PD-L1: From Cancer Immunotherapy to Therapeutic Implications in Multiple Disorders.

The PD-L1/PD-1 signaling pathway is the gold standard for cancer immunotherapy. Therapeutic antibodies targeting PD-1, such as nivolumab (Opdivo) and pembrolizumab (Keytruda), and PD-L1, including atezolizumab (Tecentriq), durvalumab (Imfinzi), and avelumab (Bavencio) have received FDA approval and are currently being used to treat various cancers. Traditionally, PD-L1 is known as an immune checkpoint protein that binds to the PD-1 receptor on its surface to inhibit the activity of T cells, which are the primary effector cells in antitumor immunity. However, it also plays a role in cancer progression, which goes beyond traditional understanding. Here, we highlight the multifaceted mechanisms of action of PD-L1 in cancer cell proliferation, transcriptional regulation, and systemic immune suppression. Moreover, we consider the potential role of PD-L1 in the development and pathogenesis of diseases other than cancer, explore PD-L1-focused therapeutic approaches for these diseases, and assess their clinical relevance. Through this review, we hope to provide deeper insights into the PD-L1/PD-1 signaling pathway and present a broad perspective on potential therapeutic approaches for cancer and other diseases.

Fine-scaled climate variation in equatorial Africa revealed by modern and fossil primate teeth.

Variability in resource availability is hypothesized to be a significant driver of primate adaptation and evolution, but most paleoclimate proxies cannot recover environmental seasonality on the scale of an individual lifespan. Oxygen isotope compositions (δ18O values) sampled at high spatial resolution in the dentitions of modern African primates (n = 2,352 near weekly measurements from 26 teeth) track concurrent seasonal precipitation, regional climatic patterns, discrete meteorological events, and niche partitioning. We leverage these data to contextualize the first δ18O values of two 17 Ma Afropithecus turkanensis individuals from Kalodirr, Kenya, from which we infer variably bimodal wet seasons, supported by rainfall reconstructions in a global Earth system model. Afropithecus' δ18O fluctuations are intermediate in magnitude between those measured at high resolution in baboons (Papio spp.) living across a gradient of aridity and modern forest-dwelling chimpanzees (Pan troglodytes verus). This large-bodied Miocene ape consumed seasonally variable food and water sources enriched in 18O compared to contemporaneous terrestrial fauna (n = 66 fossil specimens). Reliance on fallback foods during documented dry seasons potentially contributed to novel dental features long considered adaptations to hard-object feeding. Developmentally informed microsampling recovers greater ecological complexity than conventional isotope sampling; the two Miocene apes (n = 248 near weekly measurements) evince as great a range of seasonal δ18O variation as more time-averaged bulk measurements from 101 eastern African Plio-Pleistocene hominins and 42 papionins spanning 4 million y. These results reveal unprecedented environmental histories in primate teeth and suggest a framework for evaluating climate change and primate paleoecology throughout the Cenozoic.

Assessment of skin sensitization potential of zinc oxide, aluminum oxide, manganese oxide, and copper oxide nanoparticles through the local lymph node assay: 5-bromo-deoxyuridine flow cytometry method.

The advent of nanotechnology has significantly spurred the utilization of nanoparticles (NPs) across diverse sectors encompassing industry, agriculture, engineering, cosmetics, and medicine. Metallic oxides including zinc oxide (ZnO), copper oxide (CuO), manganese oxide (Mn2O3), and aluminum oxide (Al2O3), in their NP forms, have become prevalent in cosmetics and various dermal products. Despite the expanding consideration of these compounds for dermal applications, their potential for initiating skin sensitization (SS) has not been comprehensively examined. An in vivo assay, local lymph node assay: 5-bromo-2-deoxyuridine-flow cytometry method (LLNA: BrdU-FCM) recognized as an alternative testing method for screening SS potential was used to address these issues. Following the OECD TG 442B guidelines, NPs suspensions smaller than 50 nm size were prepared for ZnO and Al2O3 at concentrations of 10, 25, and 50%, and Mn2O3 and CuO at concentrations of 5, 10, and 25%, and applied to the dorsum of each ear of female BALB/c mice on a daily basis for 3 consecutive days. Regarding the prediction of test substance to skin sensitizer if sensitization index (SI)≥2.7, all 4 NPs were classified as non-sensitizing. The SI values were below 2.06, 1.33, 1.42, and 0.99 for ZnO, Al2O3, Mn2O3, and CuO, respectively, at all test concentrations. Although data presented were negative with respect to adverse SS potential for these 4 NPs, further confirmatory tests addressing other key events associated with SS adverse outcome pathway need to be carried out to arrive at an acceptable conclusion on the skin safety for both cosmetic and dermal applications.

