Lactate dehydrogenase B noncanonically promotes ferroptosis defense in KRAS-driven lung cancer.

Ferroptosis is an oxidative, non-apoptotic cell death frequently inactivated in cancer, but the underlying mechanisms in oncogene-specific tumors remain poorly understood. Here, we discover that lactate dehydrogenase (LDH) B, but not the closely related LDHA, subunits of active LDH with a known function in glycolysis, noncanonically promotes ferroptosis defense in KRAS-driven lung cancer. Using murine models and human-derived tumor cell lines, we show that LDHB silencing impairs glutathione (GSH) levels and sensitizes cancer cells to blockade of either GSH biosynthesis or utilization by unleashing KRAS-specific, ferroptosis-catalyzed metabolic synthetic lethality, culminating in increased glutamine metabolism, oxidative phosphorylation (OXPHOS) and mitochondrial reactive oxygen species (mitoROS).

Crispr-mediated genome editing reveals a preponderance of non-oncogene addictions as targetable vulnerabilities in pleural mesothelioma.

Pleural mesothelioma (PM) is an aggressive cancer with limited treatment options. In particular, the frequent loss of tumor suppressors, a key oncogenic driver of the disease that is therapeutically intractable, has hampered the development of targeted cancer therapies. Here, we interrogate the PM genome using CRISPR-mediated gene editing to systematically uncover PM cell susceptibilities and provide an evidence-based rationale for targeted cancer drug discovery.

Chemotherapy increases CDA expression and sensitizes malignant pleural mesothelioma cells to capecitabine treatment.

The combination of cisplatin and pemetrexed remains the gold standard chemotherapy for malignant pleural mesothelioma (MPM), although resistance and poor response pose a significant challenge. Cytidine deaminase (CDA) is a key enzyme in the nucleotide salvage pathway and is involved in the adaptive stress response to chemotherapy. The cytidine analog capecitabine and its metabolite 5'-deoxy-5-fluorocytidine (5'-DFCR) are converted via CDA to 5-fluorouracil, which affects DNA and RNA metabolism.

Second Primary Cancer Among Patients With Papillary Thyroid Carcinoma Following the Chernobyl Disaster.

Importance: To our knowledge, there are no complete population-based studies of the risks of developing second malignant tumors after papillary thyroid carcinoma (PTC) in patients following the Chernobyl nuclear accident.

Objective: To study the risk of second primary cancers in patients with PTC after the Chernobyl disaster.

Design, Setting, And Participants: This was a retrospective cohort study conducted in the Republic of Belarus over a 31-year time frame evaluating patients with primary PTC and second malignant tumors.

MEK1 drives oncogenic signaling and interacts with PARP1 for genomic and metabolic homeostasis in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a lethal malignancy etiologically caused by asbestos exposure, for which there are few effective treatment options. Although asbestos carcinogenesis is associated with reactive oxygen species (ROS), the bona fide oncogenic signaling pathways that regulate ROS homeostasis and bypass ROS-evoked apoptosis in MPM are poorly understood. In this study, we demonstrate that the mitogen-activated protein kinase (MAPK) pathway RAS-RAF-MEK-ERK is hyperactive and a molecular driver of MPM, independent of histological subtypes and genetic heterogeneity.

Dissecting the Immunological Profiles in -Amplified LUSC through Integrative Multi-Scale Analyses.

The histone H3 lysine 36 (H3K36) methyltransferase , a neighboring gene of , has been identified as a critical genetic driver of lung squamous cell carcinoma (LUSC). However, the molecular characteristics, especially the immunological roles of in driving carcinogenesis, are poorly understood. In this study, we systematically integrated multi-omics data (e.

Programmed Death-Ligand 1 Expression in Lung Cancer and Paired Brain Metastases-a Single-Center Study in 190 Patients.

Introduction: Expression of programmed death-ligand 1 (PD-L1) is the only routinely used tissue biomarker for predicting response to programmed cell death protein 1/PD-L1 inhibitors. It is to date unclear whether PD-L1 expression is preserved in brain metastases (BMs).

Methods: In this single-center, retrospective study, we evaluated PD-L1 expression using the SP263 assay in consecutively resected BMs of lung carcinomas and paired primary tumors, diagnosed from 2000 to 2015, with correlation to clinicopathological and molecular tumor and patient characteristics.

