2006 and 2022, 205 children had centrally reviewed type I or Ir PPB 39% of children with type I and 5% of children with type Ir PPB received chemotherapy. Outcomes were favorable, although 11 children (nine with type I and two with type Ir PPB) experienced progression to type IIIII (n 8) or regrowth of type I PPB at the surgical site (n 3), none of whom received chemotherapy before progression. Age and cyst size in combination were more suitable than either factor alone in predicting whether a particular lesion was type I or Ir PPB. For young children with type I PPB, outcomes are favorable, but complete resection is indicated because of the risk for progression. Chemotherapy may be useful in a subset of children at increased risk for recurrenceprogression. Efforts to risk stratify children with type I PPB to optimize outcomes while reducing treatment-related side effects are underway.

Developing a comorbidity score in cancer patients using healthcare utilization databases during the COVID-19 pandemic An experience from Italy.

A strong relationship has been observed between comorbidities and the risk of severefatal COVID-19 manifestations, but no score is available to evaluate their association in cancer patients. To make up for this lacuna, we aimed to develop a comorbidity score for cancer patients, based on the Lombardy Region healthcare databases. We used hospital discharge records to identify patients with a new diagnosis of solid cancer between February and December 2019 61 comorbidities were retrieved within 2 years before cancer diagnosis. This cohort was split into training and validation sets. In the training set, we used a LASSO-logistic model to identify comorbidities associated with the risk of developing a severefatal form of COVID-19 during the first pandemic wave (March-May 2020). We used a logistic model to estimate comorbidity score weights and then we divided the score into five classes (<-1, 0, 1, 2-4, >5). In the validation set, we assessed score performance by areas under the receiver operating characteristic curve (AUC) and calibration plots. We repeated the process on second pandemic wave (October-December 2020) data. We identified 55,425 patients with an incident solid cancer. We selected 21 comorbidities as independent predictors. The first four score classes showed similar probability of experiencing the outcome (0.2% to 0.5%), while the last showed a probability equal to 5.8%. The score performed well in both the first and second pandemic waves AUC 0.85 and 0.82, respectively. Our results were robust for major cancer sites too (i.e., colorectal, lung, female breast, and prostate). We developed a high performance comorbidity score for cancer patients and COVID-19. Being based on administrative databases, this score will be useful for adjusting for comorbidity confounding in epidemiological studies on COVID-19 and cancer impact.

Identification of prognostic factors and nomogram model for patients with advanced lung cancer receiving immune checkpoint inhibitors.

Some patients with lung cancer can benefit from immunotherapy, but the biomarkers that predict immunotherapy response were not well defined. Baseline characteristic of patients may be the most convenient and effective markers. Therefore, our study was designed to explore the association between baseline characteristics of patients with lung cancer and the efficacy of immunotherapy. A total of 216 lung cancer patients from Tianjin Medical University Cancer Institute Hospital who received immunotherapy between 2017 and 2021 were included in the retrospective analysis. All baseline characteristic data were collected and then univariate log-rank analysis and multivariate COX regression analysis were performed. Kaplan-Meier analysis was used to evaluate patients progression-free survival (PFS). A nomogram based on significant biomarkers was constructed to predict PFS rate of patients receiving immunotherapy. We evaluated the prediction accuracy of nomogram using C-indices and calibration curves. Univariate analysis of all collected baseline factors showed that age, clinical stage, white blood cell (WBC), lymphocyte (LYM), monocyte (MON), eosinophils (AEC), hemoglobin (HB), lactate dehydrogenase (LDH), albumin (ALB) and treatment line were significantly associated with PFS after immunotherapy. Then these 10 risk factors were included in a multivariate regression analysis, which indicated that age (HR 1.95, 95% CI 1.01-3.78, Age, ALB, MON, LDH, line can be used as reliable predictive biomarkers for PFS, response rate and cancer control in patients with lung cancer receiving immunotherapy. The nomogram based on age, ALB, MON, LDH, line was of great significance for predicting 1-year-PFS, 2-year-PFS and 3-year-PFS in patients with advanced lung cancer treated with immunotherapy.

Growth Hormone-Releasing Hormone Antagonist JV-1-36 Suppresses Reactive Oxygen Species Generation in A549 Lung Cancer Cells.

Growth hormone-releasing hormone (GHRH) and its receptors are expressed in a variety of human cancers, and have been involved in malignancies. GHRH antagonists (GHRHAnt) were developed to suppress tumor progression and metastasis. Previous studies demonstrate the involvement of reactive oxygen species (ROS) in cancer progression. Herein, we investigate the effect of a commercially available GHRH antagonist, namely JV-1-36, in the redox status of the A549 human cancer cell line. Our results suggest that this peptide significantly reduces ROS production in those cells in a time-dependent manner and counteracts H

Efficacy and Safety of the PD-1 Inhibitor Combined with Albumin-Bound Paclitaxel and Nedaplatin in Preoperative Neoadjuvant Therapy of Unresectable Stage III Lung Squamous Cell Carcinoma.

To investigate the efficacy and safety of preoperative neoadjuvant therapy (PD-1 inhibitor plus nab-PTX and nedaplatin) for resectable stage III lung squamous cell carcinoma (SCC) patients. Patients with locally advanced lung SCC (stage IIIA, IIIB) who received PD-1 inhibitor combined with nab-PTX and NED between February 2019 and June 2021 in Weihai Municipal Hospital were included and underwent surgical treatment 4 weeks after 2-4 cycles neoadjuvant therapy. The rate of resection R0, the effective rate, the complete pathological remission rate (pCR) and the rate of major pathological remission (MPR) were observed. A total of 14 initially unresectable male patients with lung SCC were included and received neoadjuvant treatment after evaluation. Nine out of 14 patients (64.3%) experienced treatment-related adverse events (TRAE), among which 8 (57.1%) experienced grade (G) I-II TRAEs including nausea, vomiting, fatigue, constipation, elevated ALT and AST, hyperthyroidism, hypothyroidism, rash, granulocytopenia, and thrombocytopenia, and 1 (7.1%) experienced grade III-V TRAEs (G), including granulocytopenia and atelectasis. Thirteen patients (92.86%) achieved RECIST-assessed partial remission (PR), while 1 patient (7.14%) achieved stable disease (SD) on imaging assessment after neoadjuvant treatment and continued to be progression-free for 26 months. Of the 11 patients who underwent resection, all were alive and recurrenceprogression-free. MPR and pCR were observed in 2 (18.18%) and 9 (81.82%), respectively. IHC results exhibited that all NSCLC patients exhibited positive PD-L1 expression (914, TPS ≥50% or greater 514, 1% < TPS < 50%). Two were negative for ALK, EGFR, and ros-1, and the rest were not examined for driver oncogene mutation. The neoadjuvant therapy of the PD-1 inhibitor combined with nab-PTX and NED demonstrated remarkable therapeutic efficacy and good safety on stage III lung SCC without increasing the risk of TRAE, mortality and surgery-related complications, or impede surgery feasibility.

Impact of the COVID-19 Pandemic on Diagnosis of Lung Cancer.