Oral subacute polypropylene microplastics administration effect on potential immunotoxicity in ICR mice.

Exposure to microplastics may be associated with damage of immune system. Polypropylene microplastics (PP-MPs) with a wide range of beneficial applications have not been extensively studied with respect to the immune system. The aim of this investigation is to examine the influence of two different sizes of PP-MPs (5.2 and 23.9 µm diameter) on immune system components in ICR mice. PP-MPs were administered orally to female and male mice at 0 (corn oil vehicle), 500, 1000, or 2000 mg/kg/d for single and daily for 4-week repeated toxicity test, respectively. No significant differences were observed in number of thymic CD4+, CD8+, CD4+CD8+ T lymphocytes, splenic helper T cells, cytotoxic T cells, and B cells. The ratio of interferon-γ to interleukin-4 in culture supernatants from activated splenocytes ex vivo (48 hr) was lower in females which were repeatedly administered with PP-MPs compared to vehicle irrespective of PP-MPs size and dose. In contrast, the opposite trend was observed in males. Production of tumor necrosis factor-α was upregulated in females that were repeatedly exposed to PP-MPs. The serum IgG2a/IgG1 ratio was lowered in female receiving large-size PP-MPs. Data suggest that immune disturbances resulting in predominant type-2 helper T cell reactivity may occur in mice, especially in females, when repeatedly exposed to PP-MPs. Further investigations with longer exposure periods are necessary to determine the immunotoxicities attributed to PP-MPs.

Increasing the accuracy of the asthma diagnosis using an operational definition for asthma and a machine learning method.

INTRODUCTION: Analysis of the National Health Insurance data has been actively carried out for the purpose of academic research and establishing scientific evidences for health care service policy in asthma. However, there has been a limitation for the accuracy of the data extracted through conventional operational definition. In this study, we verified the accuracy of conventional operational definition of asthma, by applying it to a real hospital setting. And by using a machine learning technique, we established an appropriate operational definition that predicts asthma more accurately. METHODS: We extracted asthma patients using the conventional operational definition of asthma at Seoul St. Mary's hospital and St. Paul's hospital at the Catholic University of Korea between January 2017 and January 2018. Among these extracted patients of asthma, 10% of patients were randomly sampled. We verified the accuracy of the conventional operational definition for asthma by matching actual diagnosis through medical chart review. And then we operated machine learning approaches to predict asthma more accurately. RESULTS: A total of 4,235 patients with asthma were identified using a conventional asthma definition during the study period. Of these, 353 patients were collected. The patients of asthma were 56% of study population, 44% of patients were not asthma. The use of machine learning techniques improved the overall accuracy. The XGBoost prediction model for asthma diagnosis showed an accuracy of 87.1%, an AUC of 93.0%, sensitivity of 82.5%, and specificity of 97.9%. Major explanatory variable were ICS/LABA,LAMA and LTRA for proper diagnosis of asthma. CONCLUSIONS: The conventional operational definition of asthma has limitation to extract true asthma patients in real world. Therefore, it is necessary to establish an accurate standardized operational definition of asthma. In this study, machine learning approach could be a good option for building a relevant operational definition in research using claims data.

When Doctors Swear, Do Patients Care? Two Experiments Examining Physicians Cursing in the Presence of Patients.

