Neutrophil-to-lymphocyte ratio is a prognostic factor reflecting immune condition of tumor microenvironment in squamous cell lung cancer.

Inflammatory factors in the peripheral blood, such as the C-reactive protein level and neutrophil-to-lymphocyte ratio (NLR), are prognostic markers in multiple types of cancer, including non-small cell lung cancer (NSCLC). However, the association between inflammatory factors and prognosis based on histological types has not been adequately reported. In addition, the relationship between these factors and the immune condition of the tumor microenvironment (TME) is unclear. In this single center, retrospective study, we first investigated the relationship between preoperative inflammatory markers and clinical outcomes in 176 patients with NSCLC who underwent surgery. Lung adenocarcinoma (LUAD) showed no significant prognostic marker, whereas for lung squamous cell carcinoma (LUSC), a multivariate analysis showed that a high NLR was significantly associated with postoperative recurrence. In LUSC patients, the median time of postoperative recurrence-free survival in patients with a low NLR was longer than that in patients with a high NLR. We then compared the tumor-infiltrating lymphocyte (TIL) profile with inflammatory markers in peripheral blood and found that the NLR was negatively correlated with the frequencies of T cells and B cells in LUSC tissues. Thus, the NLR is a useful predictive biomarker for postoperative recurrence and may reflect the immune condition of the TME in LUSC.

Tumor-infiltrating Leukocyte Profiling Defines Three Immune Subtypes of NSCLC with Distinct Signaling Pathways and Genetic Alterations.

Resistance to immune checkpoint blockade remains challenging in patients with non-small cell lung cancer (NSCLC). Tumor-infiltrating leukocyte (TIL) quantity, composition, and activation status profoundly influence responsiveness to cancer immunotherapy. This study examined the immune landscape in the NSCLC tumor microenvironment by analyzing TIL profiles of 281 fresh resected NSCLC tissues. Unsupervised clustering based on numbers and percentages of 30 TIL types classified adenocarcinoma (LUAD) and squamous cell carcinoma (LUSQ) into the cold, myeloid cell-dominant, and CD8+ T cell-dominant subtypes. These were significantly correlated with patient prognosis; the myeloid cell subtype had worse outcomes than the others. Integrated genomic and transcriptomic analyses, including RNA sequencing, whole-exome sequencing, T-cell receptor repertoire, and metabolomics of tumor tissue, revealed that immune reaction-related signaling pathways were inactivated, while the glycolysis and K-ras signaling pathways activated in LUAD and LUSQ myeloid cell subtypes. Cases with ALK and ROS1 fusion genes were enriched in the LUAD myeloid subtype, and the frequency of TERT copy-number variations was higher in LUSQ myeloid subtype than in the others. These classifications of NSCLC based on TIL status may be useful for developing personalized immune therapies for NSCLC. Significance: The precise TIL profiling classified NSCLC into novel three immune subtypes that correlates with patient outcome, identifying subtype-specific molecular pathways and genomic alterations that should play important roles in constructing subtype-specific immune tumor microenvironments. These classifications of NSCLC based on TIL status are useful for developing personalized immune therapies for NSCLC.

Six Cases of Hemoptysis with Angiogenesis from Non-Bronchial Systemic Arteries.

BACKGROUND Although bronchial arteries are the most common cause of hemoptysis, other systemic arteries can cause hemoptysis and are potential pitfalls for successful embolization. CASE REPORT We present 6 cases of hemoptysis showing vascularization from systemic arteries other than bronchial arteries that presented to our department between 2013 and 2020. Chronic inflammatory diseases such as tuberculosis and pulmonary aspergillosis were the underlying diseases in 4 of the 6 cases. In all 6 cases, the lesions were close to the pleura. The abnormal non-bronchial systemic arteries were the internal thoracic artery in 4 cases, intercostal artery in 2 cases, lateral thoracic artery in 2 cases, and the subclavian, thyrocervical, and inferior phrenic arteries in 1 case each, all of which formed a shunt with the pulmonary artery. Additionally, depending on the location of the lesion, the non-bronchial systemic arteries near the lesion proliferated into the lung parenchyma through the adherent pleura. CONCLUSIONS When lesions are in contact with the pleura, various non-bronchial systemic arteries near the lesion can develop in the pulmonary parenchyma via the adherent pleura, which can cause hemoptysis. In patients with hemoptysis, it may be useful to evaluate chest contrast-enhanced computed tomography and angiography, while always accounting for the potential involvement of non-bronchial systemic arteries to ensure a safer and more reliable treatment.