Non-COVID hospital admissions decreased during the COVID-19 pandemic and follow-up of people in the lung cancer risk group was delayed. There are not enough studies on the effects of the pandemic period on the diagnosis of lung cancer. In this study, it was aimed to determine the characteristics of patients diagnosed with lung cancer in the pre-pandemic and pandemic period and to investigate the effects of the pandemic on the diagnosis of lung cancer. Patients with newly diagnosed lung cancer 16 months before and after the detection of the first COVID-19 case were retrospectively analyzed for their characteristics at the time of diagnosis. Age, gender, pathological diagnosis, distant organ metastasis status, and also pathological stages at the time of diagnosis of the patients were analyzed. Two hundred forty-six patients were included in the study. One hundred forty-five of the patients were diagnosed in the pre-pandemic period and 101 during the pandemic period. Mean age of patients was 64.24 years and 91.87% were male. Pathological diagnosis distributions were similar in the pre-pandemic group and the pandemic period group. Distant organ metastases were present in 59.31% of the pre-pandemic group and 65.35% of the pandemic group. There was no significant difference in terms of the stages of the patients at the time of diagnosis. Number of patients diagnosed with lung cancer during the pandemic period was lower. The characteristics of the patients were similar. These results may have resulted from the decrease in applications to health institutions due to social isolation and fear of COVID-19 infection, and limitations in accessing health services.

Forthcoming Phase II Study of Durvalumab (MEDI4736) Plus Chemotherapy for Small Cell Lung Cancer with Brain Metastases.

The standard of care for extensive-stage small cell lung cancer (ES-SCLC) is an immune checkpoint inhibitor (ICI) combined with platinum-etoposide (PE) chemotherapy. At initial diagnosis, about 25% of ES-SCLC patients have brain metastases, which are associated with a poor prognosis. The decision as to whether to treat brain metastases with local therapies such as surgery or radiotherapy before initiation of systemic chemoimmunotherapy is based on symptoms due to the brain lesions and the general condition of the patient. Subset analysis of the CASPIAN study showed that combination therapy with PE plus durvalumab (MEDI4736) is promising for ES-SCLC with brain metastases. However, data required in daily clinical practice, such as intracranial response rate and duration of intracranial response, are insufficient for such patients. We have designed a single-arm phase II trial of durvalumab plus PE for patients aged ≥20 years with chemotherapy-naïve ES-SCLC and at least one brain metastasis ≥5 mm in size that has not been previously treated. Patients receive durvalumab intravenously combined with four cycles of PE. Enrollment of 50 patients over 2 years at 25 oncology facilities in Japan is planned. The primary endpoint is intracranial response rate. This is the first prospective study to evaluate the effects of an ICI with PE specifically in ES-SCLC patients with brain metastases. If it demonstrates intracranial efficacy, this regimen will be a potential treatment option for such individuals, and radiation therapy or surgery for brain metastases can be avoided or postponed.

Relationship Between

Ferritin-Enhanced Direct MicroRNA Detection via Controlled Radical Polymerization.

Accurate quantitative detection of tracing nucleic acids remains a great challenge in cancer genetic testing. It is crucial to propose a low-cost and highly sensitive direct gene detection method for cancer prevention and treatment. Herein, this work reports an ultrasensitive biosensor via a ferritin-enhanced atom-transfer radical polymerization (Ft-ATRP) process. Intriguingly, microRNA-21, an early marker of lung cancer, can be detected without being transcribed in advance by an innovative signal amplification strategy using ferritin-mediated aggregation of hydrophilic nitroxide radical monomers as an electrochemical biosensor. The sensor uses peptide nucleic acid probes modified on a gold electrode to accurately bind the target lung cancer marker in the sample, and then ferritin, which is naturally present in human blood, induces Ft-ATRP on the electrode surface under mild conditions. Many of 4-methacryloyloxy-2,2,6,6-tetramethylpiperidine 1-oxyl free radical (MATMP) monomers with electrochemical signals are combined into polymeric chains to be modified on target assays. The limit of detection (LOD) of microRNA-21 is as low as 6.03 fM, and the detection concentration ranges from 0.01 to 100 pM (

The Scan, the Needle, or the Knife National Trends in Diagnosing Stage I Lung Cancer.

Indeterminate lung nodules have been increasingly discovered since the expansion of lung cancer screening programs. The diagnostic approach for suspicious nodules varies based on institutional resources and preferences. The aim of this study is to analyze factors associated with diagnostic modalities used for early-stage non-small cell lung cancer (NSCLC). The National Cancer Database was queried for all patients with stage I NSCLC from 2004 to 2015. Four diagnostic modalities were identified, including clinical radiography alone (CRA), bronchial cytology (BC), procedural biopsy (PB), and surgical biopsy (SB). A multivariable multinomial logistic regression was used to assess associations of patient demographics, cancer characteristics, and facility characteristics with these modalities. Of 250,614 patients, 4,233 (1.7%) had CRA, 5,226 (2.1%) had BC, 147,621 (59.9%) had PB, and 93,534 (37.3%) had SB. Older patients were more likely to receive CRA (adjusted odds ratio ORadj 5.3) and less likely to receive SB (ORadj 0.73). Black patients were less likely to receive SB (ORadj 0.83) and more likely to receive BC (ORadj 1.31). Private insurance was associated with SB (ORadj 1.11), whereas Medicaid was associated with BC (ORadj 1.21). Patients more than 50 miles from the facility were more likely to undergo SB (ORadj 1.25 vs PB ORadj 1.30 vs CRA ORadj 1.38 vs BC). Patients receiving SB had shorter days from diagnosis to treatment (23.0 vs 53.5 to 64.7 for other modalities, Diagnostic SB to confirm early-stage NSCLC was associated with younger age, greater travel distance, and shorter time to treatment in comparison with other modalities. Black race and non-private insurance were less likely to be associated with SB.

Anatomical type analysis of right interlobar artery based on chest thin-slice CT scan and three-dimensional reconstruction.

To analyse and summarize branching pattern types of the interlobar portion of right pulmonary arteries (RPA) through chest thin-slice CT scans and three-dimensional reconstruction. A total of 179 patients (58 males and 121 females, with an average age of 53.9 years) at the Thoracic Surgery Department of Ningbo First Hospital were retrospectively included from December 2020 to December 2021. All patients completed preoperative thin-slice CT scans and three-dimensional reconstructions of the chest. The clinical data and branching patterns were collected. Data were analysed using SPSS 21.0. The branching pattern types of the interlobar portion of RPA were divided into 4 types according to the order and number of branches Type I (145179, 81.0%), Asc. A2, MA, A6 Type II (28179, 15.6%), Asc. A2 deletion, MA, A6 Type III (5179, 2.8%), Asc. A2, A6, MA and Type IV (1179, 0.6%), MA, Asc. A2, A6. Type I was the most common pattern. Furthermore, according to the number of branches of MA and A6, this pattern can be subdivided into 15 subcategories. Chest thin-slice CT scans and 3D reconstructions can provide surgeons with accurate lung anatomy, which helps surgeons perform preoperative planning and complete surgery successfully.

Pulmonary effects of exposure to indium and its compounds cross-sectional survey of exposed workers and experimental findings in rodents.

