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The Landscape of Gene Expression during Hyperfilamentous Biofilm Development in Oral

The filamentation ability of

RAGE Inhibitors for Targeted Therapy of Cancer A Comprehensive Review.

The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin family that is overexpressed in several cancers. RAGE is highly expressed in the lung, and its expression increases proportionally at the site of inflammation. This receptor can bind a variety of ligands, including advanced glycation end products, high mobility group box 1, S100 proteins, adhesion molecules, complement components, advanced lipoxidation end products, lipopolysaccharides, and other molecules that mediate cellular responses related to acute and chronic inflammation. RAGE serves as an important node for the initiation and stimulation of cell stress and growth signaling mechanisms that promote carcinogenesis, tumor propagation, and metastatic potential. In this review, we discuss different aspects of RAGE and its prominent ligands implicated in cancer pathogenesis and describe current findings that provide insights into the significant role played by RAGE in cancer. Cancer development can be hindered by inhibiting the interaction of RAGE with its ligands, and this could provide an effective strategy for cancer treatment.

The Potential Importance of CXCL1 in the Physiological State and in Noncancer Diseases of the Cardiovascular System, Respiratory System and Skin.

In this paper, we present a literature review of the role of CXC motif chemokine ligand 1 (CXCL1) in physiology, and in selected major non-cancer diseases of the cardiovascular system, respiratory system and skin. CXCL1, a cytokine belonging to the CXC sub-family of chemokines with CXC motif chemokine receptor 2 (CXCR2) as its main receptor, causes the migration and infiltration of neutrophils to the sites of high expression. This implicates CXCL1 in many adverse conditions associated with inflammation and the accumulation of neutrophils. The aim of this study was to describe the significance of CXCL1 in selected diseases of the cardiovascular system (atherosclerosis, atrial fibrillation, chronic ischemic heart disease, hypertension, sepsis including sepsis-associated encephalopathy and sepsis-associated acute kidney injury), the respiratory system (asthma, chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis, coronavirus disease 2019 (COVID-19), influenza, lung transplantation and ischemic-reperfusion injury and tuberculosis) and the skin (wound healing, psoriasis, sunburn and

Leveraging Natural Killer Cell Innate Immunity against Hematologic Malignancies From Stem Cell Transplant to Adoptive Transfer and Beyond.

Numerous recent advancements in T-cell based immunotherapies have revolutionized the treatment of hematologic malignancies. In the race towards the first approved allogeneic cellular therapy product, there is growing interest in utilizing natural killer (NK) cells as a platform for off-the-shelf cellular therapies due to their scalable manufacturing potential, potent anti-tumor efficacy, and superior safety profile. Allogeneic NK cell therapies are now being actively explored in the setting of hematopoietic stem cell transplantation and adoptive transfer. Increasingly sophisticated gene editing techniques have permitted the engineering of chimeric antigen receptors, ectopic cytokine expression, and tumor recognition signals to improve the overall cytotoxicity of NK cell therapies. Furthermore, the enhancement of antibody-dependent cellular cytotoxicity has been achieved through the use of NK cell engagers and combination regimens with monoclonal antibodies that act synergistically with CD16-expressing NK cells. Finally, a greater understanding of NK cell biology and the mechanisms of resistance have allowed the preclinical development of NK checkpoint blockade and methods to modulate the tumor microenvironment, which have been evaluated in early phase trials. This review will discuss the recent clinical advancements in NK cell therapies in hematologic malignancies as well as promising avenues of future research.

Betulin Acid Ester Derivatives Inhibit Cancer Cell Growth by Inducing Apoptosis through Caspase Cascade Activation A Comprehensive In Vitro and In Silico Study.

Betulin, or naturally occurring triterpene, possesses promising antiproliferative activity. To further explore this potential, thirty-eight betulin acid ester derivatives modified at the C-28 position were tested for antitumor activities. Four human cancer cell lines, MV4-11 (leukemia), A549 (lung), PC-3 (prostate), MCF-7 (breast) as well as the normal BALB3T3 (mouse fibroblasts) cell line were examined using MTT and SRB assays. A few derivatives exhibited strong antiproliferative activity with IC

Matched Analyses of Brain Metastases versus Primary Non-Small Cell Lung Cancer Reveal a Unique microRNA Signature.

Distant spreading of tumor cells to the central nervous system in non-small cell lung cancer (NSCLC) occurs frequently and poses major clinical issues due to limited treatment options. RNAs displaying differential expression in brain metastasis versus primary NSCLC may explain distant tumor growth and may potentially be used as therapeutic targets. In this study, we conducted systematic microRNA expression profiling from tissue biopsies of primary NSCLC and brain metastases from 25 patients. RNA analysis was performed using the nCounter Human v3 miRNA Expression Assay, NanoString technologies, followed by differential expression analysis and in silico target gene pathway analysis. We uncovered a panel of 11 microRNAs with differential expression and excellent diagnostic performance in brain metastasis versus primary NSCLC. Five microRNAs were upregulated in brain metastasis (miR-129-2-3p, miR-124-3p, miR-219a-2-3p, miR-219a-5p, and miR-9-5p) and six microRNAs were downregulated in brain metastasis (miR-142-3p, miR-150-5p, miR-199b-5p, miR-199a-3p, miR-199b-5p, and miR-199a-5p). The differentially expressed microRNAs were predicted to converge on distinct target gene networks originating from five to twelve core target genes. In conclusion, we uncovered a unique microRNA profile linked to two target gene networks. Our results highlight the potential of specific microRNAs as biomarkers for brain metastasis in NSCLC and indicate plausible mechanistic connections.

Simulated Microgravity Influences Immunity-Related Biomarkers in Lung Cancer.

Microgravity is a novel strategy that may serve as a complementary tool to develop future cancer therapies. In lung cancer, the influence of microgravity on cellular processes and the migratory capacity of cells is well addressed. However, its effect on the mechanisms that drive lung cancer progression remains in their infancy. In this study, 13 differentially expressed genes were shown to be associated with the prognosis of lung cancer under simulated microgravity (SMG). Using gene set enrichment analysis, these genes are enriched in humoral immunity pathways. In lieu, alveolar basal-epithelial (A549) cells were exposed to SMG via a 2D clinostat system in vitro. In addition to morphology change and decrease in proliferation rate, SMG reverted the epithelial-to-mesenchymal transition (EMT) phenotype of A549, a key mechanism in cancer progression. This was evidenced by increased epithelial E-cadherin expression and decreased mesenchymal N-cadherin expression, hence exhibiting a less metastatic state. Interestingly, we observed increased expression of

Effects of CYP3A43 Expression on Cell Proliferation and Migration of Lung Adenocarcinoma and Its Clinical Significance.

The cytochrome P450s (CYP450s) include key oxidative enzymes involved in the metabolism of various carcinogens and anticancer drugs. Bioinformatic studies have demonstrated the association of CYP3A43 with liver cancer and ovarian cancer. However, the biological function of CYP3A43 in tumor progression remains unclear. To further reveal the role of CYP3A43 in tumor progression, we first analyzed the data from the UALCAN database and found that CYP3A43 was negatively correlated to the cancer staging and lymph node metastasis of lung adenocarcinoma (LUAD). We established stable CYP3A43-knockdown LUAD H1299 cell line and found that its knockdown enhanced cell proliferation, colony formation, and migration in vitro, and promoted the growth of tumor xenograft in vivo. Interestingly, when CYP3A43 was ectopically-expressed in the LUAD cell lines, decreased cell proliferation and ERK12 phosphorylation level were observed. Lastly, we also identified CYP3A43 co-expressed genes in LUAD from LinkedOmics database followed by GO and KEGG analyses. In conclusion, our results indicate the unprecedented role of CYP3A43 in the suppression of LUAD and provide new possibilities for targeted therapy of this life-threatening disease.

May EPHEphrin Targeting Revolutionize Lung Cancer Treatment

Lung cancer (LC) is the leading cause of cancer death in the United States. Erythropoietin-producing hepatocellular receptors (EPHs) comprise the largest receptor tyrosine kinases (RTKs) family in mammals. EPHs along with their ligands, EPH-family receptor-interacting proteins (ephrins), have been found to be either up- or downregulated in LC cells, hence exhibiting a defining role in LC carcinogenesis and tumor progression. In their capacity as membrane-bound molecules, EPHsephrins may represent feasible targets in the context of precision cancer treatment. In order to investigate available therapeutics targeting the EPHephrin system in LC, a literature review was conducted, using the MEDLINE, LIVIVO, and Google Scholar databases. EPHA2 is the most well-studied EPHephrin target in LC treatment. The targeting of EPHA2, EPHA3, EPHA5, EPHA7, EPHB4, EPHB6, ephrin-A1, ephrin-A2, ephrin-B2, and ephrin-B3 in LC cells or xenograft models not only directly correlates with a profound LC suppression but also enriches the effects of well-established therapeutic regimens. However, the sole clinical trial incorporating a NSCLC patient could not describe objective anti-cancer effects after anti-EPHA2 antibody administration. Collectively, EPHsephrins seem to represent promising treatment targets in LC. However, large clinical trials still need to be performed, with a view to examining the effects of EPHephrin targeting in the clinical setting.

Design and Synthesis of Acridine-Triazole and Acridine-Thiadiazole Derivatives and Their Inhibitory Effect against Cancer Cells.

We report herein the design and synthesis of a series of novel acridine-triazole and acridine-thiadiazole derivatives. The newly synthesized compounds and the key intermediates were all evaluated for their antitumor activities against human foreskin fibroblasts (HFF), human gastric cancer cells-803 (MGC-803), hepatocellular carcinoma bel-7404 (BEL-7404), large cell lung cancer cells (NCI-H460), and bladder cancer cells (T24). Most of the compounds exhibited high levels of antitumor activity against MGC-803 and T24 but low toxicity against human normal liver cells (LO2), and their effect was even better than the commercial anticancer drugs, 5-fluorouracil (5-FU) and cis-platinum. Further, pharmacological mechanisms such as topo I, cell cycle, cell apoptosis, and neovascularization were all evaluated. Only a few compounds exhibited potent topo I inhibitory activity at 100 μM. In addition, the most active compounds with an IC

Detection of Circulating Tumor Cells Using the Attune NxT.

Circulating tumor cells (CTCs) have been detected in many patients with different solid malignancies. It has been reported that presence of CTCs correlates with worse survival in patients with multiple types of cancer. Several techniques have been developed to detect CTCs in liquid biopsies. Currently, the only method for CTC detection that is approved by the Food and Drug Administration is CellSearch. Due to low abundance of CTCs in certain cancer types and in early stages of disease, its clinical application is currently limited to metastatic colorectal cancer, breast cancer and prostate cancer. Therefore, we aimed to develop a new method for the detection of CTCs using the Attune NxT-a flow cytometry-based application that was specifically developed to detect rare events in biological samples without the need for enrichment. When healthy donor blood samples were spiked with variable amounts of different EpCAMEGFR tumor cell lines, recovery yield was on average 75%. The detection range was between 1000 and 10 cells per sample. Cell morphology was confirmed with the Attune CytPix. Analysis of blood samples from metastatic colorectal cancer patients, as well as lung cancer patients, demonstrated that increased EpCAMEGFR events were detected in more than half of the patient samples. However, most of these cells showed no (tumor) cell-like morphology. Notably, CellSearch analysis of blood samples from a subset of colorectal cancer patients did not detect CTCs either, suggesting that these blood samples were negative for CTCs. Therefore, we anticipate that the Attune NxT is not superior to CellSearch in detection of low amounts of CTCs, although handling and analysis of samples is easier. Moreover, morphological confirmation is essential to distinguish between CTCs and false positive events.

Mutational Analysis of EGFR Mutations in Non-Small Cell Lung Carcinoma-An Indian Perspective of 212 Patients.

Lung cancer is the worlds leading cause of cancer-related deaths. Epidermal growth factor receptor (EGFR) is one of the critical oncogenes and plays a significant role in tumor proliferation and metastasis. Patients with sensitizing mutations in the EGFR gene have better clinical outcomes when treated with tyrosine kinase inhibitors (TKI). This study expands our knowledge of the spectrum of EGFR mutations among lung cancer patients in the Indian scenario. This is a retrospective descriptive study of all newly diagnosed patients with lung cancer in tertiary care hospital in India. All the samples were subjected to real-time PCR (q-PCR) analysis and confirmation of rare novel mutations was done using Sanger sequencing. Clinicopathological characteristics, mutational EGFR status, and location on the exon and metastatic sites were evaluated. An analysis of total 212 samples showed mutations in 38.67% of cases. Among these, five (5.9%) samples had mutations in exon 18, 41 (48.8%) samples had mutations in exon 19, 12 (14.28%) samples had mutations in exon 20, and 26 (30.95%) samples had mutations in exon 21. Eleven (13.41%) were found to be uncommon EGFR mutations. Additionally, six (21.4%) samples that had EGFR mutations were also positive for brain metastasis. Future testing on bigger panels will help to characterize the incidence of genetic mutations and to determine the appropriate targeted treatment choices for NSCLC patients.

Health Effects of Exposure to Indoor Semi-Volatile Organic Compounds in Chinese Building Environment A Systematic Review.

People spend a considerable portion of their lives indoors thus, the quality of the indoor environment is crucial. Semi-volatile organic compounds (SVOCs) are among the primary indoor pollutants responsible for various health risks. This paper systematically reviews the impact of SVOC exposure on human health in Chinese built environments. Based on a set of criteria, we judged 12 publications as providing sufficient information on both SVOC exposure and health effects to inform the relationship. Out of six studies on polycyclic aromatic hydrocarbons (PAHs), three observed a positive association between PAH exposure and lung cancer. Out of six studies of phthalate exposure, two studies reported a significant positive association between DEP and DiBP and asthma, between DEP and DEHP and dry cough among children, and between DBP and rhinitis among younger adults. The results of this review suggest that there might be a link between phthalate exposure and asthma and allergies, as well as a link between PAH exposure and lung cancer. However, due to the limited number of studies conducted, more evidence is necessary to definitively guide the establishment of standards for SVOC control in China.

Chronic Home Radon Exposure Is Associated with Higher Inflammatory Biomarker Concentrations in Children and Adolescents.

Children are particularly vulnerable to the deleterious impacts of toxic environmental exposures, though the effects of some rather ubiquitous toxins have yet to be characterized in youths. One such toxin, radon gas, is known to accumulate to hazardous levels in homes, and has been linked with the incidence of lung cancer in aging adults. However, the degree to which chronic home radon exposure may impact risk for health problems earlier in life is unknown. Herein, we explored the degree to which chronic home radon exposure relates to biomarkers of low-grade inflammation in 68 youths ages 6- to 14 years old residing in an area of the United States prone to high home radon concentrations. Parents completed a home radon test kit, and youths provided a saliva sample to assess concentrations of five biomarkers. Using a multiple regression approach, we found that greater radon exposure was specifically associated with higher levels of C-reactive protein (β 0.31,

A Systematic Review of Electronic Medical Record Driven Quality Measurement and Feedback Systems.

Historically, quality measurement analyses utilize manual chart abstraction from data collected primarily for administrative purposes. These methods are resource-intensive, time-delayed, and often lack clinical relevance. Electronic Medical Records (EMRs) have increased data availability and opportunities for quality measurement. However, little is known about the effectiveness of Measurement Feedback Systems (MFSs) in utilizing EMR data. This study explores the effectiveness and characteristics of EMR-enabled MFSs in tertiary care. The search strategy guided by the PICO Framework was executed in four databases. Two reviewers screened abstracts and manuscripts. Data on effect and intervention characteristics were extracted using a tailored version of the Cochrane EPOC abstraction tool. Due to study heterogeneity, a narrative synthesis was conducted and reported according to PRISMA guidelines. A total of 14 unique MFS studies were extracted and synthesized, of which 12 had positive effects on outcomes. Findings indicate that quality measurement using EMR data is feasible in certain contexts and successful MFSs often incorporated electronic feedback methods, supported by clinical leadership and action planning. EMR-enabled MFSs have the potential to reduce the burden of data collection for quality measurement but further research is needed to evaluate EMR-enabled MFSs to translate and scale findings to broader implementation contexts.

Spatial and Temporal Volatility of PM2.5, PM10 and PM10-Bound BaP Concentrations and Assessment of the Exposure of the Population of Silesia in 2018-2021.