Transient Receptor Potential Melastatin 3 Is Functionally Expressed in Oligodendrocyte Precursor Cells and Is Upregulated in Ischemic Demyelinated Lesions.

Oligodendrocyte precursor cells (OPCs) are glial cells that differentiate into oligodendrocytes and myelinate axons. The number of OPCs is reportedly increased in brain lesions in some demyelinating diseases and during ischemia; however, these cells also secrete cytokines and elicit both protective and deleterious effects in response to brain injury. The mechanism regulating the behaviors of OPCs in physiological and pathological conditions must be elucidated to control these cells and to treat demyelinating diseases. Here, we focused on transient receptor potential melastatin 3 (TRPM3), a Ca2+-permeable channel that is activated by the neurosteroid pregnenolone sulfate (PS) and body temperature. Trpm3+/Pdgfra+ OPCs were detected in the cerebral cortex (CTX) and corpus callosum (CC) of P4 and adult rats by in situ hybridization. Trpm3 expression was detected in primary cultured rat OPCs and was increased by treatment with tumor necrosis factor α (TNFα). Application of PS (30-100 µM) increased the Ca2+ concentration in OPCs and this effect was inhibited by co-treatment with the TRP channel blocker Gd3+ (100 µM) or the TRPM3 inhibitor isosakuranetin (10 µM). Stimulation of TRPM3 with PS (50 µM) did not affect the differentiation or migration of OPCs. The number of Trpm3+ OPCs was markedly increased in demyelinated lesions in an endothelin-1 (ET-1)-induced ischemic rat model. In conclusion, TRPM3 is functionally expressed in OPCs in vivo and in vitro and is upregulated in inflammatory conditions such as ischemic insults and TNFα treatment, implying that TRPM3 is involved in the regulation of specific behaviors of OPCs in pathological conditions.

Effectiveness of pulmonary vasodilators on pulmonary hypertension associated with POEMS syndrome.

Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare plasma cell disease. Patients with POEMS syndrome are considered to be at a high risk of developing pulmonary hypertension (PH). We report a 51-year-old woman diagnosed with PH associated with POEMS syndrome. She was started on dexamethasone and thalidomide. Although, the plasma vascular endothelial growth factor (VEGF) level decreased, systolic pulmonary artery pressure (sPAP) remained high. Auto-peripheral blood stem cell transplantation improved the plasma VEGF and sPAP levels. Four years later, she presented with dyspnoea on exertion, and elevated plasma VEGF and sPAP levels. Subsequently, on administering sildenafil and macitentan, the plasma VEGF and PH levels improved. Pulmonary vasodilators can be considered when PH remains after treatment of POEMS syndrome.

[Efficacy and Safety of Gefitinib as First-Line Chemotherapy for Elderly Patients with Advanced Non-Small Cell Lung Cancer(NSCLC)].

Epidermalgrowth factor receptor tyrosine kinase inhibitor(EGFR-TKI)is the first choice for the treatment of EGFR mutation- positive advanced non-small cell lung cancer(NSCLC). There have been few reports on the efficacy and safety of gefitinib in elderly patients with EGFR mutation-positive advanced NSCLC. We retrospectively assessed the efficacy and safety of gefitinib as first-line chemotherapy in 22 patients with advanced NSCLC aged 75 years or older and who were treated with gefitinib. The response rate was 81.8%, and the disease controlrate was 95.5%. The median progression-free survivaltime was 14.2 months, and the median survivaltime was 30.7 months. The common adverse events were skin toxicities(50.0%), liver dysfunction(18.2%), and diarrhea(18.2%). The dose of gefitinib was reduced in 36.3% of the patients, and the treatment of gefitinib was discontinued in 18.2% of the patients. Gefitinib is effective and safe for elderly patients with advanced NSCLC.