Many studies have shown that occupational exposure to indium and its compounds could induce lung disease. Although animal toxicological studies and human epidemiological studies suggest indium exposure may cause lung injury, inflammation, pulmonary fibrosis, emphysema, pulmonary alveolar proteinosis, and even lung cancer, related data collected from humans is currently limited and confined to single workplaces, and the early effects of exposure on the lungs are not well understood. This study combined population studies and animal experiments to examine the links of indium with pulmonary injury, as well as its mechanism of action. A cross-sectional epidemiological study of indium-exposed workers from China was conducted to evaluate associations between occupational indium exposure and serum biomarkers of early effect. This study also compares and analyzes the causal perspectives of changes in human serum biomarkers induced by indium compound exposure and indium exposure-related rat lung pathobiology, and discusses possible avenues for their recognition and prevention. This is a study of 57 exposed (at least 6 h per day for one year) workers from an indium ingot production plant, and 63 controls. Indium concentration in serum, urine, and airborne as exposure indices were measured by inductively coupled plasma-mass spectrometry. Sixteen serum biomarkers of pulmonary injury, inflammation, and oxidative stress were measured using ELISA. The associations between serum indium and 16 serum biomarkers were analyzed to explore the mechanism of action of indium on pulmonary injury in indium-exposed workers. Animal experiments were conducted to measure inflammatory factors levels in bronchoalveolar lavage fluid (BALF) and lung tissue protein expressions in rats. Four different forms of indium compound-exposed rat models were established (intratracheal instillation twice per week, 8 week exposure, 8 week recovery). Model I 0, 1.2, 3, and 6 mgkg bw indium tin oxide group Model II 0, 1.2, 3, and 6 mgkg bw indium oxide (In In the production workshop, the airborne indium concentration was 78.4 μgm In indium-exposed workers, biomarker findings indicated lung damage, oxidative stress and an inflammatory response. In rat models of the four forms of indium encountered in a workplace, the biomarkers response to all compounds overall corresponded to that in humans. In addition, pulmonary alveolar proteinosis was found following exposure to indium tin oxide and indium oxide in the rat models, and interstitial fibrosis was found following exposure to indium tin oxide and indium trichloride, supporting previous report of human disease. Serum SP-A levels were positively associated with indium exposure and may be considered a potential biomarker of exposure and effect in exposed workers.

ANK2 as a novel predictive biomarker for immune checkpoint inhibitors and its correlation with antitumor immunity in lung adenocarcinoma.

Immune checkpoint inhibitors (ICIs) have been shown to significantly improve the survival of patients with advanced lung adenocarcinoma (LUAD). However, only limited proportion of patients could benefit from ICIs. Novel biomarkers with strong predictability are needed for clinicians to maximize the efficacy of ICIs. Our study aimed to identify potential biomarkers predicting ICIs efficacy in LUAD. The Cancer Genome Atlas (TCGA) PanCancer Atlas studies in cBioportal were used to evaluate the mutation frequency of ANK2 across multiple cancers. Clinical and mutational data for LUAD from ICIs-treated cohorts (Hellmann et al. and Rizvi et al.) were collected to explore the correlation between ANK2 mutation and clinical outcomes. In addition, the relationship between ANK2 expression and clinical outcomes was analyzed using LUAD data from TCGA and Gene Expression Omnibus. Furthermore, the impact of ANK2 mutation and expression on the tumor immune microenvironment of LUAD was analyzed using TCGA and TISIDB databases. Patients with ANK2 mutation benefited more from ICIs. In ICIs-treated cohort, prolonged progression-free survival (PFS) (median PFS NR (not reached) vs. 5.42 months, HR (hazard ratio) 0.31, 95% CI 0.18-0.54 P 0.0037), improved complete response rate (17.65% vs. 1.85%, P 0.0402), and improved objective response rate (64.71% vs. 24.07%, P 0.0033) were observed in LUAD patients with ANK2 mutation compared to their wild-type counterparts. Regarding ANK2 expression, it was observed that ANK2 expression was decreased in LUAD (P < 0.05) and a higher level of ANK2 expression was associated with longer overall survival (HR 0.69, 95% CI 0.52-0.92 P 0.012) in TCGA LUAD cohort. Moreover, ANK2 mutation or higher ANK2 expression correlated with enhanced antitumor immunity and hot tumor microenvironment in LUAD, which could be potential mechanisms that ANK2 mutation facilitated ICIs therapy and patients with higher ANK2 expression survived longer. Our findings suggest that ANK2 mutation or increased ANK2 expression may serve as a favorable biomarker for the efficacy of ICIs in patients with LUAD.

The predictive association between radiological findings and lung cancer development in patients exposed to sulfur mustard gas 4 decades follow up of 719 victims.

Respiratory diseases are the leading cause of morbidity and mortality in the survivors exposed to Sulfur Mustard (SM). The late abnormalities can be present as chronic bronchitis, tracheobronchial stenosis, asthma, bronchiectasis, airway narrowing, lung fibrosis, and lung cancers. This study aims to investigate the association between radiological findings and lung cancer development in patients exposed to sulfur mustard gas. We entered 719 victims exposed to SM during the Iran-Iraq war into our follow-up study in a consensus manner. They were periodically followed with Chest HRCT scans from 2001 to an interval of 2014-2019. The mean year interval between exposure and the last follow-up was 38 years. For confirming the lung cancer in those with evidence of malignancy in their imaging, fine needle aspirationbiopsy andor surgical intervention were done. Among 719 patients, 57% were free from any pathologic findings in their HRCT scan. Among the subjects who had the abnormal radiologic findings, Air Trapping (AT), Lung Fibrosis (LF), Bronchiectasis (B), and the evidence of lung cancer were found in 265 (36.9%), 207 (28.8%), 151 (21.0%), and 42 (5.8%), respectively. Adenocarcinoma (38.1%) was the most common type of cancer. The right lung was involved more than the left one regarding LF, B, and cancer (p value < 0.05). Considering the laterality, a significant correlation was found between the side of LF and B and the tumor side. Furthermore, it was shown that the lung lobes with LF were statistically correlated to tumor-involved lobes. The relative risk of AT and B existence for tumor development was 11.73 4.87-28.26 and 10.14 5.12-20.090, respectively. The most predictive finding was LF which caused the risk of developing tumor 17.75 7.35-42.86 times higher in the patient with this pathology. By each increment of the number of LF and B, the risk of developing tumors increased by 51% and 76%, respectively. In survivors exposed to Sulfur Mustard, those with bronchiectasis and lung fibrosis have a significantly higher risk of developing lung cancers, so a close follow-up of these victims is recommended. Trial registration This study was confirmed by the institutional review board and ethics committee at Shiraz University of Medical Sciences (SUMS) with the ethical code IR.SUMS.MED.REC.1399.637.

Effect of chlorhexidine Mouthrinse on prevention of microbial contamination during EBUS-TBNA a randomized controlled trial.

Although endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive procedure, fatal infectious complications have been reported. However, adequate preventive strategies have not been determined. We aimed to investigate the effect of chlorhexidine mouthrinse on the prevention of microbial contamination during EBUS-TBNA. In this single-center, assessor-blinded, parallel-group randomized controlled trial, we randomly assigned adult participants undergoing EBUS-TBNA using a convex probe to gargle for 1 minute with 100 mL of 0.12% chlorhexidine gluconate before EBUS-TBNA or to receive usual care (no chlorhexidine mouthrinse). Aspiration needle wash samples were collected immediately after completion of EBUS-TBNA by instilling sterile saline into the used needle. The primary outcome was colony forming unit (CFU) counts per mL of needle wash samples in aerobic cultures. Secondary outcomes were CFU counts per mL of needle wash samples in anaerobic cultures, fever within 24 hours after EBUS-TBNA, and infectious complications within 4 weeks after EBUS-TBNA. From January 2021 to June 2021, 106 patients received either chlorhexidine mouthrinse (n 51) or usual care (n 55). The median CFU counts of needle wash samples in aerobic cultures were not significantly different in the two groups (10 CFUmL vs 20 CFUmL P 0.70). There were no significant differences between the groups regarding secondary outcomes, including median CFU counts in anaerobic cultures (P 0.41) and fever within 24 hours after EBUS-TBNA (11.8% vs 5.6%, P 0.31). There were no infectious complications within 4 weeks in both groups. Chlorhexidine mouthrinse did not reduce CFU counts in needle wash samples of EBUS-TBNA. ClinicalTrials.gov, NCT04718922 . Registered on 22012021.