Air pollution both indoors and outdoors is a major cause of various diseases and premature deaths. Negative health effects are more frequently observed in a number of European countries characterized by significant pollution. In Poland, especially in Upper Silesia, the most serious problem is the high concentration of particulate matter (PM) and PM10-bound benzoapyrene (BaP). The main source of these two pollutants is so-called low emissions associated with the burning of solid fuels mainly in domestic boilers and liquid fuels in road traffic. This study examined the variability in the PM and PM10-bound BaP concentrations and their relationships with meteorological parameters, i.e., atmospheric pressure, air temperature and wind speed, in 2018-2021 at 11 monitoring stations. In many Silesian cities, the average annual concentrations of PM10, PM2.5 and BaP were much higher than those recorded in other European countries. At each station, the average daily PM10 concentrations were exceeded on 12 to 126 days a year. Taking into account the WHO recommendation for PM2.5, the highest recorded average daily concentration exceeded the permissible level by almost 40 times. The same relationships were observed in all measurement years PM10 concentrations were negatively correlated with air temperature (R -0.386) and wind speed (R -0.614). The highest concentrations were observed in the temperature range from -15 °C to -5 °C, when the wind speed did not exceed 0.5 m·s

Human Health Impacts of Residential Radon Exposure Updated Systematic Review and Meta-Analysis of Case-Control Studies.

This study investigated the impact of residential radon exposure on human cancers (i.e., lung cancer and childhood leukemia) through a systematic review and meta-analysis of case-control studies. A total of 9724 articles obtained from electronic databases were assessed however, only 55 case-control studies were eligible after manually screening and eliminating unnecessary studies. The causal associations were addressed by determining the meta-analysiss estimated size effects (i.e., ORsRRs) of the meta-analysis. Residential radon was revealed to significantly increase the incidence of lung cancer and childhood leukemia with pooled ORs of 1.38 1.19 1.60 (I

Prediction of Asbestos-Related Diseases (ARDs) and Chrysotile Asbestos Exposure Concentrations in Asbestos-Cement (AC) Manufacturing Factories in Zimbabwe.

The use of historical asbestos measurement data in occupational exposure assessment is essential as it allows more quantitative analysis of possible exposure response relationships in asbestos-related disease (ARD) occurrence. The aim of this study was to predict possible ARDs, namely lung cancer, mesothelioma, gastrointestinal cancer, and asbestosis, in two chrysotile asbestos cement (AC) manufacturing factories. Prediction of ARDs was done using a specific designed job-exposure matrix for airborne chrysotile asbestos fibre concentrations obtained from the Harare and Bulawayo AC factories and through application of OSHAs linear dose effect model in which ARDs were estimated through extrapolation at 1, 10, 20, and 25 years of exposure. The results show that more cancer and asbestosis cases are likely to be experienced among those exposed before 2008 as exposure levels and subsequently cumulative exposure were generally much higher than those experienced after 2008. After a possible exposure period of 25 years, overall cancer cases predicted in the Harare factory were 325 cases per 100,000 workers, while for the Bulawayo factory, 347 cancer cases per 100,000 workers exposed may be experienced. Possible high numbers of ARDs are likely to be associated with specific tasksjob titles, e.g., saw cutting, kollergang, fettling table, ground hard waste, and possibly pipe-making operations, as cumulative exposures, though lower than reported in other studies, may present higher risk of health impairment. The study gives insights into possible ARDs, namely lung cancer, mesothelioma, gastrointestinal cancer, and asbestosis, that may be anticipated at various cumulative exposures over 1, 10, 20, and 25 years of exposure in AC manufacturing factories in Zimbabwe. Additionally, results from the study can also form a basis for more in-depth assessment of asbestos cancer morbidity studies in the AC manufacturing industries.

A Seed-and-Soil Radiomics Model Predicts Brain Metastasis Development in Lung Cancer Implications for Risk-Stratified Prophylactic Cranial Irradiation.

Brain is a major site of metastasis for lung cancer, and effective therapy for developed brain metastasis (BM) is limited. Prophylactic cranial irradiation (PCI) has been shown to reduce BM rate and improve survival in small cell lung cancer, but this result was not replicated in unselected non-small cell lung cancer (NSCLC) and had the risk of inducing neurocognitive dysfunctions. We aimed to develop a radiomics BM prediction model for BM risk stratification in NSCLC patients. 256 NSCLC patients with no BM at baseline brain magnetic resonance imaging (MRI) were selected 128 patients developed BM within three years after diagnosis and 128 remained BM-free. For radiomics analysis, both the BM and non-BM groups were randomly distributed into training and testing datasets at an 70%30% ratio. Both brain MRI (representing the soil) and chest computed tomography (CT, representing the seed) radiomic features were extracted to develop the BM prediction models. We first developed the radiomic models using the training dataset (89 non-BM and 90 BM cases) and subsequently validated the models in the testing dataset (39 non-BM and 38 BM cases). A radiomics BM score (RadBM score) was generated, and BM-free survival were compared between RadBM score-high and RadBM score-low groups. The radiomics model developed from baseline brain MRI features alone can predict BM development in NSCLC patients. A fusion model integrating brain MRI features with primary tumor CT features (seed-and-soil model) provided synergetic effect and was more efficient in predicting BM (areas under the receiver operating characteristic curve 0.84 (95% confidence interval 0.80-0.89) and 0.80 (95% confidence interval 0.71-0.88) in the training and testing datasets, respectively). BM-free survival was significantly shorter in the RadBM score-high group versus the RadBM score-low group (Log-rank, The results demonstrated that intrinsic features of a non-metastatic brain exert a significant impact on BM development, which is first-in-class in metastasis prediction studies. A radiomics BM prediction model utilizing both primary tumor and pre-metastatic brain features might provide a useful tool for individualized PCI administration in NSCLC patients more prone to develop BM.

Longitudinal Plasma Proteomics-Derived Biomarkers Predict Response to MET Inhibitors for MET-Dysregulated NSCLC.

MET inhibitors have shown promising efficacy for MET-dysregulated non-small cell lung cancer (NSCLC). However, quite a few patients cannot benefit from it due to the lack of powerful biomarkers. This study aims to explore the potential role of plasma proteomics-derived biomarkers for patients treated with MET inhibitors using mass spectrometry. We analyzed the plasma proteomics from patients with MET dysregulation (including

The Association between Baseline Proton Pump Inhibitors, Immune Checkpoint Inhibitors, and Chemotherapy A Systematic Review with Network Meta-Analysis.

(1) Although emerging evidence suggests that proton pump inhibitor (PPI)-induced dysbiosis negatively alters treatment response to immune checkpoint inhibitors (ICIs) in cancer patients, no study systematically investigates the association between PPIs, ICIs, and chemotherapy (2) Cochrane Library, Embase, Medline, and PubMed were searched from inception to 20 May 2022, to identify relevant studies involving patients receiving ICIs or chemotherapy and reporting survival outcome between PPI users and non-users. Survival outcomes included overall survival (OS) and progression-free survival (PFS). Network meta-analyses were performed using random-effects models.

A Survey of Naturally Occurring Molecules as New Endoplasmic Reticulum Stress Activators with Selective Anticancer Activity.

The last century has witnessed the establishment of neoplastic disease as the second cause of death in the world. Nonetheless, the road toward desirable success rates of cancer treatments is still long and paved with uncertainty. This work aims to select natural products that act via endoplasmic reticulum (ER) stress, a known vulnerability of malignant cells, and display selective toxicity against cancer cell lines. Among an in-house chemical library, nontoxic molecules towards noncancer cells were assessed for toxicity towards cancer cells, namely the human gastric adenocarcinoma cell line AGS and the lung adenocarcinoma cell line A549. Active molecules towards at least one of these cell lines were studied in a battery of ensuing assays to clarify the involvement of ER stress and unfolded protein response (UPR) in the cytotoxic effect. Several natural products are selectively cytotoxic against malignant cells, and the effect often relies on ER stress induction. Berberine was the most promising molecule, being active against both cell models by disrupting Ca

Robust Performance of the Novel Research-Use-Only Idylla GeneFusion Assay Using a Diverse Set of Pathological Samples with a Proposed 1-Day Workflow for Advanced NSCLC Evaluation.

A range of different techniques are available for predictive biomarker testing for non-small-cell lung cancer (NSCLC) clinical management. International guidelines suggest next-generation sequencing (NGS) as the preferred procedure, but other reverse transcriptase-polymerase chain reaction (RT-PCR)-based methods are rapidly evolving. In this study, we evaluated the reliability and accuracy of the Idylla

Telomere Status of Advanced Non-Small-Cell Lung Cancer Offers a Novel Promising Prognostic and Predictive Biomarker.

Telomere length appears to correlate with survival in early non-small-cell lung cancer (NSCLC), but the prognostic impact of telomere status in advanced NSCLC remains undetermined. Our purpose was to evaluate telomere parameters as prognostic and predictive biomarkers in advanced NSCLC. In 79 biopsies obtained before treatment, we analyzed the telomere length and expression of

Habitat Imaging Biomarkers for Diagnosis and Prognosis in Cancer Patients Infected with COVID-19.

Cancer patients have worse outcomes from the COVID-19 infection and greater need for ventilator support and elevated mortality rates than the general population. However, previous artificial intelligence (AI) studies focused on patients without cancer to develop diagnosis and severity prediction models. Little is known about how the AI models perform in cancer patients. In this study, we aim to develop a computational framework for COVID-19 diagnosis and severity prediction particularly in a cancer population and further compare it head-to-head to a general population. We have enrolled multi-center international cohorts with 531 CT scans from 502 general patients and 420 CT scans from 414 cancer patients. In particular, the habitat imaging pipeline was developed to quantify the complex infection patterns by partitioning the whole lung regions into phenotypically different subregions. Subsequently, various machine learning models nested with feature selection were built for COVID-19 detection and severity prediction. These models showed almost perfect performance in COVID-19 infection diagnosis and predicting its severity during cross validation. Our analysis revealed that models built separately on the cancer population performed significantly better than those built on the general population and locked to test on the cancer population. This may be because of the significant difference among the habitat features across the two different cohorts. Taken together, our habitat imaging analysis as a proof-of-concept study has highlighted the unique radiologic features of cancer patients and demonstrated effectiveness of CT-based machine learning model in informing COVID-19 management in the cancer population.

A Cross-Sectional Study on the Acceptability of Implementing a Lung Cancer Screening Program in Belgium.

Lung cancer is the most common and deadliest cancer in the world, and its incidence is expected to grow. Nonetheless, this growth can be contained through smoking cessation programs and effective lung cancer screening programs. In 2018, Belgium had the seventh highest incidence of lung cancer in the world, with lung cancer incidence accounting for 11.8% of all cancers diagnosed and 23.8% of all cancer-related deaths that same year. The aims of this study were to determine the overall acceptability of a lung cancer screening program in the Flemish population and to determine the main factors that would influence the overall acceptability of such a program. A questionnaire-based cross-sectional study was performed in the Flemish population and distributed online and on paper. The results are presented with the variables of interest and the main outcome, i.e., the acceptability of participating in such a program if implemented. Odds ratios were used to compare acceptability between subgroups. A multivariate regression model was used to determine the key factors that would have the largest impact on the level of acceptability and, thus, on the possible efficiency of such a program. This study estimated that acceptability of participating in a lung cancer screening program was 92%. Irrespective of the smoking status, levels of acceptability were higher than 89%. The key factors which could significantly influence the acceptability of a lung cancer screening program were individuals with low education, low protective factor knowledge and total knowledge, and lung cancer screening reimbursement, which were significantly associated with acceptability (0.01, 0.001, 0.01, and 0.05 respectively). Low protective factor knowledge decreased the log odds of acceptability 3.08-fold. In conclusion, the acceptability of implementing a lung cancer screening program in Flanders seems to be extremely high and would be well received by all. When implementing such a program, policymakers should aim for it to be reimbursed, campaigns should be gender-specific, focused on those with lower educational and socioeconomic status, and there should be investment in increasing total knowledge about lung cancer and knowledge about protective factors.

Radiotherapy Fraction in Limited-Stage Small Cell Lung Cancer in the Modern Era A Systematic Review and Meta-Analysis of 8006 Reconstructed Individual Patient Data.

The optimal thoracic radiotherapy (TRT) dose and fractionation for limited-stage small cell lung cancer (LS-SCLC) using modern techniques remain unclear. We conducted systematic review and meta-analyses of the efficacy and safety differences between definitive hypofractionated TRT (HypoTRT), conventional TRT (ConvTRT) and hyperfractionated TRT (HyperTRT), especially in the modern era. Eligible randomized controlled trials (RCTs), real-world cohorts, and single-arm trials published between 1990 and 2021 were identified. Two meta-analyses of overall survival (OS) were conducted (i) a random-effects meta-analysis based on reconstructed individual-patient data (IPD) of all studies and (ii) a Bayesian network meta-analysis based on study-level aggregated data (AD) of RCTs. The incidences of severe radiation-related toxicities were compared using the random-effects meta-regression model. Overall, 53 of the 30,031 publications met the inclusion criteria, and a total of 8006 IPD were reconstructed. After adjusting for key treatment variables and stratification by study type, there were no significant differences in the OS rates between the altered fractionation regimens (HypoTRT vs. HyperTRT, aHR adjusted HR 1.05, 95% CI 0.93-1.19 ConvTRT vs. HyperTRT, aHR 1.00, 95% CI 0·90-1.11 HypoTRT vs. ConvTRT, aHR 1.05, 95% CI 0.91-1.20). In the modern era, the survival outcomes of all three schedules, while remaining comparable, have improved significantly. Results of the AD-based network meta-analysis were consistent with those of IPD analysis, and HypoTRT was ranked as the best regimen (SUCRA 81%). There were no significant differences in toxicities between groups when using modern radiation techniques. In the modern era, no significant differences in OS or severe radiation-related toxicities were observed between altered schedules in LS-SCLC. HypoTRT may be associated with moderate and non-significant OS improvements, which should be further confirmed in prospective randomized phase III trials.

Tumor Microenvironment before and after Chemoradiation in Locally Advanced Rectal Cancer Beyond PD-L1.

In locally advanced rectal cancer treatment, neoadjuvant concurrent chemoradiation therapy (cCRT) is the standard of care. The tumor microenvironment (TME) is a complex entity comprising of tumor cells, immune cells and surrounding stroma and is closely associated with tumor growth and survival, response to antitumor therapies and also resistance to treatment. We aimed to assess the change in biomarkers associated with TME following standard neoadjuvant cCRT in rectal cancer. We accessed archival tissue from rectal cancer patients treated with neoadjuvant cCRT at Allegheny Health Network (AHN) facilities over the past 14 years. Pre-treatment and post-treatment biopsies were assayed for PD-L1, CD8 T-cells, CXCL9, TIM-3, IDO-1, IFN-G, IL17RE, LAG-3, and OX40 in 41 patients. We found statistically significant upregulation in multiple biomarkers namely CD8, IL17RE, LAG3 and OX40 post neoadjuvant cCRT and a trend towards upregulation, although not statistically significant, in biomarkers PD-L1, CXCL9, TIM-3, IDO-1 and IFN-G expression. This provides a glimpse into the TME before and after neoadjuvant cCRT. We suggest that the biomarkers noted to be upregulated could be used for designing appropriate clinical trials and development of therapeutic targeted drug therapy in an effort to achieve better response to neoadjuvant therapy, increasing clinical and pathological complete response rates and improved overall outcomes.

Mucoepidermoid Carcinoma of the Salivary Gland Demographics and Comparative Analysis in U.S. Children and Adults with Future Perspective of Management.

Salivary gland neoplasms are uncommon in both pediatric and adult populations. Mucoepidermoid carcinoma (MEC) is one of the most common salivary gland tumors and usually presents with atypical clinical features. This study sought to evaluate the demographic and clinical factors affecting outcomes in adults and pediatric populations with MEC that could be used to risk stratification for treatment selection and clinical trial enrollment. Data on 4507 MEC patients were extracted from the Surveillance Epidemiology and End Result (SEER) database (2000-2018). Patients aged ≤ 18 years were classified into the pediatric population, and those older than 18 years were placed in the adult group. Kaplan-Meier survival curves were created to analyze survival probabilities for various independent factors. The pediatric population comprised 3.7% of the entire cohort, with a predominance of females (51.5%), while the adult population constituted 96.3% of the cohort, with a predominance of female patients (52.2%). Caucasians were the predominant race overall (75.3%), while more African Americans were seen in the pediatric group. In tumor size of lt2 cm overall, poorly differentiated tumors with higher metastasis rates were observed more in adults (11.3% and 9.3%) than in the pediatric population (3.0% and 4.8%, Mucoepidermoid carcinoma of the salivary glands primarily affects Whites and is more aggressive in adults than in the pediatric population. Even with surgical resection, the overall survival is poor in the adult population as compared to its pediatric counterparts. Advanced age, larger tumor size, male sex, and lymph node invasion are associated with increased mortality.

