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Positron emission tomography (PET) is a non-invasive imaging method to measure the molecule in vivo. PET imaging can evaluate the central nervous system drugs as target engagement in the human brain. For antipsychotic drugs, adequate dopamine D2 receptor occupancy ("therapeutic window") is reported to be from 65%-70% to 80% to achieve the antipsychotic effect without extrapyramidal symptoms. For antidepressants, the clinical threshold of serotonin transporter (5-HTT) occupancy is reported to be 70%-80% although the relation between the side effect and 5-HTT occupancy has not yet been established. Evaluation of norepinephrine transporter (NET) occupancy for antidepressant is ongoing as adequate PET radioligands for NET were developed recently. Measurement of the target occupancy has been a key element to evaluate the in vivo target engagement of the drugs. In order to evaluate new drug targets for disease conditions such as negative symptoms/cognitive impairment of schizophrenia and treatment-resistant depression, new PET radioligands need to be developed concurrently with the drug development.Background In advanced non-small cell lung cancer (NSCLC), cytologic specimens from transbronchial needle aspiration (TBNA) or transthoracic needle aspiration are often the only cancer tissue material available for the analysis of programmed death ligand 1 (PD-L1) expression. This study was aimed at assessing the concordance of PD-L1 expression in histologic and cytologic samples and at evaluating interobserver agreement on specimens in this setting. Methods One hundred and thirty-eight specimens from 60 patients with NSCLC were analyzed. Histologic specimens were represented by endoscopic samples obtained with forceps (biopsies), whereas cytologic specimens were from TBNA and bronchial lavage (BL). PD-L1 expression was quantified with the immunohistochemistry (IHC)-based Ventana SP263 assay. For cytologic specimens, IHC was performed on cell block sections. Two independent pathologists who were blinded to the clinical data evaluated partial or complete membrane IHC staining. Concordance between 2 methods and between 2 pathologists was evaluated with normal and weighted Cohen's κ coefficients, overall agreement, and Bland-Altman plots. Results PD-L1 expression was quantified in 138 specimens from 60 patients. Concordance between cytologic and histologic approaches was moderate (κ = 0.56; weighted κ = 0.55). Also, concordance in the biopsy-TBNA and biopsy-BL subgroups was moderate (κ = 0.43 and κ = 0.47, respectively), whereas interobserver agreement was substantial (weighted κ = 0.72). A Bland-Altman plot showed an underestimation in PD-L1 values from cytologic samples in comparison with histologic ones. Conclusions The results demonstrate that in the absence of available histologic specimens, PD-L1 positivity in cytologic samples could be a reliable data for the oncologist to consider immune checkpoint inhibitor therapy. find more However, a comparison of cytologic and histologic samples has shown an underestimation of PD-L1 values in cytologic samples.The aging process is characterized by a chronic, low-grade inflammatory state, termed "inflammaging." It has been suggested that macrophage activation plays a key role in the induction and maintenance of this state. In the present study, we aimed to elucidate the mechanisms responsible for aging-associated changes in the myeloid compartment of mice. The aging phenotype, characterized by elevated cytokine production, was associated with a dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis and diminished serum corticosteroid levels. In particular, the concentration of corticosterone, the major active glucocorticoid in rodents, was decreased. This could be explained by an impaired expression and activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), an enzyme that determines the extent of cellular glucocorticoid responses by reducing the corticosteroids cortisone/11-dehydrocorticosterone to their active forms cortisol/corticosterone, in aged macrophages and peripheral leukocytes. These changes were accompanied by a downregulation of the glucocorticoid receptor target gene glucocorticoid-induced leucine zipper (GILZ) in vitro and in vivo. Since GILZ plays a central role in macrophage activation, we hypothesized that the loss of GILZ contributed to the process of macroph-aging. The phenotype of macrophages from aged mice was indeed mimicked in young GILZ knockout mice. In summary, the current study provides insight into the role of glucocorticoid metabolism and GILZ regulation during aging.Transcription factors represent the crucial role of controlling gene transcription in cancer development and progression. However, their functions in gastric cancer have not been thoroughly characterized. For this study, we comprehensively evaluated the correlation between infiltration patterns of tumor microenvironment (TME) cells and TFs expression in the cohort of stomach adenocarcinoma (STAD) from TCGA database. We integrally explored differential expression panel and prognostic value of candidate TFs in TCGA-STAD cohort. Notably, we found a key transcription factor named HEYL, which its expression level was correlated with stromal component transformation of TME. HEYL was regularly high expressed in gastric cancer and correlated with patients' poor prognosis. Knockdown of HEYL prominently abrogated the tendency of cell proliferation, migration, and progression in gastric cancer. Consistently, overexpression of HEYL strikingly accelerated the gastric carcinoma development through activating oncogenic signaling pathways and transcriptional activation of cadherin 11 (CDH11). Our findings not only identified the close relationship between TFs and TME phenotype, but also emphasized the crucial importance of TFs, especially HEYL, which could be identified as a candidate biomarker to evaluate prognostic risk and therapeutic effect in gastric cancer.Transmembrane protein 88 (TMEM88) is a potential 2-transmembrane-type protein that interacts with the PDZ domain of Dishevelled-1 (DVL-1), a crucial component of Wnt signalling pathway through its C-terminal Val-Trp-Val (VWV) motif in Xenopus embryo cells. Since the significant function of β-catenin in liver fibrosis, it is urgent to study the TMEM88 mechanism in liver fibrosis. The current research was for evaluating the function of TMEM88 in the process of the liver fibrosis and clarifying the inherent mechanism. The study found that TMEM88 is decreased in human fibrotic liver tissues. Functionally, TMEM88 significantly reduced the expression levels of α-smooth muscle actin (α-SMA) and collagen type I (Col.I) and repressed extracellular matrix (ECM) accumulation by restoring the balance between matrix metalloproteinases (MMPs) and TIMPs (tissue inhibitor of metalloproteinases). TMEM88 inhibited HSCs proliferation and evaluated the apoptosis of activated LX-2 cells by regulating Wnt3a, Wnt2b and β-catenin of Wnt/β-catenin signalling pathway.
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