Provider and patient perspectives to improve lung cancer screening with low-dose computed tomography 5 years after Medicare coverage a qualitative study.

Lung cancer remains the leading cause of cancer-related deaths for both men and women in the U.S., yet uptake of preventive cancer screening for people with a heavy smoking history remains low. This qualitative interview study of patients and providers from a large ambulatory healthcare system in northern and central California reevaluated perceptions of lung cancer screening with low-dose computed tomography (LCS-LDCT) 5 years after Medicare coverage. We hypothesized that initial attitudes and barriers within the LCS-LDCT discussion and process have likely persisted with little change since Medicare coverage and we sought to understand how these attitudes continue to impact effective implementation and uptake of screening with the goal of identifying opportunities for improvement. Between 2019 and 2020, interviews were conducted with 10 primary care physicians and 30 patients using semi-structured interview guides. Providers and patients expressed that they were both aware and supportive of LCS-LDCT, a change from earlier studies, but continued to report little to no shared decision making nor use of a decision aid despite being Medicare requirements. Creation and incorporation of a single-page, graphic heavy decision aid may help address many of the persistent barriers around implementation for both providers and patients. Given recently expanded guidelines from the U.S. Preventive Services Task Force for LCS-LDCT screening and their coverage by Medicare, it is important for healthcare systems to understand provider and patient perceptions to further improve the implementation of LCS-LDCT to ultimately reduce lung cancer mortality.

Isolation and characterization of a SARS-CoV-2 variant with a Q677H mutation in the spike protein.

We isolated 20 SARS-CoV-2 strains from positive clinical samples collected in Columbus, Ohio, and investigated the replication of one pair of isolates a clade 20G strain and a variant of this strain carrying a Q677H mutation in the spike protein and six other amino acid mutations. The OSU.20G variant replicated to a higher peak infectious titer than the 20G base strain in Vero-E6 cells, but the titers were similar when both strains were grown in Calu-3 cells. These results suggest that the OSU.20G variant has increased replication fitness compared to the 20G base strain. This may have contributed to its emergence in December 2020-January 2021.

Comparative efficacy and tolerability of targeted and immunotherapy combined with chemotherapy as first-line treatment for advanced gastric cancer a Bayesian network meta-analysis.

The use of target agents and immune checkpoint inhibitors have changed the treatment landscape for AGC in the first-line setting. However, the crosswise comparison between each regimen is rare. Therefore, we estimated the efficacy and safety of targeted therapy or immunotherapy with chemotherapy in AGC patients as the first-line treatment. Included studies were divided into average or specific positivity group according to whether the patients were selected by a certain pathological expression. We conducted a Bayesian network meta-analysis for all regimens in both groups. In average group, no regimen showed significant improvements in overall survival (OS) and progression free survival (PFS), while pembrolizumab and nivolumab combined with chemotherapy were ranked first and second respectively without an obvious safety difference. In specific positivity group, zolbetuximab plus chemotherapy significantly prolonged OS (HR 0.53, 95% CI 0.36-0.79) and PFS (HR 0.45, 95% CI 0.25-0.81). The top three regimens were zolbetuximab-chemotherapy, trastuzumab plus pertuzuma-chemotherapy and nivolumab-chemotherapy respectively, with no significant safety risk. For average patients, immune checkpoint inhibitor PD-1 plus chemotherapy will be the promising regimen. For patients with overexpression of CLDN18.2, zolbetuximab combined with chemotherapy comes with greater survival benefits, while for patients who have PD-L1 expression with no HER-2 or CLDN18.2 positivity, additional immune checkpoint inhibitor of PD-1 will be a good considered option.

CircPIM3 regulates taxol resistance in non-small cell lung cancer via miR-338-3pTNFAIP8 axis.

Numerous work has revealed the involvement of circular RNA (circRNA) in regulating chemotherapy resistance. Here, we investigate circPIM3 role in taxol (Tax) resistance in non-small cell lung cancer (NSCLC). CircPIM3, microRNA (miR)-338-3p and tumor necrosis factor-alpha-induced protein-8 (TNFAIP8) expression were detected via quantitative real-time PCR, western blot or immunohistochemistry assay. Tax resistance was evaluated using cell counting kit-8, cell proliferation was measured by colony formation assay, cell cycle and apoptosis were examined via flow cytometry. The interplay between miR-338-3p and circPIM3 or TNFAIP8 was confirmed by dual-luciferase reporter assay. Finally, the effect of circPIM3 on Tax resistance in NSCLC in vivo was investigated by xenograft models. CircPIM3 and TNFAIP8 were upregulated in Tax-resistant NSCLC tissue and cell samples. Reducing circPIM3 expression inhibited Tax resistance, proliferation and induced cycle arrest and apoptosis in Tax-resistant NSCLC cells. Mechanically, circPIM3 absence led to downregulation of TNFAIP8 via absorbing miR-338-3p. Additionally, circPIM3 depletion increased Tax sensitivity of NSCLC in vivo. Silencing of circPIM3 suppressed Tax resistance in Tax-resistant NSCLC cells through regulation of the miR-338-3pTNFAIP8 axis.

Circ0058608 contributes to the progression and taxol resistance of non-small cell lung cancer by sponging miR-1299 to upregulate GBP1.

Circular RNAs (circRNAs) act as key regulators in human cancers and chemoresistance. Here, we aimed to explore the role and mechanism of circ0058608 in nonsmall cell lung cancer (NSCLC) and taxol resistance. The expression of circ0058608, microRNA-1299 (miR-1299) and guanylate binding protein 1 (GBP1) mRNA was determined by quantitative real-time PCR. In-vitro and in-vivo assays were conducted using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2-deoxyuridine (EdU), colony formation, transwell assays, flow cytometry and animal xenograft experiments. The interaction between miR-1299 and circ0058608 or GBP1 was confirmed by the dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Circ0058608 was overexpressed in NSCLC tissuescells and taxol-resistant NSCLC tissuescells. Circ0058608 knockdown inhibited NSCLC cell proliferation and metastasis and also suppressed tumor growth in vivo. Moreover, circ0058608 knockdown increased taxol sensitivity by increasing taxol-induced apoptosis in taxol-resistant NSCLC cells. Moreover, circ0058608 silencing enhanced taxol-induced tumor growth of NSCLC in vivo. MiR-1299 was a target of circ0058608, and the effects of circ0058608 knockdown on NSCLC cell progression and taxol resistance were reversed by miR-1299 inhibition. Additionally, miR-1299 could interact with GBP1, and miR-1299 suppressed NSCLC cell progression and taxol resistance by targeting GBP1. Furthermore, circ0058608 could regulate GBP1 expression by sponging miR-1299. Circ0058608 promoted the progression and taxol resistance of NSCLC by regulating the miR-1299GBP1 axis.

Chemotherapy A partnership with immunotherapy in non-small cell lung cancer.