Potential Therapeutic Use of Aptamers against HAT1 in Lung Cancer.

Lung cancer is one of the leading causes of death worldwide and the most common of all cancer types. Histone acetyltransferase 1 (HAT1) has attracted increasing interest as a potential therapeutic target due to its involvement in multiple pathologies, including cancer. Aptamers are single-stranded RNA or DNA molecules whose three-dimensional structure allows them to bind to a target molecule with high specificity and affinity, thus making them exceptional candidates for use as diagnostic or therapeutic tools. In this work, aptamers against HAT1 were obtained, subsequently characterized, and optimized, showing high affinity and specificity for HAT1 and the ability to inhibit acetyltransferase activity in vitro. Of those tested, the apHAT610 aptamer reduced cell viability, induced apoptosis and cell cycle arrest, and inhibited colony formation in lung cancer cell lines. All these results indicate that the apHAT610 aptamer is a potential drug for the treatment of lung cancer.

Hepcidin as a Diagnostic Biomarker in Anaemic Lung Cancer Patients.

We aim to describe the characteristics of hepcidin, IL-6, and TNF-α levels in anaemia of lung cancer patients with operative tumour as well as to investigate the potential diagnostic capabilities of hepcidin in combination with IL-6, TNF-α, and acute phase proteins. We present a retrospective study of 112 lung cancer patients (41 women and 71 men) who were surgically treated at the Lower Silesian Centre for Lung Diseases in Wroclaw, Poland. Serum blood samples were collected from all these patients prior to any surgical treatment and used to determine hepcidin, IL-6, TNF-α, SAA

Phase II Trial of the Combination of Alectinib with Bevacizumab in Alectinib Refractory

Anaplastic lymphoma kinase (

Intrinsic and Extrinsic Transcriptional Profiles That Affect the Clinical Response to PD-1 Inhibitors in Patients with Non-Small Cell Lung Cancer.

Using a machine learning method, we investigated the intrinsic and extrinsic transcriptional profiles that affect the clinical response to PD-1 inhibitors in 57 patients with non-small cell lung cancer (NSCLC). Among the top 100 genes associated with the responsiveness to PD-1 inhibitors, the proportion of intrinsic genes in lung adenocarcinoma (LUAD) (69%) was higher than in NSCLC overall (36%) and lung squamous cell carcinoma (LUSC) (33%). The intrinsic gene signature of LUAD (mean area under the ROC curve (AUC) 0.957 and mean accuracy 0.9) had higher predictive power than either the intrinsic gene signature of NSCLC or LUSC or the extrinsic gene signature of NSCLC, LUAD, or LUSC. The high intrinsic gene signature group had a high overall survival rate in LUAD (

Different Tyrosine Kinase Inhibitors Used in Treating EGFR-Mutant Pulmonary Adenocarcinoma with Brain Metastasis and Intracranial Intervention Have No Impact on Clinical Outcomes.

Brain metastasis in patients with non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations is a factor of poor prognosis. We conducted a retrospective study to determine the optimal treatment strategy for EGFR-mutant NSCLC patients with brain metastasis receiving or not receiving intracranial intervention. A total of 186 patients treated with an EGFR TKI were enrolled in the study, and 79 (42%) received intracranial intervention. Patients who received intracranial intervention and those who did not had a similar treatment response rate (RR), progression-free survival (PFS) (median PFS 11.0 vs. 10.0 months,

Tumor Response, Disease Control, and Progression-Free Survival as Surrogate Endpoints in Trials Evaluating Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer Study- and Patient-Level Analyses.

Atypical Response in Metastatic Non-Small Cell Lung Cancer Treated with PD-1PD-L1 Inhibitors Radiographic Patterns and Clinical Value of Local Therapy.

To explore the clinical characteristics, management, and survival outcomes of advanced NSCLC patients treated with PD-1PD-L1 inhibitors who presented with an atypical response (AR). A total of 926 PD-1PD-L1-inhibitor-treated patients with metastatic NSCLC from three academic centers were retrospectively reviewed. All measurable lesions were evaluated by RECIST version 1.1. Fifty-six (6.1%) patients developed AR. The median time to the occurrence of AR was 2.0 months. Patients with no fewer than 3 metastatic organs at baseline were more prone to develop AR in advanced NSCLC ( AR was not an uncommon event in patients with metastatic NSCLC treated with PD-1PD-L1 inhibitors, and it had a comparable prognosis to those with TR. Proper local therapy targeting progressive lesions without discontinuing original PD-1PD-L1 inhibitors may improve patient survival.

Single-Cell Transcriptomic Profiles of Lung Pre-Metastatic Niche Reveal Neutrophil and Lymphatic Endothelial Cell Roles in Breast Cancer.

The establishment of a pre-metastatic niche (PMN) is critical for cancer metastasis. However, it remains unclear as to which phenotypes induce changes in the PMN. Single-cell transcriptomic profiling of all cells of the lung in cancer-bearing MMTV-PyVT mice revealed an increased infiltration of N2-type neutrophils and classical monocytes associated with chronic inflammation notably, lung neutrophils isolated from mice with primary cancer exhibited similar N2-type phenotypes and expressed high levels of inflammatory and angiogenic factors. We also discovered a new cluster of Ki67-upregulated lymphatic endothelial cells (ECs) that activated several cell division-related pathways. Receptor-ligand interactions within the lung potentially mediated PMN formation these were exemplified by the cross talk of lymphatic EC-N2-type neutrophil via S100A6. In vitro study revealed S100A6 impaired EC tight junction and increased the transendothelial migration of neutrophils. Our results highlight the molecular mechanisms that shape lung PMN and inspire preventive strategies for lung metastasis in breast cancer.

Phenotypic Characterization of Circulating Tumor Cells Isolated from Non-Small and Small Cell Lung Cancer Patients.

In the present study, we evaluated the expression of JUNB and CXCR4 in circulating tumor cells (CTCs) of lung cancer patients and investigated whether these proteins have prognostic clinical relevance. Peripheral blood from 30 patients with non-small-cell lung cancer (NSCLC) was filtered using ISET membranes, and cytospins from 37 patients with small-cell lung cancer (SCLC) were analyzed using confocal and VyCAP microscopy. Both JUNB and CXCR4 were expressed in the vast majority of lung cancer patients. Interestingly, the phenotypic patterns differed between NSCLC and SCLC patients the (CKJUNBCXCR4) phenotype was present in 50% of NSCLC vs. 71% of SCLC patients. Similarly, the (CKJUNBCXCR4-) was present in 44% vs. 71%, the (CKJUNB-CXCR4) in 6% vs. 71%, and the (CKJUNB-CXCR4-) phenotype in 38% vs. 84%. In NSCLC, the presence of ≥1 CTCs with the (CKJUNBCXCR4) phenotype was associated with worse progression-free survival (PFS) (

Phytochemical Compounds and Anticancer Activity of

Many of the chemotherapeutic drugs for the treatment of cancer are molecules identified and isolated from plants or their synthetic derivatives. This work aimed to identify the bioactive compounds using LC-MS and GC-MS and to evaluate the anticancer activity of the methanolic extracts of roots, stems, leaves, and flowers from

Immune Response and Effects of COVID-19 Vaccination in Patients with Lung Cancer-COVID Lung Vaccine Study.

Lung cancer patients represent a subgroup of special vulnerability in whom the SARS-CoV-2 infection could attain higher rates of morbidity and mortality. Therefore, those patients were recommended to receive SARS-CoV-2 vaccines once they were approved. However, little was known at that time regarding the degree of immunity developed after vaccination or vaccine-related adverse events, and more uncertainty involved the real need for a third dose. We sought to evaluate the immune response developed after vaccination, as well as the safety and efficacy of SARS-CoV-2 vaccines in a cohort of patients with lung cancer. Patients were identified through the OncologyHematology Outpatient Vaccination Program. Anti-Spike IgG was measured before any vaccine and at 3-6-, 6-9- and 12-15-month time points after the 2nd dose. Detailed clinical data were also collected. In total, 126 patients with lung cancer participated and received at least one dose of the SARS-CoV-2 vaccine. At 3-6 months after 2nd dose, 99.1% of baseline seronegative patients seroconverted and anti-Spike IgG titers went from a median value of 9.45 to 720 UImL. At the 6-9-month time point, titers raised to a median value of 924 UImL, and at 12-15 months, after the boost dose, they reached a median value of 3064 UImL. Adverse events to the vaccine were mild, and no SARS- CoV-2 infection-related deaths were recorded. In this lung cancer cohort, COVID-19 vaccines were safe and effective irrespective of the systemic anticancer therapy. Most of the patients developed anti-Spike IgG after the second dose, and these titers were maintained over time with low infection and reinfection rates with a mild clinical course.

Serum Extracellular Vesicle-Derived microRNAs as Potential Biomarkers for Pleural Mesothelioma in a European Prospective Study.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with a dismal prognosis. Early therapeutic interventions could improve patient outcomes. We aimed to identify a pattern of microRNAs (miRNAs) as potential early non-invasive markers of MPM. In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition cohort, we screened the whole miRNome in serum extracellular vesicles (EVs) of preclinical MPM cases. In a subgroup of 20 preclinical samples collected five years prior MPM diagnosis, we observed an upregulation of miR-11400 (fold change (FC) 2.6, adjusted

EGFR-Tyrosine Kinase Inhibitors Induced Activation of the Autocrine CXCL10CXCR3 Pathway through Crosstalk between the Tumor and the Microenvironment in EGFR-Mutant Lung Cancer.

CXCL10 is a cytokine that is elevated during EGFR-TKI treatment in the tumor microenvironment of lung cancer. Here, we report an original study that the impact of the CXCL10CXCR3 pathway on EGFR-TKI resistance in EGFR-mutant lung cancer through a cytokine array analysis during in vitro coculture with tumor cells and activated PBMCs treated with EGFR-TKI, as well as the serial analysis of CXCL10 in EGFR-mutant lung cancer transgenic mice during EGFR-TKI treatment. In EGFR-mutant tumor cells cocultured with activated PBMCs, EGFR-TKI treatment increased CXCL10 in the supernatant this activated CXCR3 in the tumor cells to induce the phosphorylation of Src and the NF-κB subunit, p65, and the expression of HIF-1α. CXCL10 siRNA treatment of EGFR-mutant tumor cells also decreased CXCL10 in the supernatant from coculturing with activated PBMCs, suggesting that the effects of CXCL10 occur via autocrine and paracrine pathways. Importantly, elevated CXCL10CXCR3 signaling was recapitulated in a transgenic lung cancer mouse model. Our results show that increased CXCL10 levels during early EGFR-TKI treatment stimulate oncogenic signaling of persistent tumor cells to contribute to EGFR-TKI resistance via autocrine and paracrine pathways.

Targeted Therapy with PI3K, PARP, and WEE1 Inhibitors and Radiotherapy in HPV Positive and Negative Tonsillar Squamous Cell Carcinoma Cell Lines Reveals Synergy while Effects with APR-246 Are Limited.

Human papillomavirus positive (HPV

Immunodeficiencies Push Readmissions in Malignant Tumor Patients A Retrospective Cohort Study Based on the Nationwide Readmission Database.

Immunodeficiency diseases (IDDs) are associated with an increased proportion of cancer-related morbidity. However, the relationship between IDDs and malignancy readmissions has not been well described. Understanding this relationship could help us to develop a more reasonable discharge plan in the special tumor population. Using the Nationwide Readmissions Database, we established a retrospective cohort study that included patients with the 16 most common malignancies, and we defined two groups non-immunodeficiency diseases (NOIDDs) and IDDs. To identify whether the presence or absence of IDDs was associated with readmission, we identified 603,831 patients with malignancies at their time of readmission in which 0.8% had IDDs and in which readmission occurred in 47.3%. Compared with NOIDDs, patients with IDDs had a higher risk of 30-day (hazard ratio (HR) of 1.32 95% CI of 1.25-1.40), 90-day (HR of 1.27 95% CI of 1.21-1.34) and 180-day readmission (HR of 1.28 95% CI of 1.22-1.35). More than one third (37.9%) of patients with IDDs had readmissions that occurred within 30 days and most (82.4%) of them were UPRs. An IDD was an independent risk factor for readmission in patients with colorectal cancer (HR of 1.32 95% CI of 1.01-1.72), lung cancer (HR of 1.23 95% CI of 1.02-1.48), non-Hodgkins lymphoma (NHL) (HR of 1.16 95% CI of 1.04-1.28), prostate cancer (HR of 1.45 95% CI of 1.07-1.96) or stomach cancer (HR of 2.34 95% CI of 1.33-4.14). Anemia (44.2%), bacterial infections (28.6%) and pneumonia (13.9%) were the 30-day UPR causes in these populations. (4) Conclusions IDDs were independently associated with higher readmission risks for some malignant tumors. Strategies should be considered to prevent the causes of readmission as a post discharge plan.

Potent Anticancer Activity of CXCR4-Targeted Nanostructured Toxins in Aggressive Endometrial Cancer Models.

Patients with advanced endometrial cancer (EC) show poor outcomes. Thus, the development of new therapeutic approaches to prevent metastasis development in high-risk patients is an unmet need. CXCR4 is overexpressed in EC tumor tissue, epitomizing an unexploited therapeutic target for this malignancy. The in vitro antitumor activity of two CXCR4-targeted nanoparticles, including either the

Impact of Infections in Patients Receiving Pembrolizumab-Based Therapies for Non-Small Cell Lung Cancer.

Immune checkpoint inhibitor (ICI) therapy has significantly improved outcomes across a range of malignancies. While infections are a well-known contributor to morbidity and mortality amongst patients receiving systemic chemotherapy regimens, little is known about the impact of infections on patients receiving ICI therapy. This study aims to assess incidence, risk factors, and outcomes in patients who develop infections while on pembrolizumab-based therapies for non-small cell lung cancer (NSCLC). Patients receiving pembrolizumab for stage IIIIV NSCLC from 112017-812021 across seven hospitals were identified. Incidence and type of infection were characterized. Covariates including baseline demographics, treatment information, treatment toxicities, and immunosuppressive use were collected and compared between infected and non-infected patients. Outcomes included the rate of infections, all-cause hospital admissions, median number of treatment cycles, overall survival (OS), and progression free survival (PFS). Univariable and multivariable analysis with reported odds ratio (OR) and 95% confidence intervals (CI) were utilized to evaluate infection risks. OS and PFS were analyzed by Kaplan-Meier analysis and tested by log-rank test. There were 243 NSCLC patients that met the inclusion criteria. Of these, 111 (45.7%) had one documented infection, and 36 (14.8%) had two or more. Compared to non-infected patients, infected patients had significantly more all-cause Emergency Department (ED) 37 (33.3%) vs. 26 (19.7%), Infections occurred in nearly half of patients receiving pembrolizumab-based therapies for NSCLC. Infected patients had frequent hospitalizations, treatment delays, and poorer survival. ECOG status and anti-infective use at ICI initiation conferred a higher infection risk. Infection prevention and control strategies are needed to ameliorate the risk for infections in patients receiving ICIs.

Nanoplatform for the Delivery of Topotecan in the Cancer Milieu An Appraisal of its Therapeutic Efficacy.

Chemotherapy has been the predominant treatment modality for cancer patients, but its overall performance is still modest. Difficulty in penetration of tumor tissues, a toxic profile in high doses, multidrug resistance in an array of tumor types, and the differential architecture of tumor cells as they grow are some of the bottlenecks associated with the clinical usage of chemotherapeutics. Recent advances in tumor biology understanding and the emergence of novel targeted drug delivery tools leveraging various nanosystems offer hope for developing effective cancer treatments. Topotecan is a topoisomerase I inhibitor that stabilizes the transient TOPO I-DNA cleavable complex, leading to single-stranded breaks in DNA. Due to its novel mechanism of action, TOPO is reported to be active against various carcinomas, namely small cell lung cancer, cervical cancer, breast cancer, and ovarian cancer. Issues of cross-resistance with numerous drugs, rapid conversion to its inactive form in biological systems, appended adverse effects, and higher water solubility limit its therapeutic efficacy in clinical settings. Topotecan nanoformulations offer several benefits for enhancing the therapeutic action of this significant class of chemotherapeutics. The likelihood that the target cancer cells will be exposed to the chemotherapeutic drug while in the drug-sensitive s-phase is increased due to the slow and sustained release of the chemotherapeutic, which could provide for a sustained duration of exposure of the target cancer cells to the bioavailable drug and result in the desired therapeutic outcome. This article explores nanoenabled active and passive targeting strategies and combinatorial therapy employing topotecan to ameliorate various cancers, along with a glimpse of the clinical studies utilizing the said molecule.