Schedule-Dependent Treatment Increases Chemotherapy Efficacy in Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare but aggressive thoracic malignancy with limited treatment options. One of the standard treatments for MPM is chemotherapy, which consists of concurrent treatment with pemetrexed and cisplatin. Pemetrexed limits tumor growth by inhibiting critical metabolic enzymes involved in nucleotide synthesis.

The development of machine learning in lung surgery: A narrative review.

Background: Machine learning reflects an artificial intelligence that allows applications to improve their accuracy to predict outcomes, eliminating the need to conduct explicit programming on them. The medical field has increased its focus on establishing tools for integrating machine learning algorithms in laboratory and clinical settings. Despite their importance, their incorporation is minimal in the medical sector yet.

The effect of neoadjuvant therapy on PD-L1 expression and CD8+lymphocyte density in non-small cell lung cancer.

PD-L1 expression is the routine clinical biomarker for the selection of patients to receive immunotherapy in non-small cell lung cancer (NSCLC). However, the application and best timing of immunotherapy in the resectable setting is still under investigation. We aimed to study the effect of chemotherapy on PD-L1 expression and tumor infiltrating lymphocytes (TILs), which is to date still poorly understood.

Targeting lactate dehydrogenase B-dependent mitochondrial metabolism affects tumor initiating cells and inhibits tumorigenesis of non-small cell lung cancer by inducing mtDNA damage.

Once considered a waste product of anaerobic cellular metabolism, lactate has been identified as a critical regulator of tumorigenesis, maintenance, and progression. The putative primary function of lactate dehydrogenase B (LDHB) is to catalyze the conversion of lactate to pyruvate; however, its role in regulating metabolism during tumorigenesis is largely unknown. To determine whether LDHB plays a pivotal role in tumorigenesis, we performed 2D and 3D in vitro experiments, utilized a conventional xenograft tumor model, and developed a novel genetically engineered mouse model (GEMM) of non-small cell lung cancer (NSCLC), in which we combined an LDHB deletion allele with an inducible model of lung adenocarcinoma driven by the concomitant loss of p53 (also known as Trp53) and expression of oncogenic KRAS (G12D) (KP).

Extended resection for potentially operable patients with stage III non-small cell lung cancer after induction treatment.

Objective: Surgical treatment of locally advanced non-small cell lung cancer including single or multilevel N2 remains a matter of debate. Several trials demonstrate that selected patients benefit from surgery if R0 resection is achieved. We aimed to assess resectability and outcome of patients with locally advanced clinical T3/T4 (American Joint Committee on Cancer 8 edition) tumors after induction treatment followed by surgery in a pooled analysis of 3 prospective multicenter trials.

Multi-scale integrative analyses identify THBS2 cancer-associated fibroblasts as a key orchestrator promoting aggressiveness in early-stage lung adenocarcinoma.

Subsets of patients with early-stage lung adenocarcinoma (LUAD) have a poor post-surgical course after curative surgery. However, biomarkers stratifying this high-risk subset and molecular underpinnings underlying the aggressive phenotype remain unclear. We integrated bulk and single-cell transcriptomics, proteomics, secretome and spatial profiling of clinical early-stage LUAD samples to identify molecular underpinnings that promote the aggressive phenotype.

Functional and molecular characterization of PD1 tumor-infiltrating lymphocytes from lung cancer patients.

Antibody-mediated cancer immunotherapy targets inhibitory surface molecules, such as PD1, PD-L1, and CTLA-4, aiming to re-invigorate dysfunctional T cells. We purified and characterized tumor-infiltrating lymphocytes (TILs) and their patient-matched non-tumor counterparts from treatment-naïve NSCLC patient biopsies to evaluate the effect of PD1 expression on the functional and molecular profiles of tumor-resident T cells. We show that PD1+ CD8+ TILs have elevated expression of the transcriptional regulator ID3 and that the cytotoxic potential of CD8 T cells can be improved by knocking down ID3, defining it as a potential regulator of T cell effector function.

Neoadjuvant immunotherapy facilitates resection of surgically-challenging lung squamous cell cancer.

Background: Locally-advanced lung squamous cell carcinoma represents a special subset that is challenging to resect completely with surgery alone. Immunotherapy has achieved great success in treating late-stage lung cancer. However, whether neoadjuvant immunotherapy can facilitate resection of initially locally-advanced and surgically-difficult locally-advanced lung squamous cell carcinoma remains to be investigated.

Tumor-infiltrating lymphocytes are functionally inactivated by CD90+ stromal cells and reactivated by combined Ibrutinib and Rapamycin in human pleural mesothelioma.