Chemotherapy (CT) and immunotherapy (IO) act synergically in the treatment of non-small cell lung cancer (NSCLC). However, the molecular basis of such interaction is poorly understood. The aim of this review was to explore the mechanisms of CT to potentiate the immune system and, consequently, the action of IO. The most up-to-date knowledge concerning the interaction of CT and IO in NSCLC was reviewed and a bibliographic search was made in PubMedMedline database, using the mentioned keywords, with preference given to recently published articles in English. In addition to the direct cytotoxic effect, CT affects the immune system leading indirectly to cell death. The immune response triggered by PD-1 inhibition is enhanced by the cytotoxic immunogenic effects of CT. This potentiation phenomenon occurs due to an increase in effector cells relatively to regulatory cells, inhibition of myeloid derived suppressor cells, increased potential for cross-presentation by dendritic cells after the death of tumor cells or blocking the STAT6 pathway to increase dendritic cell activity. In conclusion, the effects of CT on the immune system work in synergy with the actions of IO, transforming cold tumors into hot tumors, which are more visible to the immune system.

A Case of Second Primary Small Cell Lung Carcinoma after Radiotherapy for Breast Cancer.

We report the case of a 72-year-old woman who underwent partial mastectomy due to left breast cancer(invasive ductal carcinoma)in March 20XX-4. This was followed by radiotherapy(50 Gy25 Fr)and hormone therapy. In July 20XX, she was referred to our department because a chest computed tomography(CT)scan performed at the postoperative follow-up revealed a band-like consolidation adjacent to the pleura in the lingular segment, with enlarged ipsilateral hilar and mediastinal lymph nodes. CT-guided lung tumor biopsy was performed, and she was diagnosed with limited-stage small cell lung cancer. Chemotherapy with carboplatin, etoposide, and atezolizumab was initiated. Radiotherapy was not performed due to the overlap between the distribution of the lung tumor and the postoperative irradiation field of breast cancer. Due to the difference in the histopathological findings of the first and second primary tumors, and the location of the tumor in the postoperative irradiation field, the second cancer was considered to be radiation-induced cancer despite the short latency period.

Patients Preferences for Attributes of Molecular Targeting Therapies for Advanced Non-Small Cell Lung Cancer with EGFR Mutations in Japan-A Discrete-Choice Experiment.

This study aims to evaluate Japanese patients preferences in first-line therapy choice for advanced non-small cell lung cancer(NSCLC)with epidermal growth factor receptor(EGFR)mutations. A cross-sectional discrete-choice experiment was conducted on advanced NSCLC patients in Japan. Participants completed the online questionnaire that included different levels of 5 treatment attributes time to disease progression, chance of rash, next therapy option, frequency of health care visits and administration route. The primary analysis estimated the relative attribute importance. The preferences of EGFR mutation-positive patients were compared with those of EGFR mutation-negativeunknown patients to observe whether preference differs by mutation status. A total of 158 participants completed the survey. The analysis on the overall study population revealed next therapy option(mean relative attribute importanceSD 39.30 17.07)as the most important attribute, followed by time to disease progression(25.5210.51), chance of rash(21.58 11.74), with administration route(7.636.99)and frequency of health care visits(5.963.40)the least preferred. The results in the subgroups by EGFR mutation status were similar. Next therapy option is the major influencing factor for treatment choice of molecular targeting therapy among advanced NSCLC patients in Japan, emphasizing the importance of communicating the next treatment options to patients at the time of their first treatment.

Advanced Medical Care.

Advanced medical care is a system that allows the use of off-label treatments in conjunction with insurance reimbursement, and is used for clinical trials to evaluate off-label treatments. Since pemetrexed has been not approved for patients with resected non-small cell lung cancer(NSCLC)in Japan, we conducted the randomized phase Ⅲ study(JIPANG)to evaluate the efficacy of pemetrexed plus cisplatin versus vinorelbine plus cisplatin as adjuvant chemotherapy in patients with stage Ⅱ-ⅢA nonsquamous NSCLC. This study needed 5-year registration period, and 5-year follow-up after registration of the last patient. The JIPANG study failed to show the superiority of pemetrexed plus cisplatin in terms of recurrence-free survival, as primary endpoint. In Japan, the challenges in conducting academia-led clinical trials of unapproved drugs and drugs for off-label use are the establishment of a system for conducting trials, the provision of drugs, and the procurement of funds.

Lung, Lymph Nodes and Pleural Metastasis of Breast Cancer Developed Thirty-two Years after Radical MastectomyReport of a Case.

We report a case of distant metastases developed 32 years after radical mastectomy for right breast cancer. A 70s-year-old women visited the local hospital because of productive cough. Chest computed tomography (CT) showed a 10 mm nodule in the right middle lobe, multiple lymph nodes swelling and small pleural nodules. Surgical biopsy of lung and pleural tumor provides the pathological diagnosis of solid-tubular carcinoma expressing estrogen receptor and progesterone receptor, suggesting metastatic lesions of breast cancer.

Surgical Case of the Primary Pulmonary LeiomyosarcomaReport of a Case.

A 70-year-old man was referred for an abnormal chest shadow. Enhanced computed tomography (CT) revealed a well-circumscribed lung tumor of 53 mm in diameter in the left upper lobe with slight enhancement. Positron emission tomography-CT showed a high maximum standardized uptake value for the tumor but no metastasis in the lymph nodes or other organs. Although a definitive diagnosis could not be made by transbronchial biopsy, the tumor was highly suspected to be malignant based on the radiological findings, and a left upper lobectomy with mediastinal lymph nodes dissection was performed for definitive diagnosis and treatment. A pathological examination showed the tumor to be composed of mitotic spindle-shaped cells, which were positive for α-smooth muscle actin, desmin, and caldesmon. The MIB-1 labelling index was 6070%. According to these pathologic findings, the tumor was identified as a leiomyosarcoma. Metastases to the skin of chest and hilar lymph nodes were noted six months after the surgery for which radiotherapy was performed.

Thoracoscopic Superior and Subsuperior Segmentectomy of the Right Lower Lung for Lung Cancer.

The subsuperior segment (S) is not frequently observed between the superior (S6) and posterior basal segments (S10). We present a case of video-assisted thoracoscopic surgery of S6S segmentectomy for a primary lung cancer patient. A 71-year-old man with a 20-mm nodule on the right S6, suspected of primary lung cancer( cT1bN0M0, stageⅠA2), was admitted to our hospital. Three-dimensional chest computed tomography (CT) revealed a subsuperior segmental bronchus (B), originating from the common trunk of the lateral basal segmental bronchus( B9) and posterior basal segmental bronchus (B10). In order to obtain enough surgical margin, we performed S6S segmentectomy. The pathological diagnosis was invasive adenocarcinoma( pT1cN0M0, stageⅠA3). S segmentectomy was considered to be useful method to ensure sufficient surgical margin when the lesion is in S or in segments adjacent to it.

Post-Operative Outcomes of Pre-Thoracic Surgery Respiratory Muscle Training vs Aerobic Exercise Training A Systematic Review and Network Meta-analysis.