A Comprehensive Analysis of the Effects of Key Mitophagy Genes on the Progression and Prognosis of Lung Adenocarcinoma.

The aim of our study was to perform a comprehensive analysis of the gene expression, copy number variation (CNV) and mutation of key mitophagy genes in the progression and prognosis of lung adenocarcinoma (LUAD). We obtained the data from The Cancer Genome Atlas (TCGA). Clustering analysis was performed to stratify the mitophagy related groups. The least absolute shrinkage and selection operator (LASSO) based cox model was used to select hub survival genes. An independent validation cohort was retrieved from Gene Expression Omnibus database. We found 24 out of 27 mitophagy genes were aberrantly expressed between tumor and normal samples. CNV gains were associated with higher expression of mitophagy genes in 23 of 27 mitophagy genes. The clustering analysis identified high and low risk mitophagy groups with distinct survival differences. The high risk mitophagy groups had higher tumor mutation burden, stemness phenotype, total CNVs and lower CD4 T cells infiltration. Drugs targeted to high risk mitophagy groups were identified including the PI3KAKTmTOR inhibitor, HDAC inhibitor and chemotherapy agents such as cisplatin and gemcitabine. In addition, the differentially expressed genes (DEGs) were identified between mitophagy groups. Further univariate Cox analysis of each DEG and subsequent LASSO-based Cox model revealed a mitophagy-related prognostic signature. The risk score model of this signature showed a strong ability to predict the overall survival of LUAD patients in training and validation datasets. In conclusion, the mitophagy genes played an important role in the progression and prognosis of LUAD, which might provide useful information for the treatment of LUAD.

Non-Coding RNAs in Airway Diseases A Brief Overview of Recent Data.

Inflammation of the human lung is mediated in response to different stimuli (e.g., physical, radioactive, infective, pro-allergenic, or toxic) such as cigarette smoke and environmental pollutants. These stimuli often promote an increase in different inflammatory activities in the airways, manifesting themselves as chronic diseases (e.g., allergic airway diseases, asthma chronic bronchitischronic obstructive pulmonary disease, or even lung cancer). Non-coding RNA (ncRNAs) are single-stranded RNA molecules of few nucleotides that regulate the gene expression involved in many cellular processes. ncRNA are molecules typically involved in the reduction of translation and stability of the genes of mRNAs s. They regulate many biological aspects such as cellular growth, proliferation, differentiation, regulation of cell cycle, aging, apoptosis, metabolism, and neuronal patterning, and influence a wide range of biologic processes essential for the maintenance of cellular homeostasis. The relevance of ncRNAs in the pathogenetic mechanisms of respiratory diseases has been widely established and in the last decade many papers were published. However, once their importance is established in pathogenetic mechanisms, it becomes important to further deepen the research in this direction. In this review we describe several of most recent knowledge concerning ncRNA (overall miRNAs) expression and activities in the lung.

Co-Targeting Luminal B Breast Cancer with S-Adenosylmethionine and Immune Checkpoint Inhibitor Reduces Primary Tumor Growth and Progression, and Metastasis to Lungs and Bone.

Breast cancer (BCa) is the most prevalent cancer in females and has a high rate of mortality, especially due to increased metastasis to skeletal and non-skeletal sites. Despite the marked clinical accomplishment of immune checkpoint inhibitor (CPI) therapy in patients with several cancers, it has had limited success in luminal subtypes of BCa. Accordingly, recent efforts have focused on combination therapy with CPI, including epigenetic modulators, to increase response rates of CPI in luminal BCa. We have previously shown that S-adenosylmethionine (SAM), the ubiquitous methyl donor, has strong anti-cancer effects in various cancers, including all subtypes of BCa. In the current study, we took a novel approach and examined the effect of CPI alone and in combination with SAM on tumor growth and metastasis in a syngeneic mouse model of luminal B BCa. We showed that SAM decreases cell proliferation, colony-formation (survival), and invasion of luminal B BCa cell lines (Eo771, R221A) in vitro. In in vivo studies, in Eo771 tumor-bearing mice, either SAM or anti-PD-1 antibody treatment alone significantly reduced tumor growth and progression, while the SAManti-PD-1 combination treatment had the highest anti-cancer efficacy of all groups. The SAManti-PD-1 combination reduced the percentage of animals with lung metastasis, as well as total metastatic lesion area, compared to control. Additionally, the SAManti-PD-1 combination significantly reduced the skeletal lesion area and protected tibial integrity to a greater extent than the monotherapies in an Eo771 bone metastasis model. Transcriptome analysis of Eo771 primary tumors revealed significant downregulation of pro-metastatic genes, including Matrix metalloproteinases (MMPs) and related pathways. On the other hand, CD8

Timosaponin AIII Inhibits Migration and Invasion Abilities in Human Cervical Cancer Cells through Inactivation of p38 MAPK-Mediated uPA Expression In Vitro and In Vivo.

Cervical cancer is one of the most common gynecologic cancers globally that require novel approaches. Timosaponin AIII (TSAIII) is a steroidal saponin that displays beneficial effects in antitumor activities. However, the effect of TSAIII on human cervical cancer remains unknown. In this study, we found that TSAIII showed no influence on cell viability, cytotoxicity, cell cycle distribution and apoptosis induction in human cervical cancer cells. TSAIII was revealed to have a significant inhibitory effect on cell migration and invasion through the downregulation of invasion-related uPA expression and p38 MAPK activation in both human cervical cancer cells and cervical cancer stem cells (CCSCs), indicating that the p38 MAPK-uPA axis mediated the TSAIII-inhibited capacity of cellular migration and invasion. In a synergistic inhibition assay, a TSAIII plus p38 siRNA cotreatment revealed a greater inhibition of uPA expression, migration and invasion in human cervical cancer cells. In an immunodeficient mouse model, TSAIII significantly inhibited lung metastases from human cervical cancer SiHa cells without TSAIII-induced toxicity. These findings first revealed the inhibitory effects of TSAIII on the progression of human cervical cancer through its downregulation of p38 MAPK-uPA axis activation. Therefore, TSAIII might provide a potential strategy for auxiliary therapy in human cervical cancer.

Evolutionary Analysis of TCGA Data Using Over- and Under- Mutated Genes Identify Key Molecular Pathways and Cellular Functions in Lung Cancer Subtypes.

We identify critical conserved and mutated genes through a theoretical model linking a genes fitness contribution to its observed mutational frequency in a clinical cohort. Passenger gene mutations do not alter fitness and have mutational frequencies determined by gene size and the mutation rate. Driver mutations, which increase fitness (and proliferation), are observed more frequently than expected. Non-synonymous mutations in essential genes reduce fitness and are eliminated by natural selection resulting in lower prevalence than expected. We apply this evolutionary triage principle to TCGA data from

Anti-Oxidant and Pro-Oxidant Effects of Peroxiredoxin 6 A Potential Target in Respiratory Diseases.

Peroxiredoxin 6 (PRDX6) is widely distributed in several organs, especially the lungs. The role of PRDX6 in oxidative stress is controversial and even contradictory, as indicated by research conducted over the past 20 years. PRDX6 has anti-oxidant or pro-oxidant effects on oxidative stress in different diseases. It can even exhibit both anti-oxidant and pro-oxidant effects in the same disease. These findings are attributed to the fact that PRDX6 is a multifunctional enzyme. The peroxidase and phospholipase A2 activity of PRDX6 is closely related to its anti-oxidant and pro-oxidant effects, which leads to the conflicting regulatory effects of PRDX6 on oxidative stress in respiratory diseases. Moreover, PRDX6 interacts with multiple redox signaling pathways to interfere with cell proliferation and apoptosis. PRDX6 has become a new target in respiratory disease research due to its important regulatory role in oxidative stress. In this paper, the role of PRDX6 in oxidative stress in respiratory diseases and the research progress in targeting PRDX6 are reviewed.

Oral Squamous Cell Carcinoma Cells with Acquired Resistance to Erlotinib Are Sensitive to Anti-Cancer Effect of Quercetin via Pyruvate Kinase M2 (PKM2).

Oral squamous cell carcinoma (OSCC) frequently carries high epidermal growth factor receptor (EGFR) expression. Erlotinib, a small molecule tyrosine kinase inhibitor (TKI), is an effective inhibitor of EGFR activity however, resistance to this drug can occur, limiting therapeutic outcomes. Therefore, in the current study, we aimed to unveil key intracellular molecules and adjuvant reagents to overcome erlotinib resistance. First, two HSC-3-derived erlotinib-resistant cell lines, ERL-R5 and ERL-R10, were established both exhibited relatively higher growth rates, glucose utilization, epithelial-mesenchymal transition (EMT), and invasiveness compared with parental cells. Cancer aggressiveness-related proteins, such as N-cadherin, Vimentin, Twist, MMP-2, MMP-9, and MMP-13, and the glycolytic enzymes PKM2 and GLUT1 were upregulated in ERL-R cells. Notably, ERL-R cells were sensitive to quercetin, a naturally-existing flavonol phytochemical with anti-cancer properties against various cancer cells. At a concentration of 5 μM, quercetin effectively arrested cell growth, reduced glucose utilization, and inhibited cellular invasiveness. An ERL-R5-derived xenograft mouse model confirmed the growth-inhibitory efficacy of quercetin. Additionally, knock-down of PKM2 by siRNA mimicked the effect of quercetin and re-sensitized ERL-R cells to erlotinib. Furthermore, adding quercetin blocked the development of erlotinib-mediated resistance by enhancing apoptosis. In conclusion, our data support the application of quercetin in anti-erlotinib-resistant OSCC and indicate that PKM2 is a determinant factor in erlotinib resistance and quercetin sensitivity.

Relationship between Tumor Infiltrating Immune Cells and Tumor Metastasis and Its Prognostic Value in Cancer.

Tumor metastasis is an important reason for the difficulty of tumor treatment. Besides the tumor cells themselves, the tumor microenvironment plays an important role in the process of tumor metastasis. Tumor infiltrating immune cells (TIICs) are one of the main components of TME and plays an important role in every link of tumor metastasis. This article mainly reviews the role of tumor-infiltrating immune cells in epithelial mesenchymal transformation, extracellular matrix remodeling, tumor angiogenesis and formation of pre-metastatic niche. The value of TIICs in the prognosis of cervical cancer, lung cancer and breast cancer was also discussed. We believe that accurate prognosis of cancer treatment outcomes is conducive to further improving treatment regimens, determining personalized treatment strategies, and ultimately achieving successful cancer treatment. This paper elucidates the relationship between tumor and TIICs in order to explore the function of immune cells in different diseases and provide new ideas for the treatment of cancer.

The Structure, Function and Regulation of Protein Tyrosine Phosphatase Receptor Type J and Its Role in Diseases.

Protein tyrosine phosphatase receptor type J (PTPRJ), also known as DEP-1, HPTPη, or CD148, belongs to the R3 subfamily of receptor protein tyrosine phosphatases (RPTPs). It was first identified as an antioncogene due to its protein level being significantly downregulated in most epithelial tumors and cancer cell lines (e.g., colon, lung, thyroid, breast, and pancreas). PTPRJ regulates mouse optic nerve projection by inhibiting the phosphorylation of the erythropoietin-producing hepatocellular carcinoma (Eph) receptor and abelson murine leukemia viral oncogene homolog 1 (c-Abl). PTPRJ is crucial for metabolism. Recent studies have demonstrated that PTPRJ dephosphorylates JAK2 at positions Y813 and Y868 to inhibit leptin signaling. Akt is more phosphorylated at the Ser473 and Thr308 sites in

Mesenchymal Stem Cells in Radiation-Induced Pulmonary Fibrosis Future Prospects.

Radiation-induced pulmonary fibrosis (RIPF) is a general and fatal side effect of radiotherapy, while the pathogenesis has not been entirely understood yet. By now, there is still no effective clinical intervention available for treatment of RIPF. Recent studies revealed mesenchymal stromal cells (MSCs) as a promising therapy treatment due to their homing and differentiation ability, paracrine effects, immunomodulatory effects, and MSCs-derived exosomes. Nevertheless, problems and challenges in applying MSCs still need to be taken seriously. Herein, we reviewed the mechanisms and challenges in the applications of MSCs in treating RIPF.

Volume-Outcome Relationship in Cancer Survival Rates Analysis of a Regional Population-Based Cancer Registry in Japan.

There is limited data on the relationship between hospital volumes and outcomes with respect to cancer survival in Japan. The primary objective of this study was to evaluate the effect of hospital volume on cancer survival rate using a population-based cohort database. Using the Kanagawa cancer registry, propensity score matching was employed to create a dataset for each cancer type by selecting 11 matches for cases from high- and other-volume hospitals. The 5-year survival rate was estimated and the hazard ratio (HR) for hospital volume was calculated using a Cox proportional hazard model. Additional analyses were performed limited to cancer patients who underwent surgical operation, chemotherapy, and other treatments in each tumor stage and at the time of diagnosis. The number of cases with complete data, defined as common cancers (prostate, kidney, bladder, esophagus, stomach, liver, pancreas, colon, breast, and lung), was 181,039. Adjusted HR differed significantly among hospital volume categories for the most common cancers except bladder, and the trends varied according to cancer type. The HR ranged from 0.76 (95%CI, 0.74-0.79) for stomach cancer to 0.85 (0.81-0.90) for colon cancer. This study revealed that a relationship may exist between hospital volume and cancer survival in Japan.

Oncologic Outcome after Pulmonary Metastasectomy as Part of Multidisciplinary Treatment in a Tertiary Oncological Center.

(1) Background Pulmonary metastases are encountered in approximately one-third of patients with malignancies, especially from colorectal, lung, breast, and renal cancers, and sarcomas. Pulmonary metastasectomy is the ablative approach of choice, when possible, as part of the multidisciplinary effort to integrate and personalize the oncological treatment. (2) Methods The study includes 58 consecutive cases of pulmonary metastasectomies, retrospectively analyzed, performed in 12 consecutive months, in which the pathology reports confirmed lung metastases. (3) Results Most frequent pathological types of metastases were 14 of colorectal cancer, 10 breast, 8 lung, and 8 sarcomas. At the time of primary cancer diagnosis, 14 patients (24.14%) were in the metastatic stage. The surgical approach was minimally invasive through uniportal VATS (Video-Assisted Thoracic Surgery) in 34 of cases (43 patients, 74%). Almost 20% of resections were typical (lobectomy, segmentectomy). Lymphadenectomy was associated in almost 12 of patients and lymph node metastases were found in 11.11% of cases. The mortality rate (intraoperative and 90 days postoperative) is zero. The OS after pulmonary metastasectomy is 87% at 18 months, and the estimated OS for cancer is 90% at 5 years. The worst outcome presents the patients with sarcomas and the best outcome-colorectal and lung cancer. The patients with 1 or 2 resected metastases presented 96% survival at 24 months. (4) Conclusions After pulmonary metastasectomy, survival is favored by the small number of metastases resected (1 or 2), and by the dimension of metastases under 20.5 mm. The non-anatomic (wedge) type of lung resection may present a lower risk of death compared to lobectomy. No statistical significance on survival has the presence of lymphadenectomy, the laterality rightleft lung, the upperlower lobes. In the future, longer follow-up and prospective randomized trials are needed for drawing definitive conclusions.

Right Ventricle and Radiotherapy More Questions than Answers.

The injury of the left ventricle (LV) during anticancer therapy has long been recognized, and guidelines recommend a specific set of parameters for determination of LV impairment. The influence of anticancer therapy on the right ventricle (RV) has been insufficiently investigated, and there are only a few studies that have considered the effect of radiotherapy on RV remodeling. On the other hand, large number of patients with different types of cancers located in the chest are treated with radiotherapy, and the negative clinical effects of this treatment such as accelerated coronary artery disease, valve degeneration and heart failure have been documented. The anatomical position of the RV, which is in the front of the chest, is responsible for its large exposure during radiation treatment, particularly in patients with left-sided breast and lung cancers and mediastinal cancers (hematological malignancies, esophagus cancers, thymomas, etc.). For the same reason, but also due to its anatomical complexity, the RV remains under-investigated during echocardiographic examination, which remains the cornerstone of cardiac imaging in everyday practice. In the last decade many new echocardiographic imaging techniques that enable better evaluation of RV structure, function and mechanics appeared, and they have been used in detection of early and late signs of RV injuries in oncological patients. These investigations are related to some important restrictions that include limited numbers of patients, used parameters and imaging techniques. Many questions about the potential impact of these changes and possible predictions of adverse events remain to be evaluated in future large longitudinal studies. The current body of evidence indicates an important role of radiotherapy in RV remodeling, and therefore, the aim of this review is to summarize currently available data regarding RV changes in patients with various oncological conditions and help clinicians in the assessment of possible cardiac damage.