Despite evidence suggesting that the tumor microenvironment (TME) in malignant pleural mesothelioma (MPM) is linked with poor prognosis, there is a lack of studies that functionally characterize stromal cells and tumor-infiltrating lymphocytes (TILs). Here, we aim to characterize the stromal subsets within MPM, investigate their relationship to TILs, and explore the potential therapeutic targets. We curated a core set of genes defining stromal/immune signatures expressed by mesenchymal cells within the TME using molecular analysis of The Cancer Genome Atlas (TCGA) MPM cohort.

Corrigendum to "Chaperone-Mediated Autophagy Markers LAMP2A and HSC70 Are Independent Adverse Prognostic Markers in Primary Resected Squamous Cell Carcinomas of the Lung".

[This corrects the article DOI: 10.1155/2020/8506572.].

Mutational profiles of primary pulmonary adenocarcinoma and paired brain metastases disclose the importance of KRAS mutations.

Background: Brain metastases present a significant complication in lung cancer with an unmet therapeutic need.

Methods: In this single-centre, retrospective study, we genotyped a clinico-pathologically well-annotated cohort of consecutively resected brain metastases of lung adenocarcinomas and paired primary tumours, diagnosed from 2000 to 2015, using the Ion Torrent Oncomine Comprehensive Cancer Panel v3.

Results: Among 444 consecutive brain metastases, 210 (49%) originated from lung cancer.

Peritumoral CD90+CD73+ cells possess immunosuppressive features in human non-small cell lung cancer.

Background: Although T cell abundance in solid tumours is associated with better outcomes, it also correlates with a stroma-mediated source of immune suppression driven by TGFβ1 and poor overall survival. Whether this also is observed in non-small cell lung cancer (NSCLC) is unknown.

Methods: We utilized molecular analysis of The Cancer Genome Atlas (TCGA) NSLCC cohort to correlate immune activation (IA) gene expression and extracellular matrix/stromal (ECM/stromal) gene expression with patient survival.

Smoking signature is superior to programmed death-ligand 1 expression in predicting pathological response to neoadjuvant immunotherapy in lung cancer patients.

Background: There is a paucity of biomarkers that can predict the degree of pathological response [e.g., pathological complete response (pCR) or major response (pMR)] to immunotherapy.

Chaperone-Mediated Autophagy Markers LAMP2A and HSPA8 in Advanced Non-Small Cell Lung Cancer after Neoadjuvant Therapy.

In recent years autophagy has attracted the attention of researchers from many medical fields, including cancer research, and certain anti-macroautophagy drugs in combination with cytotoxic or targeted therapies have entered clinical trials. In the present study, we focused on a less explored subtype of autophagy, i.e.

Patterns of Carbon-Bound Exogenous Compounds in Patients with Lung Cancer and Association with Disease Pathophysiology.

Asymptomatic anthracosis is the accumulation of black carbon particles in adult human lungs. It is a common occurrence, but the pathophysiologic significance of anthracosis is debatable. Using high mass resolution matrix-assisted laser desorption/ionization (MALDI) fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometry imaging analysis, we discovered noxious carbon-bound exogenous compounds, such as polycyclic aromatic hydrocarbons (PAH), tobacco-specific nitrosamines, or aromatic amines, in a series of 330 patients with lung cancer in highly variable and unique patterns.

Completely Thoracoscopic 3-Port Robotic First Rib Resection for Thoracic Outlet Syndrome.

Background: In thoracic outlet syndrome, the constriction between bony and muscular structures leads to compression of the neurovascular bundle to the upper extremity. Traditional surgical techniques using supraclavicular, infraclavicular, or transaxillary approaches to remove the first rib do not usually allow good exposure of the entire rib and neurovascular bundle. We have therefore developed a robotic approach to overcome these limitations.

Robotic-Assisted Thoracoscopic Resection of the First Rib for Vascular Thoracic Outlet Syndrome: The New Gold Standard of Treatment?

In thoracic outlet syndrome (TOS) the narrowing between bony and muscular structures in the region of the thoracic outlet/inlet results in compression of the neurovascular bundle to the upper extremity. Venous compression, resulting in TOS (vTOS) is much more common than a stenosis of the subclavian artery (aTOS) with or without an aneurysm. Traditional open surgical approaches to remove the first rib usually lack good exposure of the entire rib and the neurovascular bundle.