To compare the postoperative outcomes of preoperative respiratory muscle training (RMT) with a device to preoperative aerobic exercise training (AET) in patients undergoing thoracic surgeries (cardiac and lung). PubMed, EMBASE, Cochrane, and Web of Science were comprehensively searched upon inception to 92020. All randomized control studies, including preoperative RMT and preoperative AET compared with a non-training control group, were included. The meta-analysis was performed for outcomes including postoperative pulmonary complications (PPC), pneumonia, postoperative respiratory failure (PRF), hospital length of stay (HLOS), and mortality. We performed a network meta-analysis based on Bayesian random-effects regression models. A total of 25 studies, 2070 patients were included in this meta-analysis. Pooled data for the patients who performed RMT with a device showed a reduction in PPCs, pneumonia, PRF with odds ratio (OR) of 0.35 (P value .006), 0.38 (P value .002), and 0.22 (P value .008), respectively. Pooled data for the patients who performed AET showed reduction in PPC, pneumonia with a OR of 0.33 (P value <.00001) and OR of 0.54 (P value .01), respectively. HLOS was decreased by 1.69 days (P value <.00001) by performing RMT and 1.79 days (P value .0008) by performing AET compared with the usual group. No significant difference in all-cause mortality compared with usual care in both RMT and AET intervention groups. No significant difference in the incidence of PRF compared with usual group in RMT AET and AET alone intervention groups (OR 0.32 P.21 OR 0.94 P.87). Based on rank probability plots analysis, on network meta-analysis, RMT and AET ranked similarly on the primary outcome of PPC and secondary outcomes of pneumonia, PRF and HLOS. In thoracic surgeries, preoperative RMT is comparable with preoperative AET to prevent PPC, pneumonia, and PRF and reduce HLOS. It can be considered in patients in resource-limited settings.

miR-142-3p improves paclitaxel sensitivity in resistant breast cancer by inhibiting autophagy through the GNB2-AKT-mTOR Pathway.

Breast cancer has overtaken lung cancer as the most prevalent cancer worldwide. The development of advanced drug resistance inhibits the efficacy of paclitaxel(PTX)as a first-line chemotherapeutic agent for breast cancer. Autophagy and microRNAs (miRNAs) play a key role in chemoresistance. This study investigated the miR-142-3p effect on PTX resistance by regulating autophagy. A PTX-resistant breast cancer cell line was constructed, and miR-142-3p and G protein beta polypeptide 2 (GNB2) were filtered out using RNA sequencing and protein microarray analysis. The study revealed that miR-142-3p expression was lower in drug-resistant cells compared parental cells. Higher miR-142-3p expression inhibited the viability, migration, and autophagic flux of drug-resistant cells, while promoting apoptosis and sensitivity to PTX treatment. Mechanistically, miR-142-3p was found to amend PTX resistance by targeting GNB2, further revealing that the knockdown of GNB2 expression could activate the AKT-mTOR pathway. This study suggests that GNB2 is an essential target for miR-142-3p to restrain autophagy, providing a new reference value for improving breast cancer PTX treatment.

Genomic and transcriptomic profiling reveals key molecules in metastatic potentials and organ-tropisms of hepatocellular carcinoma.

Metastasis is a landmark event for rapid postsurgical relapse and death of HCC patients. Although distinct genomic and transcriptomic profiling of HCC metastasis had been reported previously, the causal relationships of somatic mutants, mRNA levels and metastatic potentials were difficult to be established in clinic. Therefore, 11 human HCC cell lines and 7 monoclonal derivatives with definite metastatic potentials and tropisms were subjected to whole exome sequencing (WES) and whole transcriptome sequencing (WTS). TP53, MYO5A, ROS1 and ARID2 were the prominent mutants of metastatic drivers in HCC cells. During HCC clonal evaluation, TP53, MYO5A and ROS1 mutations occurred in the early stage, EXT2 and NIN in the late stage. NF1 mutant was unique in lung tropistic cell lines, RNF126 mutant in lymphatic tropistic ones. PER1, LMO2, GAS7, NR4A3 expression levels were positively associated with relapse-free survival (RFS) of HCC patients. The integrative analysis revealed 58 genes exhibited both somatic mutation and dysregulated mRNA levels in high metastatic cells. Altogether, metastatic drivers could accumulate gradually at different stages during HCC progression, some drivers might modulate HCC metastatic potentials and the others regulate metastatic tropisms.

Miz1 promotes KRAS-driven lung tumorigenesis by repressing the protocadherin Pcdh10.

Targeting KRAS-mutated non-small-cell lung cancer (NSCLC) remains clinically challenging. Here we show that loss of function of Miz1 inhibits lung tumorigenesis in a mouse model of oncogenic KRAS-driven lung cancer. In vitro, knockout or silencing of Miz1 decreases cell proliferation, clonogenicity, migration, invasion, or anchorage-independent growth in mutant (MT) KRAS murine or human NSCLC cells but has unremarkable impact on non-tumorigenic cells or wild-type (WT) KRAS human NSCLC cells. RNA-sequencing reveals Protocadherin-10 (Pcdh10) as the top upregulated gene by Miz1 knockout in MT KRAS murine lung tumor cells. Chromatin immunoprecipitation shows Miz1 binding on the Pcdh10 promoter in MT KRAS lung tumor cells but not non-tumorigenic cells. Importantly, silencing of Pcdh10 rescues cell proliferation and clonogenicity in Miz1 knockoutknockdown MT KRAS murine or human tumor cells, and rescues allograft tumor growth of Miz1 knockout tumor cells in vivo. Miz1 is upregulated in MT KRAS lung tumor tissues compared with adjacent non-involved tissues in mice. Consistent with this, Miz1 is upregulated while Pcdh10 is downregulated in human lung adenocarcinomas (LUAD) compared with normal tissues, and high Miz1 levels or low Pcdh10 levels are associated with poor survival in lung cancer patients. Furthermore, the Miz1 signature is associated with worse survival in MT but not WT KRAS LUAD, and Pcdh10 is downregulated in MT compared to WT KRAS LUAD. Taken together, our studies implicate the Miz1Pcdh10 axis in oncogenic KRAS-driven lung tumorigenesis.

Lung cancer screening New evidence, updated guidance.

Emerging evidence supports lower thresholds for age and smoking history when screening for lung cancer. Heres how the USPSTF and others have updated their guidelines in response.

Factors Associated With Provision of Nonbeneficial Surgery A National Survey of Surgeons.

We tested the association of systems factors with the surgeons likelihood of offering surgical intervention for older adults with life-limiting acute surgical conditions. Use of surgical treatments in the last year of life is frequent. Improved risk prediction and clinician communication are solutions proposed to improve serious illness care, yet systems factors may also drive receipt of nonbeneficial treatment. We mailed a national survey to 5200 surgeons randomly selected from the American College of Surgeons database comprised of a clinical vignette describing a seriously ill older adult with an acute surgical condition, which utilized a 2×2 factorial design to assess patient and systems factors on receipt of surgical treatment to surgeons. Two thousand one hundred sixty-one surgeons responded for a weighted response rate of 53%. For an 87-year-old patient with fulminant colitis and advanced dementia or stage IV lung cancer, 40% of surgeons were inclined to offer an operation to remove the patients colon while 60% were inclined to offer comfort-focused care only. Surgeons were more likely to offer surgery when an operating room was readily available (odds ratio 4.05, P <0.001) and the family requests do everything (odds ratio 2.18, P <0.001). Factors outside the surgeons control contribute to nonbeneficial surgery, consistent with our model of clinical momentum. Further characterization of the systems in which these decisions occur might expose novel strategies to improve serious illness care for older patients and their families.

Normalization Approach by a Reference Material to Improve LC-MS-Based Metabolomic Data Comparability of Multibatch Samples.