The Feasibility of Interventional Pulmonology Methods for Detecting the T790M Mutation after the First or Second-Generation EGFR-TKI Resistance of Non-Small Cell Lung Cancer.

The development of third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) targeting T790M-mutant non-small cell lung cancer (NSCLC) has raised the importance of re-biopsy after EGFR-TKI failure. This study aimed to investigate the feasibility of interventional pulmonology (IP) procedures as re-biopsy methods for identifying the T790M mutation in EGFR-TKI-resistant patients. One hundred and thirty-nine NSCLC patients who underwent IP procedures for re-biopsy as their initial investigation after EGFR-TKI treatment failure were enrolled in this study between January 2020 and August 2022. All patients underwent a first re-biopsy with IP methods, with a diagnostic yield of 81.2% and T790M mutation detection rate of 36%. Thirty patients underwent a second re-biopsy IP methods were used for 17 (56.6%) patients and non-IP methods for 13 (43.4%) patients the T790M mutation detection rate was 36.4%. Only six patients underwent a third re-biopsy no T790M mutation was noted. The T790M mutation detection rate did not differ between IP and non-IP methods (33.6 % vs. 37.5%,

The Role of Positron Emission Tomography and Computed Tomographic (PETCT) Imaging for Radiation Therapy Planning A Literature Review.

PETCT is revolutionising radiotherapy treatment planning in many cancer sites. While its utility has been confirmed in some cancer sites, and is used in routine clinical practice, it is still at an experimental stage in many other cancer sites. This review discusses the utility of PETCT in cancer sites where the role of PETCT has been established in cases such as head and neck, cervix, brain, and lung cancers, as well as cancer sites where the role of PETCT is still under investigation such as uterine, ovarian, and prostate cancers. Finally, the review touches on PETCT utilisation in Africa.

Genetic, DNA methylation, and immune profile discrepancies between early-stage single primary lung cancer and synchronous multiple primary lung cancer.

To explore the possible carcinogenesis and help better diagnose and treat patients with synchronous multiple primary lung cancers (sMPLC), we systematically investigated the genetic and DNA methylation profiles of early-stage sMPLC and single primary lung cancer (SPLC) and explored the immune profiles in the tumor microenvironment. Hundred and ninety-one patients with 191 nodules in the SPLC group and 132 patients with 295 nodules in the sMPLC group were enrolled. All the samples were subjected to wide panel-genomic sequencing. Genome-wide DNA methylation was assessed using the Infinium Human Methylation 850 K BeadChip. RNA-seq and CIBERSORT analyses were performed to identify the immune characteristics in these two groups. Lesions from sMPLC patients had lower TMB levels than that from SPLC patients. sMPLC had a similar genetic mutational landscape with SPLC, despite some subgroup genetic discrepancies. Distinct DNA methylation patterns were identified between the two groups. The differentially methylated genes were related to immune response pathways. RNA-seq analyses revealed more immune-related DEGs in sMPLC. Accordingly, more immune-related biological processes and pathways were identified in sMPLC. Aberrant DNA methylation was associated with the abnormal expression of immune-related genes. CIBERSORT analysis revealed the infiltration of immune cells was different between the two groups. Our study for the first time demonstrated genetic, epigenetic, and immune profile discrepancies between sMPLC and SPLC. Relative to the similar genetic mutational landscape, the DNA methylation patterns and related immune profiles were significantly different between sMPLC and SPLC, indicating their essential roles in the initiation and development of sMPLC.

The miR-15b-Smurf2-HSP27 axis promotes pulmonary fibrosis.

Heat shock protein 27 (HSP27) is overexpressed during pulmonary fibrosis (PF) and exacerbates PF however, the upregulation of HSP27 during PF and the therapeutic strategy of HSP27 inhibition is not well elucidated. We have developed a mouse model simulating clinical stereotactic body radiotherapy (SBRT) with focal irradiation and validated the induction of RIPF. HSP25 (murine form of HSP27) transgenic (TG) and LLC1-derived orthotropic lung tumor models were also used. Lung tissues of patients with RIPF and idiopathic pulmonary fibrosis, and lung tissues from various fibrotic mouse models, as well as appropriated cell line systems were used. Public available gene expression datasets were used for therapeutic response rate analysis. A synthetic small molecule HSP27 inhibitor, J2 was also used. HSP27 expression with its phosphorylated form (pHSP27) increased during PF. Decreased mRNA expression of SMAD-specific E3 ubiquitin-protein ligase 2 (Smurf2), which is involved in ubiquitin degradation of HSP27, was responsible for the increased expression of pHSP27. In addition, increased expression of miRNA15b was identified with decreased expression of Smurf2 mRNA in PF models. Inverse correlation between pHSP27 and Smurf2 was observed in the lung tissues of PF animals, an irradiated orthotropic lung cancer models, and PF tissues from patients. Moreover, a HSP27 inhibitor cross-linked with HSP27 protein to ameliorate PF, which was more effective when targeting the epithelial to mesenchymal transition (EMT) stage of PF. Our findings identify upregulation mechanisms of HSP27 during PF and provide a therapeutic strategy for HSP27 inhibition for overcoming PF.

EOAI, a ubiquitin-specific peptidase 5 inhibitor, prevents non-small cell lung cancer progression by inducing DNA damage.

Targeting deubiquitinases (DUBs) has emerged as a promising avenue for anticancer drug development. However, the effect and mechanism of pan-DUB inhibitor EOAI on non-small cell lung cancer (NSCLC) remains to be studied. The expression of ubiquitin-specific peptidase 5 (USP5) in NSCLC was evaluated by immunohistochemistry. The effect of the USP5 inhibitor, EOAI, on NSCLC cell growth and cell cycle was evaluated by CCK-8 and PI staining. Apoptosis was detected by Annexin V-FITCPI double staining. Autophagy was examined by LC3 immunofluorescence. Comet assay and γ-H2AX immunofluorescence staining were used to detect DNA damage, and Western blotting was used to detect the expression of apoptosis, cycle, autophagy and DNA damage-related proteins. In vivo experiments demonstrated the effect of EOAI on NSCLC. We also found that USP5 was significantly upregulated in NSCLC tissues in this study. In addition, we show that EOAI can cause DNA damage in NSCLC cells while modulating the transcriptional activity of P53, thereby inducing cell cycle arrest in NSCLC cells, autophagy and apoptosis. In vivo experiments have shown that EOAI can inhibit tumors and synergistically enhance the anti-tumor effect of cisplatin. USP5-mediated epigenetic regulation of oncogenes promotes the occurrence of NSCLC, which provides ideas for developing potential targeted therapy.

Prognostic value of pretherapeutic FDG PETCT in non-small cell lung cancer with pulmonary lymphangitic carcinomatosis.

Pulmonary lymphangitic carcinomatosis (PLC) is associated with a poor prognosis in patients with non-small cell lung cancer (NSCLC). We sought to determine prognostic value of pretherapeutic fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography (PET)computed tomography (CT) in NSCLC with radiologically diagnosed PLC. We retrospectively reviewed 50 NSCLC patients with radiologically diagnosed PLC. Among eight clinical variables and five imaging parameters, metabolic PLC burden, which represents the overall tumor burden of PLC, and cPLC, which represents the location and extent of PLC in a three-grade system, were used. In multivariate analyses for progression-free survival, metabolic PLC burden (P 0.0181), cPLC (P 0.0401), and clinical stage (P 0.0284) were identified as independent prognostic factors. High metabolic PLC burden had a worse prognosis, and the prognosis of cPLC3 was significantly worse than that of cPLC1 or cPLC2. In univariate analyses for overall survival, only age (P 0.0073) was identified a prognostic factor. In conclusion, FDG PETCT parameters were identified as independent prognostic factors in NSCLC with radiologically diagnosed PLC. Furthermore, a combination of anatomical and metabolic information about PLC obtained using FDG PETCT provides insight into the overall tumor burden of PLC and is useful in predicting prognosis.

Benignant and malignant epidemiology among surgical resections for suspicious solitary lung cancer without preoperative tissue diagnosis.

The aim of this study was to describe the epidemiology of patients undergoing diagnostic andor curative surgical pulmonary resections for lung opacities suspected of being localized primary lung cancers without preoperative tissue confirmation. We performed a single-centre retrospective study of a prospectively implemented institutional database of all patients who underwent pulmonary resection between January 2010 and December 2020. Patients were selected when surgery complied with the Fleischner society guidelines. We performed a multivariable logistic regression to determine the preoperative variables associated with malignancy. Among 1392 patients, 213 (15.3%) had a final diagnosis of benignancy. We quantified futile parenchymal resections in 29 (2.1%) patients defined by an anatomical resection of >2 lung segments for benign lesions that did not modified the clinical management. Compared with patients with malignancies, patients with benignancies were younger (57.5 vs 63.9 years, P < 0.001), had lower preoperative risk profile (thoracoscore 0.4 vs 2.1, P < 0.001), had a higher proportion of wedge resection (50.7% vs 12.2%, P < 0.01) and experienced a lower burden of postoperative complication (Clavien-Dindo IV or V, 0.4% vs 5.6%, P < 0.001). Preoperative independent variables associated with malignancy were (adjusted odd ratio 95% confident interval) age 1.02 1.00 1.04, smoking (year-pack) 1.005 (1.00 1.01), history of cardiovascular disease 2.06 1.30 3.30, history of controlled cancer 2.74 1.30 6.88 and clinical N involvement 4.20 1.11 37.44. Futile parenchymal lung resection for suspicious opacities without preoperative tissue diagnosis is rare (2.1%) while surgery for benign lesions represented 15.3% and has a satisfactory safety profile with very low postoperative morbi-mortality.

Postoperative radiotherapy with modern techniques does not improve survival for operable stage IIIA-N2 non-small cell lung cancer.

This study aims to evaluate whether postoperative radiotherapy using newer techniques (intensity-modulated radiotherapy IMRT) is associated with improved survival for patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) who underwent complete resection. The overall survival of patients with stage IIIA-N2 NSCLC who received postoperative IMRT versus no postoperative IMRT following induction chemotherapy and lobectomy in the National Cancer Database from 2010-2018 was assessed via Kaplan-Meier analysis, Cox proportional hazards analysis and propensity score-matched analysis. Additional survival analyses were also conducted in patients with completely resected stage IIIA-pN2 NSCLC who had upfront lobectomy (without induction therapy) followed by adjuvant chemotherapy alone or adjuvant chemotherapy with postoperative IMRT. Only patients receiving IMRT, which is a newer, more conformal radiotherapy technique, were included. Patients with positive surgical margins were excluded. A total of 3203 patients with stage IIA-N2 NSCLC who underwent lobectomy were included. Five hundred eighty-eight (18.4%) patients underwent induction chemotherapy followed by lobectomy, and 2615 (82%) underwent lobectomy followed by chemotherapy. In unadjusted, multivariable-adjusted, and propensity score--matched analyses, there were no significant differences in overall survival between the patients who also received postoperative IMRT versus those who did not. In this national analysis, the use of postoperative IMRT was not associated with improved survival in patients with completely resected stage IIIA-N2 NSCLC with or without induction chemotherapy.

Outcomes Following Treatment with FOLFOX for Patients with Resectable or Potentially Resectable Metastatic Colorectal Cancer A Population-based Cohort Study.

To evaluate the safety and effectiveness of oxaliplatin-based combination chemotherapy for patients with metastatic colorectal cancer (mCRC) to extrahepatic sites. We conducted a population-based retrospective study examining the safety and effectiveness of perioperative oxaliplatin for resectable or potentially resectable colorectal metastases in Ontario, Canada. Outcomes were also compared with patients with liver-only metastases. Patients received oxaliplatin for mCRC between 1 January 2013 and 30 June 2020. In total, 192 patients had extrahepatic metastases. Seventy per cent had R0 metastasectomy. The 3-year disease-free survival and overall survival were 62% and 79%, respectively <4% of patients died within 60 days of metastasectomy and 74-90% of patients received treatment according to recommendations from a multidisciplinary setting. Compared with liver-only controls (n 1306), patients had mCRC to the lung only (n 115), lung and liver (n 55) and liver with non-pulmonary site (n 22). Extrahepatic metastases were more likely to be found for patients whose primary colorectal resection had positive margins (14% versus 7%, P 0.005) and primary tumours located in the rectum odds ratio 4.01 (2.31-6.97). After adjustment, there was no difference in overall survival between liver-only controls and patients with lung-only hazard ratio 0.82 (0.59-1.15) or liver and lung metastases hazard ratio 1.26 (0.85-1.87) (P 0.24). In total, 79115 (69%) of patients with lung-only metastases had a metastasectomy compared with 6451306 (49%) and 1555 (27%) of patients with liver-only and liver and lung metastases, respectively. Hospital visits were similar between patients with liver-only and extrahepatic metastases. Oxaliplatin-based chemotherapy for patients with resectable or potentially resectable mCRC with extrahepatic metastases was safe and resulted in similar outcomes in appropriately selected patients when compared with patients with liver-only metastases.

BRACHY A Randomized Trial to Evaluate Symptom Improvement in Advanced Non-Small Cell Lung Cancer Treated With External Beam Radiation With or Without High-Dose-Rate Intraluminal Brachytherapy.

Uncontrolled studies suggest that the addition of high-dose-rate intraluminal brachytherapy (HDRIB) to external beam radiation therapy (EBRT) may improve palliation for patients with advanced non-small cell lung cancer (NSCLC). The purpose of this study was to evaluate the potential clinical benefit of adding HDRIB to EBRT in a multicenter randomized trial. Patients with symptomatic stage III or IV NSCLC with endobronchial disease were randomized to EBRT (20 Gy in 5 daily fractions over 1 week or 30 Gy in 10 daily fractions over 2 weeks) or the same EBRT plus HDRIB (14 Gy in 2 fractions separated by 1 week). The primary outcome was the proportion of patients who achieved symptomatic improvement in patient-reported overall lung cancer symptoms on the Lung Cancer Symptom Scale (LCSS) at 6 weeks after randomization. Secondary outcomes included improvement in individual symptoms, symptom-progression-free survival, overall survival, and toxicity. The planned sample size was 250 patients based on detection of symptomatic improvement from 40% to 60% with a 2-sided α of .05 and 80% power. A total of 134 patients were randomized over 4.5 years 67 to each arm. The study closed early owing to slow accrual. The mean age was 69.8 years, and 67% of patients had metastatic disease. At 6 weeks, 19 patients (28.4%) in the EBRT arm and 20 patients (29.9%) in the EBRT plus HDRIB arm experienced an improvement in lung cancer symptoms (P .84). When limited to patients who completed the LCSS, percentages were 40.4% versus 47.6%, respectively (P .49). Between group differences in mean change scores (0.3-0.5 standard deviations) in favor of EBRT plus HDRIB were observed for overall symptoms, but only hemoptysis was significantly improved (P .03). No significant differences were observed in progression-free or overall survival. Grade 34 toxicities were similar between groups. Small to moderate improvements were seen in symptom relief with the combined therapy, but they did not reach statistical significance. Further research is necessary before recommending HDRIB in addition to EBRT for palliation of lung cancer symptoms.

Corylin inhibits the progression of Non-small cell lung cancer cells by regulating NF-κB signaling pathway via targeting p65.

Lung cancer is characterized by high-risk and high mortality, among which non-small cell lung cancer (NSCLC) conquers a dominant position. Previous studies have reported that corylin has anti-inflammatory, anti-oxidant, and anti-tumor effects however, its role in NSCLC cells remains unclear. Corylin inhibits the progression of NSCLC cells. A lentivector NF-κB luciferase reporter was constructed by molecular cloning. Corylin was screened and identified as an NF-κB pathway inhibitor by luciferase reporter assay. Corylin inhibited the expression of NF-κB downstream genes, which was detected by qRT-PCR. The effect of corylin on NSCLC cells was detected by colony formation assay, cell apoptosis, cell proliferation, in vitro invasion, and cell scratch assay. Corylin inhibited p65 nuclear translocation and was detected by molecular docking, immunofluorescence assay, and Western blot analysis. We constructed a lentiviral expression vector, containing an NF-κB luciferase reporter and established a stable A549 cell line for its expression. Using this cell line, corylin was screened and identified as an NF-κB pathway inhibitor. It was found that corylin inhibited the expression of NF-κB downstream genes and inhibited the proliferation and migration of NSCLC cells. Meanwhile, it was also found that corylin significantly reversed the increased proliferation of NSCLC cell lines induced by p65 overexpression. Molecular docking analysis showed that corylin could bind to p65 by hydrogen bonding. Further study showed that corylin inhibited the NF-κB signaling pathway by blocking p65 nuclear translocation. Our study screened and identified corylin as an NF-κB inhibitor and elucidated the molecular mechanism by which corylin inhibits the growth of NSCLC cells. The present study provides a novel strategy for improving the prognosis and treatment of NSCLC patients.