TRPV4 is functionally expressed in oligodendrocyte precursor cells and increases their proliferation.

Oligodendrocytes, which differentiate from oligodendrocyte precursor cells (OPCs), ensheath axons with myelin, play an essential role in rapid conduction of action potentials and metabolically support neurons. Elucidation of the mechanisms underlying the proliferation, migration, differentiation, and survival of OPCs is considered indispensable for determining the causes of central nervous system diseases. However, the relationship between these functions of OPCs and their intracellular Ca2+ signaling has not been fully elucidated. Here, we investigated the function of transient receptor potential vanilloid 4 (TRPV4), a Ca2+-permeable channel that responds to hypo-osmolarity, mild temperature, mechanical stimulation, and endogenous arachidonic acid metabolites, in OPCs. Trpv4 mRNA was detected in OPCs in vivo and in primary cultured rat OPCs. In Ca2+ imaging experiments, treatment with the selective TRPV4 agonist GSK1016790A induced sustained elevation of the intracellular Ca2+ concentration in OPCs in a concentration-dependent manner, which was almost completely suppressed by co-treatment with the selective TRPV4 antagonist HC067047. Stimulation of TRPV4 by GSK1016790A augmented OPC proliferation, which was abolished by co-treatment with HC067047, the intracellular Ca2+ chelator BAPTA-AM, and the protein kinase C inhibitor bisindolylmaleimide II. By contrast, GSK1016790A did not significantly affect the migration or differentiation of OPCs. Taken together, these results suggest that TRPV4 is functionally expressed in OPCs and increases the proliferation of these cells without affecting their ability to differentiate into oligodendrocytes.

Tremor dominant Kyoto (Trdk) rats carry a missense mutation in the gene encoding the SK2 subunit of small-conductance Ca2+-activated K+ channel.

Tremor dominant Kyoto (Trdk) is an autosomal dominant mutation that appeared in F344/NSlc rats mutagenized with N-ethyl-N-nitrosourea (ENU). In this study, we characterized and genetically analyzed F344-Trdk/+ heterozygous rats. The rats exhibited a tremor that was especially evident around weaning but persisted throughout life. The tremors of F344-Trdk/+ rats were attenuated by drugs effective against essential tremor (ET) but not drugs used to treat Parkinson's disease-related tremor, indicating that the pharmacological phenotype of F344-Trdk/+ rats was similar to human ET. Using positional candidate approach, we identified the Trdk mutation as a missense substitution (c. 866T>A, p. I289N) in Kcnn2, which encodes the SK2 subunit of the small-conductance Ca2+-activated K+ channel. In vitro electrophysiological studies revealed that the I289N mutation diminished SK2 channel activity. These findings demonstrate that F344-Trdk/+ rats represent a novel model of ET, and strongly suggest that Kcnn2 is the causative gene for the tremor phenotype in F344-Trdk/+ rats.

PKCepsilon induces interleukin-6 expression through the MAPK pathway in 3T3-L1 adipocytes.

Recent reports have suggested that PKCepsilon contributes to systemic insulin resistance, and is involved in the pathogenesis of type 2 diabetes, however, the exact mechanism is still unknown. To elucidate the possible involvement of PKCepsilon in the pathogenesis of type 2 diabetes, we examined the role of PKCepsilon in differentiated adipocytes using mouse 3T3-L1 adipocytes. We found that the over-expression of PKCepsilon resulted in the increase of IL-6 expression in differentiated adipocytes. This PKCepsilon-induced IL-6 expression could be completely inhibited by U0126, an inhibitor of mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase. We also demonstrated that PKCepsilon increased the transcriptional activity of Est-like transcription factor (Elk-1) as well as the DNA-binding activity of activator protein-1 (AP-1) in differentiated 3T3-L1 adipocytes. These results suggest that PKCepsilon is able to increase IL-6 expression via the ERK-AP-1 pathway in differentiated adipocytes, and that PKCepsilon is involved in systemic insulin resistance by regulating plasma IL-6 concentrations.