Large cohorts of samples from multiple batches are usually required for global metabolomic studies to characterize the metabolic state of human disease. As such, it is critical to eliminate systematic variation and truly reveal the biologically associated alterations. In this study, we proposed a reference material-based approach (Ref-M) for data correction by liquid chromatography-mass spectrometry and represented by an analysis of multibatch human serum samples. The reference material was generated by mixing serum from healthy donors and distributed to each extraction batch of subject samples. Pooled quality control samples and isotopic internal standards were then applied in each acquisition batch for data quality control. Finally, each metabolite in subject samples was normalized by its counterpart in the reference serum. We demonstrated that Ref-M significantly enhanced the numbers of efficient features and effectively eliminated the batch variation of 522 serum samples of healthy individuals, benign pulmonary nodules, and lung cancer patients. Twenty differential metabolites were identified to distinguish lung cancer from healthy controls in the training set. The discriminant model was validated in an independent data set with an area under the receiver operating characteristics (ROC) curve (AUC) of 0.853. Another 40 serum samples further tested with Ref-M were achieved an AUC of 0.843 by the established model. Our results showed that the reference material-based approach presents the potential to improve the data comparability and precision for biomarker discovery in large-scale metabolomic studies.

Aptamer-Engineered Cu

Herein, fine and homogeneous Cu

Detailed dosimetric evaluation of inter-fraction and respiratory motion in lung stereotactic body radiation therapy based on daily 4D cone beam CT images.

Effect of epithelial-specific MyD88 signaling pathway on airway inflammatory response to organic dust exposure.

The Toll-like receptor (TLR) adaptor protein MyD88 is integral to airway inflammatory response to microbial-enriched organic dust extract (ODE) exposures. ODE-induced airway neutrophil influx and release of pro-inflammatory cytokines was essentially abrogated in global MyD88-deficient mice, yet these mice demonstrate an increase in airway epithelial cell mucin expression. To further elucidate the role of MyD88-dependent responses specific to lung airway epithelial cells in response to ODE

Breast cancer emerging principles of metastasis, adjuvant and neoadjuvant treatment from cancer registry data.

Growing primary breast cancers (PT) can initiate local recurrences (LR), regional lymph nodes (pLN) and distant metastases (MET). Components of these progressions are initiation, frequency, growth duration, and survival. These characteristics describe principles which proposed molecular concepts and hypotheses must align with. In a population-based retrospective modeling approach using data from the Munich Cancer Registry key steps and factors associated with metastasis were identified and quantified. Analysis of 66.800 patient datasets over four time periods since 1978, reliable evidence is obtained even in small subgroups. Together with results of clinical trials on prevention and adjuvant treatment (AT) principles for the MET process and AT are derived. The median growth periods for PTMETLRpLN comes to 12.58.853.5 years, respectively. Even if 30% of METs only appear after 10 years, a pre-diagnosis MET initiation principle not a delayed one should be true. The growth times of PTs and METs vary by a factor of 10 or more but their ratio is robust at about 1.4. Principles of AT are 50% PT eradication, the selective and partial eradication of bone and lung METs. This cannot be improved by extending the duration of the previously known ATs. A paradigm of ten principles for the MET process and ATs is derived from real world data and clinical trials indicates that there is no rationale for the long-term application of endocrine ATs, risk of PTs by hormone replacement therapies, or cascading initiation of METs. The principles show limits and opportunities for innovation also through alternative interpretations of well-known studies. The outlined MET process should be generalizable to all solid tumors.

Letter to the editor referencing Effect of inspiratory muscle training associated or not to physical rehabilitation in preoperative anatomic pulmonary resection a systemic review and meta-analysis.

The recent systematic review and meta-analysis by de Oliveria Vacchi, Martha, and Macagnan (2022) on the effect of inspiratory muscle training (IMT) and its association with physical rehabilitation in preoperative anatomic pulmonary resection raises some interesting findings, and the authors should be congratulated for their work. However, additional factors should be considered in the context of this study. These include frailty, postoperative pulmonary complications, and the high correlation between lung cancer and chronic obstructive disease. This study is paramount considering the potential to improve patient suitability for curative surgery, the high risks associated with surgery and shifting demographics with an increased prevalence of comorbidities, alongside fiscal pressures. This study suggests the need for further high-quality research in this high-risk population, considering IMT alone or with physical rehabilitation, with methodologies that are reproducible.

Quantitative CT analysis of lung parenchyma to improve malignancy risk estimation in incidental pulmonary nodules.

To assess the value of quantitative computed tomography (QCT) of the whole lung and nodule-bearing lobe regarding pulmonary nodule malignancy risk estimation. A total of 251 subjects (median IQR age, 65 (57-73) years 37% females) with pulmonary nodules on non-enhanced thin-section CT were retrospectively included. Twenty percent of the nodules were malignant, the remainder benign either histologically or at least 1-year follow-up. CT scans were subjected to in-house software, computing parameters such as mean lung density (MLD) or peripheral emphysema index (pEI). QCT variable selection was performed using logistic regression selected variables were integrated into the Mayo Clinic and the parsimonious Brock Model. Whole-lung analysis revealed differences between benign vs. malignant nodule groups in several parameters, e.g. the MLD (-766 vs. -790 HU) or the pEI (40.1 vs. 44.7 %). The proposed QCT model had an area-under-the-curve (AUC) of 0.69 (95%-CI, 0.62-0.76) based on all available data. After integrating MLD and pEI into the Mayo Clinic and Brock Model, the AUC of both clinical models improved (AUC, 0.91 to 0.93 and 0.88 to 0.91, respectively). The lobe-specific analysis revealed that the nodule-bearing lobes had less emphysema than the rest of the lung regarding benign (EI, 0.5 vs. 0.7 % p < 0.001) and malignant nodules (EI, 1.2 vs. 1.7 % p 0.001). Nodules in subjects with higher whole-lung metrics of emphysema and less fibrosis are more likely to be malignant hereby the nodule-bearing lobes have less emphysema. QCT variables could improve the risk assessment of incidental pulmonary nodules. • Nodules in subjects with higher whole-lung metrics of emphysema and less fibrosis are more likely to be malignant. • The nodule-bearing lobes have less emphysema compared to the rest of the lung. • QCT variables could improve the risk assessment of incidental pulmonary nodules.

Tetrahydroquinoline an efficient scaffold as mTOR inhibitor for the treatment of lung cancer.

Efforts have been made to find an efficient scaffold (and its substitution) that can be used for the treatment of lung cancer via mTOR inhibition. A detailed literature search was carried out for previously reported mTOR inhibitors. The present review is focused on lung cancer therefore, descriptions of some mTOR inhibitors that are currently in clinical trials for the treatment of lung cancer are provided. Based on previous research findings, tetrahydroquinoline was found to be the most efficient scaffold to be explored for the treatment of lung cancer. A possible efficient substitution of the tetrahydroquinoline scaffold could also be beneficial for the treatment of lung cancer.

Gabapentin-Induced Overflow Urinary Incontinence A Case Report and Review of the Literature.

Gabapentin (GBP) is a structural analog of gamma-aminobutyric acid (GABA) that is commonly used in palliative care for symptom management indications including neuropathic pain syndromes, hiccups, cough, and anxiety. An uncommon adverse effect of GBP is urinary incontinence (UI). We report the case of a 61-year-old male with metastatic non-small cell lung cancer who developed probable overflow UI while receiving 1200 mgday of GBP for chemotherapy-induced peripheral neuropathy. The patient self-tapered GBP to 600 mgday which resolved the overflow UI, but resulted in poorly controlled bilateral foot pain. The palliative care physician rotated the patient to pregabalin 150 mgday and his bilateral foot pain improved after his regimen was titrated to 200 mgday. The patient did not experience overflow UI while taking pregabalin despite the similar pharmacology and comparable doses to GBP. We believe this is the first case report to describe subsequent achievement of pain control by substituting pregabalin without recurrence of UI. Healthcare professionals should consider GBP as a potential cause when evaluating patients presenting with new onset overflow UI.