Programmed death ligand-1 expression and its association with the degree of differentiation and the presence of necrosis in non-small cell lung carcinoma.

The mechanisms underlying the expression of programmed death ligand-1 (PD-L1) in non-small cell lung carcinoma (NSCLC) are not yet fully clarified. In this study, surgical resections of 730 lung cancer patients with diagnosed NSCLC were analyzed. Results of PD-L1 immunohistochemistry (using clone 22C3) were correlated with clinicopathological variables including the degree of tumor differentiation and the presence of confluent areas of coagulative necrosis. PD-L1 immunohistochemistry was analyzed in tumor cells, whereas PD-L1 positivity was defined as membranous staining in ≥ 1 of tumor cells. A significantly higher proportion of PD-L1 positive cases was noted in poorly differentiated (grade 3) adenocarcinomas compared to better differentiated (grade 1 and grade 2) subtypes (63.8 % vs. 28.7 % p < 0.001). Contrary to this, better differentiated (keratinizing) and less differentiated (non-keratinizing) squamous cell carcinoma subtypes were found to have a similar proportion of PD-L1 positive cases (51.4 % vs. 55.8 % p 0.570). High levels of PD-L1 expression significantly correlated with the presence of necrosis in NSCLC seventy-nine of 109 NSCLC cases with the presence of necrosis were PD-L1 positive compared to 256 out of 621 NSCLC without necrosis (72.5 % vs. 41.2 % p < 0.001). High PD-L1 expression was not positively correlated with age, gender, and advanced T stage but a significant association between PD-L1 positivity and higher N stage was observed (p < 0.001) in NSCLC patients. In conclusion, the proportion of PD-L1 positive cases is higher only in poorly differentiated NSCLC of the adenocarcinoma type. A significantly higher overall rate of PD-L1 positive cases was noted in NSCLC with the presence of necrosis. Further investigation is suggested to elucidate the intricated interconnections between the plethora of hypoxic biomarkers and immunological factors in different types and subtypes of NSCLC.

Interventions to improve lung cancer screening among racially and ethnically minoritized groups A scoping review.

Lung cancer screening (LCS) decreases lung cancer related mortality among high-risk people who smoke cigarettes and has been endorsed by the US Preventive Services Task Force (USPSTF) since 2013. However, adoption of LCS has been limited, and disparities in LCS among racially and ethnically minoritized groups have become apparent. While recommendations to improve disparities in LCS have been made, there is a lack of information on how these recommendations have been implemented and their relative effectiveness in improving screening disparities. This scoping review addresses this knowledge gap by examining interventions that have been implemented to improve LCS among racially and ethnically minoritized groups in the United States. A comprehensive search of MEDLINE (via PubMed), EMBASE (via Elsevier), CINAHL Complete (via EBSCO), and Scopus (via Elsevier), for articles from the period 1 January 2010 through 22 October 2021 was completed. Out of 17,045 references screened, only 11 studies describing an intervention to improve disparities in LCS were identified, underscoring the dearth of data on established interventions. The interventions discussed could be categorized into three groups -- patient level (n 3), clinicinstitution level (n 3), and community level (n 5) interventions. Of those studies reporting effectiveness data (n 8), there was substantial heterogeneity in the outcomes measured and their relative effectiveness. We found that interventions which streamlined the LCS process at the level of a single clinic or institution were the most effective in improving LCS. Community-level interventions that focused on engagement and education had the greatest potential to target racially and ethnically minoritized groups. Our study underscores the need for more robust research on addressing barriers to LCS by identifying effective patient, clinic, and community-level interventions to improve LCS disparities and the need for potential standardization of intervention effectiveness outcomes.

Molecular characteristics and prognostic factors of leptomeningeal metastasis in non-small cell lung cancer.

Non-small cell lung cancer with leptomeningeal metastasis (NSCLC-LM) is emerging as a new management challenge for oncologists and is associated with poor prognosis. This study aimed to investigate the molecular characteristics and prognostic factors of NSCLC-LM. This retrospective study included 97 patients with NSCLC-LM between January 2015 and October 2021. Progression-free survival (PFS) and overall survival (OS) were evaluated. Gene mutations were detected by next-generation sequencing (NGS). The median PFS and OS were 8.4 (95 % confidence interval CI 4.839-11.901) and 14.0 (95 % CI 9.254-18.746) months, respectively. Sixty-seven patients harboured epidermal growth factor receptor-mutated (EGFRm) L858R (34), 19del (29), T790M (13), and G719C with L861Q (1). Other mutations included ALK (5), ROS1 (3), KRAS (1), TP53 (14), MET amplification (6). The detection rate and types of circulating tumour DNA (ctDNA) in the cerebrospinal fluid (CSF) samples were higher than the paired plasma samples. Patients with EGFR mutations had a longer median OS than those without mutations (19.0 vs. 13.0 months, P 0.015). Patients with gene mutations had shorter median OS than those without mutations, such as ALK (11.8 vs. 19.9 months, P 0.014), ROS1 (12.7 vs. 19.8 months, P 0.014), KRAS (4.0 vs. 19.0 months, P 0.005), TP53 (15.0 vs. 19.0 months, P 0.014), and MET amplification (6.0 vs. 19.0 months, P 0.003). Multivariate analysis indicated that MET amplification was an independent predictor of poor survival. Along with Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 3, LM accompanied with brain parenchymal metastasis (BPM), extracranial disease, and seizures were independent predictors of poor survival, whereas intrathecal chemotherapy, and third-generation EGFR-TKIs were independent predictors of favorable survival. CSF ctDNA detected using NGS had a high sensitivity for NSCLC-LM, showing high potential in detecting driver and drug-resistant gene mutations. Genomic profiles, combined with clinically relevant prognostic factors, will guide individualised treatments and improve the outcomes of NSCLC-LM patients.

Severinia buxifolia-isolated acridones inhibit lung cancer invasion and decrease HIFα protein synthesis involving 5UTR-mediated translation inhibition.

Lung cancer is one of the most common cancers worldwide and is by far the leading cause of cancer death attributed to its rapid metastasis and poor prognosis. Given that hypoxia-inducible factors (HIFs) are associated with cancer metastasis, discovering agents to inhibit HIF-mediated invasive cancer is highly desired. This study aimed to investigate the natural acridone compounds isolated from Severinia buxifolia for the potential to delay hypoxia-induced lung cancer invasiveness by HIF inhibition. Using a hypoxia-responsive element (HRE) luciferase reporter, cell migration and invasion assays, real-time PCR, Western blot, and DNA recombinant clones, compound effect on HIF activity, cancer metastasis, HIF-1α mRNA transcription, HIFs protein stability, and HIF-1α translation were observed under hypoxia conditions. Atalaphyllidine (Sbs-A) and atalaphyllinine (Sbs-B) were found to show the most potent effects on HIF transcriptional activity and HIF-1α protein expression in NSCLC cell line A549, although Sbs-A and Sbs-B might not attribute decreasing HIF-1α mRNA expression to potent inhibition of HIF activity. HIF-1α protein stability was not affected by Sbs-A also, prolyl hydroxylase and proteasome inhibitors could not reverse the inhibitory effect from compounds. Furthermore, 3 - 10 μM low concentrations of Sbs-A inhibited HIF target gene expression, gelatin zymography activity, and A549 cancer invasion. Ultimately, Sbs-A inhibited HIF-1α 5UTR-mediated translation independent of oxygen concentration, underlying the mechanism of compounds inhibiting HIF-1α protein expression. Our study proposed Severinia buxifolia-isolated acridone compounds inhibited 5-mRNA HIFA-mediated translation and provided evidence supporting the ability of acridone compounds in targeting HIFα for delayed lung cancer metastasis.

Inhibition of STAT3 signaling contributes to the anti-melanoma effects of chrysoeriol.

Melanoma is an aggressive malignancy with a high mortality rate. Signal transducer and activator of transcription 3 (STAT3), an oncoprotein, is considered as an effective target for treating melanoma. Chrysoeriol is a flavonoid compound, and possesses anti-tumor activity in lung cancer, breast cancer and multiple myeloma while whether it has anti-melanoma effects is still not known. Chrysoeriol has been shown to restrain STAT3 signaling in an inflammation mouse model. In this study, the anti-melanoma effects of chrysoeriol and the involvement of STAT3 signaling in these effects were investigated. CCK8 assays, 5-ethynyl-2-deoxyuridine (EdU) staining, Annexin V-FITCPI staining, Western blot analyses of cleaved caspase-9 and wound healing assays were used to study the anti-melanoma effects of chrysoeriol in cell models. A B16F10 melanoma bearing mouse model was used to evaluate the in vivo anti-melanoma effects of chrysoeriol. Indicators of cell proliferation, cell apoptosis and angiogeneis in melanoma tissues were detected by immunohistochemistry (IHC) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Immune cells in melanoma tissues were analyzed by flow cytometry. STAT3-overactivated cell models were used to investigate the involvement of STAT3 signaling in the anti-melanoma effects of chrysoeriol. Molecular dynamics (MD) simulations and surface plasmon resonance (SPR) assays were conducted to determine whether chrysoeriol binds to Src, an upstream kinase of STAT3. The results of cell experiments showed that chrysoeriol dose-dependently inhibited viability, proliferation and migration of, and induced apoptosis in, A375 and B16F10 melanoma cells. Chrysoeriol inhibited the phosphorylation of STAT3, and downregulated the expression of STAT3-target genes involved in melanoma growth and metastasis. Mouse studies showed that chrysoeriol restrained melanoma growth and tumor-related angiogenesis, and altered compositions of immune cells in melanoma microenvironment. Chrysoeriol also inhibited STAT3 signaling in B16F10 allografts. Chrysoeriols viability-inhibiting effects were attenuated by over-activating STAT3 in A375 cells. Furthermore, chrysoeriol bound to the protein kinase domain of Src, and suppressed Src phosphorylation in melanoma cells and tissues. This study, for the first time, demonstrates that chrysoeriol has anti-melanoma effects, and these effects are partially due to inhibiting STAT3 signaling. Our findings indicate that chrysoeriol has the potential to be developed into an anti-melanoma agent.

Formosanin C inhibits non-small-cell lung cancer progression by blocking MCT4CD147-mediated lactate export.

Tumor cells reprogram their metabolic network to maintain their uncontrolled proliferation, metastasis, and resistance to cancer therapy. Treatments targeting abnormal cellular metabolism may have promising therapeutic effects. Formosanin C (FC), a diosgenin derived from the rhizoma of Paris polyphylla var. yunnanensis, has shown potent anti-cancer activities against various cancer types. However, the effect of FC on cancer metabolism remains to be elucidated. In this research, we aimed to elucidate FCs effect and potential mechanisms on metabolism in lung cancer. Colony formation, transwell cell migration, and apoptosis were detected in multiple NSCLC cell lines to assess the cytotoxicity of FC. FC significantly inhibited monoclonal formation and migration and induced cell cycle arrest and apoptosis in NSCLC cells. FC altered the abundances of 12 metabolites in lung cancer cells and 3 metabolites in the medium. These differential metabolites are primarily involved in glycolysis, citric acid cycle, and glutathione pathways. Notably, there was a remarkable increase in intracellular lactate and a reduction in extracellular lactate after FC treatment. Mechanically, FC downregulated the expression of MCT4 and CD147, blocking the export of lactate. Furthermore, FC also evoked mitochondrial dysfunction coupled with excessive oxidative stress, decreased mitochondrial membrane potential, ATP production reduction, glutathione depletion, and Ca FC inhibits lung cancer growth by the novel mechanism in which MCT4CD147-mediated inhibition of lactate transport and disruption of mitochondrial functions are involved.

Andrographolide promoted ferroptosis to repress the development of non-small cell lung cancer through activation of the mitochondrial dysfunction.

Ferroptosis, a form of regulated cell death by lipid peroxidation, was currently considered as a key factor affecting the occurrence and progression in various cancers. Andrographolide (ADE), a major effective ingredient of Andrographis paniculate, has proven to have a substantial anti-tumor effect on multiple cancer types. However, the function and underlying mechanism of ADE in Non-Small Cell Lung Cancer remain unclear. CCK8 assay, colony-formation assay, flow cytometry, scratch test, transwell assay, western blotting, ferroptosis analysis and mitochondria analysis were performed to reveal the role and underlying mechanisms of ADE in NSCLC cell lines (H460 and H1650). In vivo, xenograft model and lung metastatic model were performed to verify the effect of ADE on the growth and metastasis of NSCLC. In this present study, we demonstrated that treatment with ADE could inhibit cell growth and metastases through eliciting ferroptosis in vitro an in vivo. The IC50 of ADE in H460 and H1650 cells were 33.16 μM and 32.45 μM respectively. In Lewis xenografted animals, i.p. ADE repressed relative tumor growth (p < 0.01) and inhibited metastases (p < 0.01). Notably, the ferroptosis inhibitor Fer-1 abrogated the anti-tumor capacity of ADE. Induction of ferroptosis by ADE was confirmed by elevated levels of reactive oxygen sepsis (ROS), glutathione (GSH), malondialdehyde (MDA), intracellular iron content and lipid ROS reduced glutathione (GSH) accumulation (p < 0.01). Furthermore, ADE inhibited the expression of ferroptosis-related protein GPX4 and SLC7A11. Simultaneously, it also disclosed that ADE enhanced mitochondrial dysfunction, as evidenced by increased mitochondrial ROS release, mitochondrial membrane potential (MMP) depolarization, and decreased mitochondrial ATP. Most interestingly, Mito-TEMPO, a mitochondria-targeted antioxidant, rescued ADE-induced ferroptosis. Our data validated that ADE treatment could restrain proliferation and metastases of NSCLC cells through induction of ferroptosis via potentiating mitochondrial dysfunction.

Efficacy and mechanism study of cordycepin against brain metastases of small cell lung cancer based on zebrafish.

Small cell lung cancer (SCLC) is an aggressive tumor with high brain metastasis (BM) potential. There has been no significant progress in the treatment of SCLC for more than 30 years. Cordycepin has shown the therapeutic potential for cancer by modulating multiple cellular signaling pathways. However, the effect and mechanism of cordycepin on anti-SCLC BM remain unknown. In this study, we focused on the anti-SCLC BM effect of cordycepin in the zebrafish model and its potential mechanism. A SCLC xenograft model based on zebrafish embryos and in vitro cell migration assay were established. Cordycepin was administrated by soaking and microinjection in the zebrafish model. RNA-seq assay was performed to analyze transcriptomes of different groups. Geno Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were performed to reveal the underlying mechanism. Real-time qPCR was used to verify the effects of cordycepin on the key genes. Cordycepin showed lower cytotoxicity in vitro compared with cisplatin, anlotinib and etoposide, but showed comparable anti-proliferation and anti-BM effects in zebrafish SCLC xenograft model. Cordycepin showed significant anti-SCLC BM effects when administrated by both soaking and microinjection. RNA-seq demonstrated that cordycepin was involved in vitamin D metabolism, lipid transport, and proteolysis in cellular protein catabolic process pathways in SCLC BM microenvironment in zebrafish, and was involved in regulating the expressions of key genes such as cyp24a1, apoa1a, ctsl. The anti-BM effect of cordycepin in SCLC was mediated by reversing the expression of these genes. Our work is the first to describe the mechanism of cordycepin against SCLC BM from the perspective of regulating the brain microenvironment, providing new evidence for the anti-tumor effect of cordycepin.

Membrane Protein Modification Modulates Big and Small Extracellular Vesicle Biodistribution and Tumorigenic Potential in Breast Cancers In Vivo.

Extracellular vesicles (EVs) are released by cells to mediate intercellular communication under pathological and physiological conditions. While small EVs (sEVs <100-200 nm, exosomes) are intensely investigated, the properties and functions of medium and large EVs (big EVs (bEVs) >200 nm, microvesicles) are less well explored. Here, bEVs and sEVs are identified as distinct EV populations, and it is determined that bEVs are released in a greater bEVsEV ratio in the aggressive human triple-negative breast cancer (TNBC) subtype. PalmGRET, bioluminescence-resonance-energy-transfer (BRET)-based EV reporter, reveals dose-dependent EV biodistribution at nonlethal and physiological EV dosages, as compared to lipophilic fluorescent dyes. Remarkably, the bEVs and sEVs exhibit unique biodistribution profiles, yet individually promote in vivo tumor growth in a syngeneic immunocompetent TNBC breast tumor murine model. The bEVs and sEVs share mass-spectrometry-identified tumor-progression-associated EV surface membrane proteins (tpEVSurfMEMs), which include solute carrier family 29 member 1, Cd9, and Cd44. tpEVSurfMEM depletion attenuates EV lung organotropism, alters biodistribution, and reduces protumorigenic potential. This study identifies distinct in vivo property and function of bEVs and sEVs in breast cancer, which suggest the significant role of bEVs in diseases, diagnostic and therapeutic applications.

Co-design of a cancer nutrition care pathway by patients, carers, and health professionals the CanEAT pathway.

Limited practical resources exist to guide optimal nutrition care for patients, carers, and health professionals (HPs). This study aimed to co-design a cancer nutrition care pathway to guide and improve the provision of consistent, evidence-based care with consumers and HPs. This study utilised an experienced-based co-design (EBCD) approach over five stages. Stage 1 involved stakeholder engagement and a literature review. Stage 2 included a survey and focus groups with patientscarers. Co-design workshops were conducted within stage 3, key stakeholder consultation within stage 4, and the finalisation and dissemination of the cancer nutrition care pathway formed stage 5. Results of stages 3 to 5 are the focus of this paper. Two co-design workshops were held with patients, carers, and HPs (n 32 workshop 1 n 32 workshop 2), who collectively agreed on areas of focus and key priorities. Following this, a consultation period was completed with patients, carers, and HPs (n 45) to refine the pathway. The collective outcome of all study stages was the co-design of a cancer nutrition care pathway (the CanEAT pathway) defining optimal cancer nutrition care that combines evidence-based practice tips into a centralised suite of resources, tools, and clinical guidance. The CanEAT pathway was co-designed by patients, carers, and HPs. The EBCD approach is a meaningful way to develop targeted improvements in cancer care. The CanEAT pathway is freely available to guide and support patients, carers, and HPs to aid the implementation of optimal nutrition care into clinical practice.

Prognosis of male lung cancer patients with urinary cancer a study from a national population-based analysis.

Lung cancer accounts for the most cancer-related deaths in the world. Our previous study suggested the improved survival of lung cancer patients, mainly female patients, with subsequent metachronous primary breast cancer. However, whether the survival advantages of the two primaries are associated with patients sex and the specific breast cancer is unclear. Whether male lung cancer patients with another primary may encounter the same survival advantage as female patients is also uncertain. The uncertainty hinders these patients from the potential benefit of lung cancer clinical trial. A total of 343 male lung adenocarcinoma patients with subsequent bladder papillary transitional cell carcinoma (LCBC), 1539 lung adenocarcinoma patients with prior bladder papillary transitional cell carcinoma (BCLC), 1181 lung adenocarcinoma patients with subsequent prostate adenocarcinoma (LCPC), 7426 lung adenocarcinoma patients with prior prostate adenocarcinoma (PCLC), and patients with single bladderprostatelung (SLC) cancer were identified from the Surveillance, Epidemiology, and End Results. Patients were classified into simultaneous two primary cancer (sTPC), metachronous two primary cancer 1 (mTPC1), or mTPC2 groups when interval time between two cancers was within 6 months, between 7 and 60 months, or over 60 months, respectively. Propensity matching score program was executed to match the two primary cancers with single primary. Cox regression and competing risk regression were performed to identify confounders associated with all-cause and cancer-specific survival, respectively. The major cancer-related and non-cancer-related death in the two primaries were lung cancer and heart disease, respectively. Median overall survival times since lung primary of LCBC and SLC were 97 and 17 months, respectively, and incidence of all-cause and cancer-specific death in LCBC since lung malignancy was significantly lower (Coef. - 1.24, 95% CI - 1.49 to 0.99 SHR 0.42, 95% CI 0.33-0.53). Among the categorized groups, prognosis values of sTPC and mTPC2 groups were not statically different from that of the matched single lung cancer, whereas increased overall survival time and decreased incidence of all-cause and cancer-specific death relative to the matched patients were observed in mTPC1 group (H.R 0.28, 95% CI 0.19-0.41 SHR 0.33, 95% CI 0.23-0.47). Similar prognosis of LCPC relative to SLC was also observed. Furthermore, a generally improved survival relative to SLC was observed in PCLC (median survival times of PCLC and SLC were 17 and 12 months, respectively Coef. - 0.32, 95% CI - 0.43 to 0.22 SHR 0.77, 95% CI 0.69-0.85), whereas prognosis of BCLC was similar to the matched ones. These results hinted that survival of lung cancer patients might vary with prior cancer history. Further analysis among groups with the two primaries suggested that advanced bladder cancer was not associated with prognosis of patients with LCBC and BCLC. On the contrary, advanced prostate cancer was associated with all-cause and cancer-specific death in patients with PCLC but not in patients with LCPC. Compared with patients with single lung cancer, male lung cancer patients with subsequent bladderprostate primary over 6 months experienced generally improved survival. These results were similar to our previous study regarding female lung cancer patients with another breast primary. On the contrary, male lung cancer patients with prior primary malignancy encountered varied prognosis improved survival relative to single lung primary was observed in lung cancer with prior prostate cancer, whereas prognosis of lung cancer with prior bladder cancer was not different. Therefore, great attention was required to characterize prognosis of lung cancer patients with another primary in advance, which was essential to eliminate the potential bias when these patients were included into the clinical trials.

Mesenchymal stem cell-derived extracellular vesicles transfer miR-598 to inhibit the growth and metastasis of non-small-cell lung cancer by targeting THBS2.

Non-small-cell lung cancer (NSCLC) is the subtype of lung cancer, which accounts for about 85% of diagnosed lung cancer cases, and is without any effective therapy. Emerging evidence has revealed microRNA-598 (miR-598) as potential therapeutic target and diagnostic marker of NSCLC. In the present study, we sought to define the role of mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) containing miR-598 in NSCLC. Co-culture experiments were conducted to examine the secretion of miR-598 by MSCs and the uptake of EVs by NSCLC cells. The expression of miR-598 in NSCLC cell lines, tissues, and MSC-derived EVs was detected by the RT-qPCR. After treatment with MSCs-EVs, CCK-8 and Transwell assays were adopted to evaluate the effects of miR-598 on proliferation, migration, and invasion capacities of NSCLC cells. Finally, the effects of miR-598 on tumor growth and metastasis were further validated in vivo through subcutaneous tumorigenesis and experimental pulmonary metastasis in nude mice. We found that MSCs-derived EVs could deliver miR-598 into NSCLC cells, where miR-598 specifically targeted and bound with mRNA of THBS2 to inhibit its translational process. By suppressing the promoting effects of THBS2 on the proliferation, migration, and invasion of NSCLC cells, the EV treatment reduced the progression of NSCLC. Notably, these inhibitory effects were reversed by concomitantly overexpressing THBS2. Overall, we find that MSCs-derived EVs containing miR-598 targets THBS2 to inhibit the proliferation and migration of NSCLC cells in vivo and in vitro.

Cervicothoracic junction instrumentation strategies following separation surgery for spinal metastases.

The cervicothoracic junction (CTJ) is a challenging region to stabilize after tumor resection for metastatic spine disease. The objective of this study was to describe the outcomes of patients who underwent posterolateral decompression and instrumented fusion (i.e., separation surgery across the CTJ for instability due to metastatic disease). The authors performed a single-institution retrospective study of a prospectively collected cohort of patients who underwent single-approach posterior decompression and instrumented fusion across the CTJ for metastatic spine disease between 2011 and 2018. Adult patients (≥ 18 years old) who presented with mechanical instability, myelopathy, and radiculopathy secondary to metastatic epidural spinal cord compression (MESCC) of the CTJ (C7-T1) from 2011 to 2018 were included. Seventy-nine patients were included, with a mean age of 62.1 years. The most common primary malignancies were non-small cell lung (n 17), renal cell (11), and prostate (8) carcinoma. The median number of levels decompressed and construct length were 3 and 7, respectively. The average operative time, blood loss, and length of stay were 179.2 minutes, 600.5 ml, and 7.7 days, respectively. Overall, 58 patients received adjuvant radiation, and median dose, fractions, and time from surgery were 27 Gy, 3 fractions, and 20 days, respectively. All patients underwent lateral mass and pedicle screw instrumentation. Forty-nine patients had tapered rods (4.05.5 mm or 3.55.5 mm), 29 had fixed-diameter rods (3.5 mm or 4.0 mm), and 1 had both. Ten patients required anterior reconstruction with poly-methyl-methacrylate. The overall complication rate was 18.8% (6 patients with wound-related complications, 7 with hardware-related complications, 1 with both, and 1 with other). For the 8 patients (10%) with hardware failure, 7 had tapered rods, all 8 had cervical screw pullout, and 1 patient also experienced rodscrew fracture. The average time to hardware failure was 146.8 days. The 2-year cumulative incidence rate of hardware failure was 11.1% (95% CI 3.7%-18.5%). There were 55 deceased patients, and the median (95% CI) overall survival period was 7.97 (5.79-12.60) months. For survivors, the median (range) follow-up was 12.94 (1.94-71.80) months. Instrumented fusion across the CTJ demonstrated an 18.8% rate of postoperative complications and an 11% overall 2-year rate of hardware failure in patients who underwent metastatic epidural tumor decompression and stabilization.

Stratifying non-small cell lung cancer patients using an inverse of the treatment decision rules validation using electronic health records with application to an administrative database.

To validate a stratification method using an inverse of treatment decision rules that can classify non-small cell lung cancer (NSCLC) patients in real-world treatment records. (1) To validate the index classifier against the TNM 7th edition, we analyzed electronic health records of NSCLC patients diagnosed from 2011 to 2015 in a tertiary referral hospital in Seoul, Korea. Predictive accuracy, stage-specific sensitivity, specificity, positive predictive value, negative predictive value, F1 score, and c-statistic were measured. (2) To apply the index classifier in an administrative database, we analyzed NSCLC patients in Korean National Health Insurance Database, 2002-2013. Differential survival rates among the classes were examined with the log-rank test, and class-specific survival rates were compared with the reference survival rates. (1) In the validation study (N 1375), the overall accuracy was 93.8% (95% CI 92.5-95.0%). Stage-specific c-statistic was the highest for stage I (0.97, 95% CI 0.96-0.98) and the lowest for stage III (0.82, 95% CI 0.77-0.87). (2) In the application study (N 71,593), the index classifier showed a tendency for differentiating survival probabilities among classes. Compared to the reference TNM survival rates, the index classification under-estimated the survival probability for stages IA, IIIB, and IV, and over-estimated it for stages IIA and IIB. The inverse of the treatment decision rules has a potential to supplement a routinely collected database with information encoded in the treatment decision rules to classify NSCLC patients. It requires further validation and replication in multiple clinical settings.

Temperature variability and common diseases of the elderly in China a national cross-sectional study.

In the context of climate change, it has been well observed that short-term temperature variability (TV) could increase the overall and cause-specific mortality and morbidity. However, the association between long-term TV and a broader spectrum of diseases is not yet well understood, especially in the elderly. Our study used data from the fourth Urban and Rural Elderly Population (UREP) study. Long-term TV was calculated from the standard deviation (SD) of daily minimum and maximum temperatures within the study periods (2010-2014, 2011-2014, 2012-2014, 2013-2014, and 2014). Ten self-reported diseases and conditions were collected by questionnaire, including cataract, hypertension, diabetes, cardio-cerebrovascular diseases, stomach diseases, arthritis, chronic lung disease, asthma, cancer, and reproductive diseases. The province-stratified logistic regression model was used to quantify the association between long-term TV and the prevalence of each disease. A total of 184,047 participants were included in our study. In general, there were significant associations between TV and the prevalence of most diseases at the national level. Cardio-cerebrovascular disease (OR 1.16, 95% CI 1.13, 1.20) generated the highest estimates, followed by stomach diseases (OR 1.15, 95% CI 1.10, 1.19), asthma (OR 1.14, 95% CI 1.06, 1.22), chronic lung diseases (OR 1.08, 95% CI 1.03, 1.13), arthritis (OR 1.08, 95% CI 1.05, 1.11), and cataract (OR 1.06, 95% CI 1.02, 1.10). Moreover, the associations varied by geographical regions and across subgroups stratified by sex, household income, physical activity, and education. Our study showed that long-term exposure to TV was associated with the prevalence of main diseases in the elderly. More attention should be paid to the elderly and targeted strategies should be implemented, such as an early warning system.

The anti-estrogen receptor drug, tamoxifen, is selectively Lethal to P-glycoprotein-expressing Multidrug resistant tumor cells.

P-glycoprotein (P-gp), a member of the ATP Binding Cassette B1 subfamily (ABCB1), confers resistance to clinically relevant anticancer drugs and targeted chemotherapeutics. However, paradoxically P-glycoprotein overexpressing drug resistant cells are collaterally sensitive to non-toxic drugs that stimulate its ATPase activity. Cell viability assays were used to determine the effect of low concentrations of tamoxifen on the proliferation of multidrug resistant cells (CHO In this report, we show that P-gp-expressing drug resistant cells (CHO This study demonstrates the use of tamoxifen as collateral sensitivity drug that can preferentially target multidrug resistant cells expressing P-gp at clinically achievable concentrations. Given the widespread use of tamoxifen in the treatment of estrogen receptor-positive breast cancers, this property of tamoxifen may have clinical applications in treatment of P-gp-positive drug resistant breast tumors.

RBM10 recruits METTL3 to induce N6-methyladenosine-MALAT1-dependent modification, inhibiting the invasion and migration of NSCLC.

Previous studies have shown that RNA binding motif 10 (RBM10) is a potential tumor suppressor protein that can inhibit proliferation and promote apoptosis of non-small cell lung cancer (NSCLC). Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays an important role in promoting the development of lung cancer. Inhibiting its m6A methylation can effectively inhibit the invasion and metastasis of lung cancer. There is concern that RBM10 could affect MALAT1 m6A methylation for the invasion and migration of NSCLC. Transwell and wound healing assays showed that RBM10 significantly inhibited the invasion and migration of NSCLC. CLIP-Seq showed that among all RBM10 binding RNAs, MALAT1 had the highest binding peak among all non-coding RNAs. RNA immunoprecipitation verified the direct combination of RBM10 and MALAT1. The rescue experiment confirmed that RBM10 affected the phosphorylation of the PI3KAKTmTOR pathway protein as well as the invasion and migration ability by regulating MALAT1. MeRIP-qPCR confirmed that RBM10 could inhibit the MALAT1 m6A methylation level by recruiting Methyltransferase Like 3 (METTL3). The study suggests that RBM10, as an RNA-binding protein, may inhibit the m6A methylation of MALAT1 by recruiting METTL3 and affecting phosphorylation of the downstream PI3KAKTmTOR pathway by binding and regulating MALAT1, ultimately affecting the invasion and migration of NSCLC.

The first case report of Paragonimus westermani infection diagnosed by transbronchial lung cryobiopsy.

We report a case of pulmonary paragonimiasis diagnosed by transbronchial lung cryobiopsy (TBLC). TBLC is likely to be a superior method to transbronchial forceps biopsy because TBLC can get larger specimens, resulting in a higher chance of containing the eggs. A male patient aged 57 years presented with hemoptysis and dyspnea on exertion. His initial chest computed tomography scans showed a cavitary nodule with a peripheral ground-glass appearance, leading to a prescription of an oral antibiotic, with an initial assumption of pneumonia. A follow-up chest computed tomography, however, revealed an appearance of a new nodule adjacent to the original nodule. TBLC and transbronchial forceps biopsy were done to rule out lung cancer and eventually, the eggs of Paragonimus westermani were found using TBLC. Praziquantel was prescribed, showing improvements in symptoms and chest X-ray findings. TBLC has more potential to be utilized as a diagnostic method than transbronchial forceps biopsy because it has a better chance to confirm pulmonary paragonimiasis, which can be initially suspected as pulmonary tuberculosis or lung cancer.

Importance of Lymph Node Evaluation in ≤2-cm Pure-Solid Non-Small Cell Lung Cancer.