Crizotinib has Preclinical Efficacy in Philadelphia-negative Myeloproliferative Neoplasms.

The Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs) polycythemia vera, essential thrombocythemia, and primary myelofibrosis are characterized by JAKSTAT pathway activation. JAK inhibitors are approved for MPN treatment, but persistence has been observed, due to JAKSTAT reactivation. Using MPN patient samples, JAK2-mutated cell lines, and MPN mouse models, we examined both the efficacy and mechanism by which crizotinib, the ALKMETRONROS1 inhibitor approved for the treatment of non-small cell lung cancer, alters MPN cell proliferation and JAKSTAT activation. We found that crizotinib suppresses proliferation and activation of JAK2STAT signaling, and decreases the disease burden in the JAK2V617F mouse model of MPN. Furthermore, we found that crizotinib could overcome JAK inhibitor persistence to ruxolitinib. Interestingly, phosphorylation of the crizotinib target RON kinase was enhanced in ruxolitinib-persistent cells. We show that phospho-JAK2 and phospho-RON can physically interact to sustain JAKSTAT signaling, and that the combination of crizotinib and ruxolitinib disrupts this interaction. Furthermore, RON knockdown suppresses proliferation and activation of JAKSTAT signaling in JAK2-mutated cells, and RON deletion in a JAK2V617F mouse MPN model decreases the disease burden. We also observed RON hyperactivation in MPN patient cells, suggesting that RON may be an important target of crizotinib in MPN. In summary, we demonstrate that crizotinib has preclinical efficacy in MPN patient cells, JAK2-mutated cell lines, and a JAK2-mutated mouse model, and that the combination of crizotinib with JAK inhibitors suppresses JAK inhibitor persistence. Our work suggests that crizotinib should be investigated for the treatment of MPN patients.

NuTracker a coordinate-based neural network representation of lung motion for intrafraction tumor tracking with various surrogates in radiotherapy.

Transcription factor ZNF488 accelerates cervical cancer progression through regulating the MEKERK signaling pathway.

Cervical cancer (CC) is one of the most common gynecological malignancies worldwide. Zinc Finger Protein 488 (ZNF488) has been identified as an oncogene in nasopharyngeal carcinoma. However, its biological role and potential mechanism in CC remain to be elucidated. In the present study, upregulation of ZNF488 expression in human CC tissues was found in clinical samples and analyzed in The Cancer Genome Atlas (TCGA) dataset, which was associated with clinical staging and lymph node metastasis. Quantitative real time polymerase chain reaction (PCR) and western blot assays indicated that the expression of ZNF488 was up-regulated in CC cells. Cell colony formation and cell cycle analysis assays suggested that ZNF488 promoted CC cell proliferation and cycle progression. Knockdown of ZNF488 inhibited tumor growth of xenograft tumor mice in vivo, in agreement with the levels of ZNF488 and Ki-67. Moreover, transwell and western assays demonstrated that ZNF488 enhanced CC cell migration and invasion. Additionally, knockdown of ZNF488 also inhibited lung metastasis of CC cells in vivo. Further mechanism analysis implied that ZNF488 promoted the MEKERK signaling pathway. ERK inhibitor PD98059 significantly weakened the proliferation and epithelial-mesenchymal transformation (EMT) promotion effect of ZNF488. Collectively, ZNF488 exerts its oncogene function partially through modulating MEKERK signaling pathway in CC, indicating that ZNF488 may provide a promising therapeutic target for the treatment of CC.

UHRF1 plays an oncogenic role in small cell lung cancer.

Small cell lung cancer (SCLC) is a malignant tumor characterized by aggressiveness and dismal prognosis. The specific role of ubiquitin-like PHD and RING finger domain (UHRF1), a frequently overexpressed cancer-promoting gene in various tumors, is poorly understood in SCLC. Herein, we explored the potential carcinogenic role of UHRF1 in SCLC. First, public databases were used to analyze the expression of UHRF1 in SCLC, and tissue specimens in our center were examined to confirm the results while clinical outcomes were collected to analyze its relationship with UHRF1. Then, UHRF1 knockdown and overexpression cell lines were established to evaluate the carcinogenic function of UHRF1 in vitro and in vivo. The mechanism of the biological consequences was determined by co-inmunoprecipitation. Moreover, we also analyzed the influence of UHRF1 on cisplatin (DDP) sensitivity of SCLC. The expression of UHRF1 was significantly higher in SCLC tissues than in normal tissues, and high levels of UHRF1 suggested a poor prognosis for SCLC. Mechanistically, UHRF1 promoted SCLC growth through yes-associated protein 1 (YAP1). Specifically, UHRF1 bound to YAP1 and inhibited YAP1 ubiquitin degradation, thus stabilizing the YAP1 protein in SCLC cells. UHRF1 downregulation enhanced DDP sensitivity in SCLC cells and was correlated with a favorable prognosis in patients with SCLC treated with platinum-based chemotherapy. UHRF1 plays an oncogenic role in SCLC by modulating YAP1. Therefore, UHRF1 could be used as a biomarker to predict the prognosis of SCLC patients and serve as a potential therapeutic target for SCLC patients.

PLIC11 drives lung cancer progression through regulating the YY1PIWIL4 axis.

Lung cancer is the leading cause of cancer related deaths worldwide. Nonsmall cell lung cancers (NSCLC), the most common histological type of lung cancer, are known to be less well characterized. Long noncoding RNAs are a new class of cancer regulators. Here, we aimed to investigate the effect of lncRNA PLIC11 in NSCLC progression. In our study, we found that PLIC11 was upregulated in lung cancer, particularly in metastatic lung cancer tissues. Overexpression of PLIC11 enhanced cell proliferation, migration, and metastasis in vitro and in vivo. Mechanically, PLIC11 could interact with YY1 and promote PIWIL4 expression by transcription activation. Therefore, PLIC11 upregulation is a potential indicator of aggressive lung cancer, Silencing of PLIC11 has great potential therapeutic strategy in NSCLC.

Neonatal hyperoxia induces activated pulmonary cellular states and sex-dependent transcriptomic changes in a model of experimental bronchopulmonary dysplasia.

Hyperoxia disrupts lung development in mice and causes bronchopulmonary dysplasia (BPD) in neonates. To investigate sex-dependent molecular and cellular programming involved in hyperoxia, we surveyed the mouse lung using single cell RNA sequencing (scRNA-seq), and validated our findings in human neonatal lung cells in vitro. Hyperoxia-induced inflammation in alveolar type (AT) 2 cells gave rise to damage-associated transient progenitors (DATPs). It also induced a new subpopulation of AT1 cells with reduced expression of growth factors normally secreted by AT1 cells, but increased mitochondrial gene expression. Female alveolar epithelial cells had less EMT and pulmonary fibrosis signaling in hyperoxia. In the endothelium, expansion of Car4 EC (Cap2) was seen in hyperoxia along with an emergent subpopulation of Cap2 with repressed VEGF signaling. This regenerative response was increased in females exposed to hyperoxia. Mesenchymal cells had inflammatory signatures in hyperoxia, with a new distal interstitial fibroblast subcluster characterized by repressed lipid biosynthesis and a transcriptomic signature resembling myofibroblasts. Hyperoxia-induced gene expression signatures in human neonatal fibroblasts and alveolar epithelial cells in vitro resembled mouse scRNA-seq data. These findings suggest that neonatal exposure to hyperoxia programs distinct sex-specific stem cell progenitor and cellular reparative responses that underpin lung remodeling in BPD.