The prevalence of lymph node (LN) metastasis in small-sized lung cancer varies depending on the tumor size and proportion of ground-glass opacity. We investigated occult LN metastasis and prognosis in patients with small-sized non-small cell lung cancer (NSCLC), mainly focusing on the pure-solid tumor. We retrospectively reviewed patients with ≤2-cm clinical N0 NSCLC who underwent lung resection with curative intent from 2003 to 2017. Among them we analyzed patients who also underwent adequate complete systematic LN dissection. Pathologic results and disease-free survival of the radiologically mixed ground-glass nodule (mGGN) and pure-solid nodule (PSN) groups were analyzed. Of 1329 patients analyzed, 591 had mGGNs and PSNs. As tumor size increased, patients in the mGGN group showed no difference in LN metastasis ≤1 cm, 2.27% 1.0 to 1.5 cm, 2.19% and 1.5 to 2.0 cm, 2.18% (P .999). However the PSN group showed a significant difference in LN metastasis as the tumor size increased ≤1 cm, 2.67% 1.0 to 1.5 cm, 12.46% and 1.5 to 2.0 cm, 21.31% (P < .001). In the multivariate analysis tumor size was a significant predictor of nodal metastasis in the PSN group but not in the mGGN group. In terms of 5-year disease-free survival, the mGGN group showed a better prognosis than the PSN group (94.4% vs 71.2%, P < .001). We need to conduct a thorough LN dissection during surgery for small-sized NSCLC, especially for pure-solid tumors ≥ 1 cm.

Hospital-Level Segregation Among Medicare Beneficiaries Undergoing Lung Cancer Resection.

Recent research has raised concern that health care segregation, the high concentration of racial groups within a subset of hospitals, is a key contributor to persistent disparities in surgical care. However, to date the extent and effect of hospital level segregation among patients undergoing resection for lung cancer remains unclear. We used 100% Medicare fee-for-service claims to evaluate the degree of hospital-level racial segregation for patients undergoing resection for lung cancer between 2014 and 2018. Hospitals serving a high volume of minority patients were defined as the top decile of hospitals by volume of racial and ethnic minority beneficiaries served. Multivariable logistic regression analysis was used to compare surgical outcomes between hospitals serving high vs low volumes of minority patients. A total of 122,943 patients were included, with racialethnic composition of 360 American Indian or Native American (0.3%), 2077 Asian or Pacific Islander (1.7%), 1146 Hispanic or Latino (0.9%), 8707 non-Hispanic Black (7.1%), and 108,665 non-Hispanic White patients. Overall, 31.6%, 15.9%, 15.0%, and 7.8% of all hospitals performed 90% of lung cancer resection for Black, Asian, Hispanic, and Native American patients, respectively. Hospitals performing higher volumes of operations for racial and ethnic minorities had higher mortality (3.9% vs 3.1% odds ratio OR, 1.19 95% CI, 1.15-1.23 P < .001), complications (18.1% vs 15.9% OR, 1.17 95% CI, 1.14-1.19 P < .001), and readmissions (11.7% vs 11.2% OR, 1.04 95% CI, 1.02-1.05 P < .001) for resections for lung cancer. Our findings suggest that a small proportion of hospitals provide a disproportionate amount of surgical care for racial and ethnic minorities with lung cancer with inferior surgical outcomes.

Expression patterns and clinical significance of estrogen receptor in non-small cell lung cancer.

Lung cancer death remains the highest among all malignancies. Gender differences show women have an increased cancer incidence while men have worse outcomes. These observations identified that some lung carcinomas express estrogen receptors (ER). This is a promising target as antiestrogen drugs can reduce tumors and improve survival. However, there is a limited understanding of ER distribution and its clinical significance to properly design antiestrogen drug clinical trials. Thus, we comprehensively analyzed ERα and ERβ expression patterns by gender, cancer cell type, and receptor location in lung cancer. We conducted a systematic review using the PubMed database from all-time through October 2022, using MeSH terms with the keywords lung cancer, estrogen receptor, and immunohistochemistry. We identified 120 studies with 21 reports being evaluated based on our inclusion criteria. We examined 4874 lung cancers from 5011 patients. ERβ is the predominant form of ER expressed, mainly found in the nucleus. The ERβ positivity rate is 51.5% in males versus 55.5% in females and was not statistically different. In contrast, ERα is predominately extranuclear in location, and ERα expression varies by gender. Males had a positivity rate of 31% versus 26.6% in females, which is statistically different. ERα is associated with a worse prognosis in some studies, while it had no effect in others. Overall, ERβ was associated with a better prognosis. We characterized ER expression patterns in 4874 lung cancers. Over 50% expressed ERβ with equal rates in both sexes and was associated with a better prognosis. ERα expression was slightly higher in males (31%) than females (26.6%) and was associated with a poor prognosis. Our findings suggest estrogen signaling may be a promising drug target in lung cancer.

Quercetin acts as a novel anti-cancer drug to suppress cancer aggressiveness and cisplatin-resistance in nasopharyngeal carcinoma (NPC) through regulating the yes-associated proteinHippo signaling pathway.

Quercetin has been proven to be effective for cancer treatment, including nasopharyngeal carcinoma (NPC). Also, Quercetin sensitizes cancer cells to current chemical drugs to improve their therapeutic efficacy. However, up until now, the molecular mechanisms that quercetin exerted its therapeutic effects on NPC have not been fully delineated. Cell proliferation abilities were examined by CCK-8 assay and colony formation assay. Real-Time qPCR and Western Blot analysis were used to detect gene expressions at RNA and protein levels. Cell mobility was determined by wound scratch assay and transwell assay. Cell death was detected using flow cytometry (FCM). Tumorigenesis of the NPC cells was determined by in vivo tumor-bearing mice models. Hematoxylin and eosin (HE) and TUNEL staining were used to detect the tumor metastasis to lung tissues and dead cells, respectively. Here, we validated that quercetin exerted its anti-tumor effects and increased cisplatin-sensitivity in NPC in vitro and in vivo. Specifically, quercetin inhibited NPC cell proliferation, viability, mobility, epithelial-mesenchymal transition (EMT), and tumorigenesis, and induced cell death, resulting in the inhibition of NPC progression. In addition, the NPC cells were subjected to a continuously increasing doses of cisplatin to generate cisplatin-resistant NPC (NPCCDDP) cells. Interestingly, quercetin significantly enhanced the cytotoxic effects of high-dose cisplatin on NPCCDDP cells. Furthermore, the potential underlying mechanisms were uncovered, and the results evidenced that quercetin inhibited Yes-associated protein (YAP) expression and its translocation to the nucleus, leading to the recovery of the Hippo pathway, inhibition of cancer progression, and increase in cisplatin-resistance. Mechanistically, upregulation of YAP by its gene manipulating vectors abrogated the inhibiting effects of quercetin on NPC malignant phenotypes, which also made NCPCDDP cells irresponsive to high-dose cisplatin-quercetin co-treatments. Collectively, our data evidenced that quercetin inhibited YAP to recover the Hippo pathway, which further inhibited NPC pathogenesis and increased susceptibility of NCPCDDP cells to cisplatin treatment.

Bisphenol A and Di(2-Ethylhexyl) Phthalate promote pulmonary carcinoma in female rats via estrogen receptor beta In vivo and in silico analysis.

The prevalence of lung cancer in women currently merits our attentions. However, cigarette exposure alone does not tell the whole story that lung cancer is more prevalent among non-smoking women. Since female lung cancer is closely linked to estrogen levels, many of endocrine disrupting chemicals (EDCs), as the substances similar to estrogen, affect hormone levels and become a potential risk of female lung cancer. Additionally, the combined toxicity of EDCs in daily environment has only been discussed on a limited scale. Consequently, this study explored the cancer-promoting effect of two representative substances of EDCs namely Bisphenol A (BPA) and Di(2-Ethylhexyl) Phthalate (DEHP) after their exposure alone or in combination, using a rat pulmonary tumor model published previously, combining bioinformatics analysis based on The Comparative Toxicogenomics Database (CTD) and The Cancer Genome Atlas (TCGA) databases. It demonstrated that BPA and DEHP enhanced the promotion of pulmonary tumor in female rats, either alone or in combination. Mechanistically, BPA and DEHP mainly directly bound and activated ESR2 protein, phosphorylated CREB protein, activated HDAC6 transcriptionally, induced the production of the proto-oncogene c-MYC, and accelerated the formation of pulmonary tumor in female rats. Remarkably, BPA, rather than DEHP, exhibited a much more critical effect in female lung cancer. Additionally, the transcription factor ESR2 was most affected in carcinogenesis, causing genetic disruption. Furthermore, the TCGA database revealed that ESR2 could enhance the promotion and progression of non-small cell lung cancer in females via activating the WNTβ-catenin pathway. Finally, our findings demonstrated that BPA and DEHP could enhance the promotion of pulmonary carcinoma via ESR2 in female rats and provide a potential and valuable insight into the causes and prevention of lung cancer in non-smoking women due to EDCs exposure.

A study of the efficacy and toxicity outcomes of extended durvalumab dosing in patients with stage III unresectable non-small cell lung cancer (NSCLC) during the COVID-19 pandemic.

Durvalumab following chemoradiation in unresectable stage III non-small cell lung cancer (NSCLC) has led to improved outcomes. The schedule of administration has been determined by pharmacokinetic studies. This study evaluates real-world efficacy and safety outcomes of extended dosing (ED) vs. standard dosing (SD) of durvalumab. Stage III NSCLC patients treated at the Cancer center of Southeastern Ontario with consolidative durvalumab from March 2017-December 2020 were included. Patient characteristics and outcomes were evaluated through retrospective review. Comparisons were made using chi-square and t-tests. Kaplan-Meier curves were used to analyze overall survival (OS). A total of 35 patients were included 15 (43%) switched to ED. Distant recurrence rates were higher in the ED group (53% vs. 20%, p 0.07), with no differences in the sites of disease recurrence. A similar proportion of patients were alive in the ED vs. SD group (93% vs. 80%, p 0.3), with no significant difference in OS. There were less grade 3 or greater immune-related adverse events in the ED group (0% vs. 20%). Treatment discontinuation occurred in 47% vs. 50% in the ED vs. SD groups, respectively, owing to toxicity in 20% of patients in the ED group vs. 40% in the SD group. Extended dosing has similar efficacy and toxicity to standard dosing however, there was a higher rate of toxicity necessitating discontinuation in the SD group, which may have impacted the clinical decision-making to switch to ED. Our data is limited by a small sample size and should be further validated in larger cohorts.

Chlorin e6-induced photodynamic effect facilitates immunogenic cell death of lung cancer as a result of oxidative endoplasmic reticulum stress and DNA damage.

Suppression of the immune microenvironment is an important endogenous contributor to treatment failure in lung cancer. Photodynamic therapy (PDT) is widely used in the treatment of malignant tumors owing to its photo-selectivity and minimal side effects. Some studies have shown the ability of photodynamic action not only to cause photo-cytotoxicity to tumor cells but also to induce immunogenic cell death (ICD). However, the mechanism by which PDT enhances tumor immunogenicity is poorly understood. The present study aimed to explore the immunogenicity effect of PDT on lung cancer and to reveal the underlying mechanism. First, we searched for effective conditions for PDT-induced apoptosis in lung cancer cells. Just as expected, chlorin e6 (Ce6) PDT could enhance the immunogenicity of lung cancer cells alongside the induction of apoptosis, characterized by up-regulation of CRT, HSP90, HMGB1 and MHC-I. Further results showed the generation of ROS by Ce6 PDT under the above conditions, which is an oxidative damaging agent. Simultaneously, PDT induced endoplasmic reticulum (ER) stress in cells, as evidenced by enhanced Tht staining and up-regulated CHOP and GRP78 expression. Moreover, PDT led to DNA damage response (DDR) as well. However, the redox inhibitor NAC abolished the ER stress and DDR caused by PDT. More importantly, NAC also attenuated PDT-induced improvement of immunogenicity in lung cancer. On this basis, the PDT-induced CRT up-regulation was found to be attenuated in response to inhibition of ER stress. In addition, PDT-induced increase in HMGB1 and HSP90 release was blocked by inhibition of DDR. In summary, Ce6 PDT could produce ROS under certain conditions, which leads to ER stress that promotes CRT translocation to the cell membrane, and the resulting DNA damage causes the expression and release of nuclear HMGB1 and HSP90, thereby enhancing the immunogenicity of lung cancer. This current study elucidates the mechanism of PDT in ameliorating the immunogenicity of lung cancer, providing a rationale for PDT in regulating the immune microenvironment for the treatment of malignant tumors.

AMPAR autoimmunity Neurological and oncological accompaniments and co-existing neural autoantibodies.

α -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) encephalitis is rare but treatable. We reviewed the clinical and autoantibody profiles of 52 AMPAR-IgG-positive patients (median age 48 years range 12-81 38 female) identified at the Mayo Clinic neuroimmunology laboratory. Main presentation was encephalitis symptoms other than encephalitis associated with co-existing antibodies (p 0.004). A tumor was found in 3344 mostly thymoma. Most patients had partial (1429) or complete (1129) immunotherapy response. Thirty-one patients had at least one co-existing antibody that predicted thymoma in paraneoplastic patients (p 0.008). In conclusion, in AMPAR encephalitis co-existing antibodies predict clinical presentation other than encephalitis and thymoma.

Short-term carcinogenicity study of N-methyl-N-nitrosourea in FVB-Trp53 heterozygous mice.

Carcinogenicity tests predict the tumorigenic potential of various substances in the human body by studying tumor induction in experimental animals. There is a need for studies that explore the use of FVBN-Trp53em2HwlKorl (FVB-Trp53-) mice, created by TALEN-mediated gene targeting in Korea, in carcinogenicity tests. This study was performed to determine whether FVB-Trp53- mice are a suitable model for short-term carcinogenicity studies. To compare the carcinogenicity at different concentrations, 25, 50, and 75 mgkg of N-methyl-N-nitrosourea (MNU), a known carcinogen, were administered intraperitoneally to FVB-Trp53- and wild-type male mice. After 26 weeks, the survival rate was significantly reduced in FVB-Trp53- mice compared to the wild-type mice in the 50 and 75 mgkg groups. The incidence of thymic malignant lymphoma (TML) in the 50 and 75 mgkg groups was 54.2 and 59.1% in FVB-Trp53- male mice, respectively. TML metastasized to the lungs, spleen, lymph nodes, liver, kidney, and heart in FVB-Trp53- male mice. Furthermore, the incidence of primary lung tumors, such as adenomas and adenocarcinomas, was 65.4, 62.5, and 45.4% in the FVB-Trp53- mice of the 25, 50, and 75 mgkg groups, respectively. The main tumor types in FVB-Trp53- mice were TML and primary lung tumors, regardless of the dose of MNU administered. These results suggest that systemic tumors may result from malfunctions in the p53 gene and pathway, which is an important factor in the pathogenesis of human cancers. Therefore, FVB-Trp53 heterozygous mice are suitable for short-term carcinogenicity tests using positive carcinogens, and that the best result using MNU, a positive carcinogen, might have a single dose of 50 mgkg.

Circular RNA Fibroblast Growth Factor Receptor 1 Promotes Pancreatic Cancer Progression by Targeting MicroRNA-532-3pPIK3CB Axis.

The aim of the study is to explore the contribution and mechanism of circular RNA fibroblast growth factor receptor 1 (circFGFR1) in pancreatic ductal adenocarcinoma (PDAC) progression. Expressions of circFGFR1, microRNA (miR)-532-3p, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB) were assessed by quantitative real-time polymerase chain reaction or in situ hybridization. Fluorescence in situ hybridization determined the subcellular localization of circFGFR1. Immunohistochemistry was used to detect PIK3CB expression in PDAC tissues. Cell growth was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assays. Wound healing, transwell, and flow cytometry assays examined the migration, invasion, and apoptosis. Dual-luciferase and RNA pull-down assay verified the interactions between circFGFR1PIK3CB and miR-532-3p. In vivo xenograft tumor growth and lung metastasis were assessed in nude mice. Functionally, knockdown of circFGFR1 restrained in vitro PDAC cell growth, migration, invasion, and in vivo xenograft tumor growth and lung metastasis. In addition, circFGFR1 could sponge miR-532-3p to upregulate PIK3CB level. Rescue experiments revealed that the tumor-suppressive effects caused by miR-532-3p mimics could be reversed by circFGFR1 or PIK3CB overexpression. Our data revealed that circFGFR1 driven the malignant progression of PDAC by targeting miR-532-3pPIK3CB axis, suggesting that inhibition of circFGFR1 might be considered as a therapeutic target for PDAC.

Ecological Study on Global Health Effects due to Source-Specific Ambient Fine Particulate Matter Exposure.

Ambient air pollution of fine particulate matter with diameters less than 2.5 μm (PM