Swearing in everyday conversation has become more normalized in recent years; but less certain, however, is how accepting Americans are when a doctor swears in their presence. Two online experiments (Study 1: n = 497; Study 2: n = 1,224) were conducted with US participants to investigate the impact of a doctor swearing in the course of examining a patient's infected wound (i.e., "You've got a lot of nasty [shit/stuff] in there that we're going to want to flush out"), or swearing when dropping papers in a patient's presence while varying the intensity of a swear (i.e., "[Shit!/Damn!/Whoops!]"), with or without an apology (i.e., "I'm sorry"). Overall findings reveal a main effect for swearing, with a swearing doctor generally seen as less likable, and in Study 1, less trustworthy, approachable, and less of an expert. However, the majority of participants exposed to a swearing doctor still said they would visit that physician again. Open-ended responses from these participants revealed that they perceived a swearing doctor as more human. Results from Study 2 also found that if a doctor swore, the negative impact was lessened if the doctor apologized immediately after cursing. While results from these studies indicate it is wise for doctors to refrain from swearing, most participants were still willing to make a future appointment with a cursing doctor.

Bakuchiol, main component of root bark of Ulmus davidiana var. japonica, inhibits TGF-ß-induced in vitro EMT and in vivo metastasis.

Cancer is a second leading cause of death worldwide, and metastasis is the major cause of cancer-related mortality. The epithelial-mesenchymal transition (EMT), known as phenotypic change from epithelial cells to mesenchymal cells, is a crucial biological process during development. However, inappropriate activation of EMT contributes to tumor progression and promoting metastasis; therefore, inhibiting EMT is considered a promising strategy for developing drugs that can treat or prevent cancer. In the present study, we investigated the anti-cancer effect of bakuchiol (BC), a main component of Ulmus davidiana var. japonica, in human cancer cells using A549, HT29 and MCF7 cells. In MTT and colony forming assay, BC exerted cytotoxicity activity against cancer cells and inhibited proliferation of these cells. Anti-metastatic effects by BC were further confirmed by observing decreased migration and invasion in TGF-ß-induced cancer cells after BC treatment. Furthermore, BC treatment resulted in increase of E-cadherin expression and decrease of Snail level in Western blotting and immunofluorescence analysis, supporting its anti-metastatic activity. In addition, BC inhibited lung metastasis of tail vein injected human cancer cells in animal model. These findings suggest that BC inhibits migration and invasion of cancers by suppressing EMT and in vivo metastasis, thereby may be a potential therapeutic agent for treating cancers.

Exposure to lead on expression levels of brain immunoglobulins, inflammatory cytokines, and brain-derived neurotropic factor in fetal and postnatal mice with autism-like characteristics.

Autism spectrum disorders (ASD) are neurodevelopmental disorders, and their incidence is increasing worldwide. Increased exposure to environmental metal lead (Pb) has been proposed as a risk factor associated with ASD. In the present study, BTBR T+ tf/J (BTBR) mice with ASD-like behavioral characteristics and control FVB mice were exposed gestationally and/or neonatally to Pb, and compared with highly social FVB mice to investigate neuroimmunological abnormalities. IgG1 and IgG2a levels in fetal brains from BTBR dams exposed to Pb (BTBR-Pb) were significantly higher than those of BTBR-controls (BTBR-C). However, this change did not occur in FVB mice exposed to Pb. The IgG1:IgG2a ratio was higher in both fetal and postnatal brains of BTBR mice compared to FVB animals regardless of Pb exposure. The IL-4:IFN-γ ratio was elevated in BTBR-Pb relative to BTBR-C mice, but this ratio was not markedly affected following Pb exposure in FVB animals. These findings suggest the potential for a Pb-driven predominant TH2-like reactivity profile in brain microenvironment present in BTBR mice. Brain-derived neurotrophic factor was decreased in fetal and postnatal BTBR-Pb brains relative to BTBR-C brains but not in FVB-Pb relative to FVB-C mice. Taken together, data demonstrate that Pb exposure might contribute to developmental brain abnormalities associated with ASD, particularly in individuals with genetic susceptibility to ASD.

Machine Learning for Mental Health in Social Media: Bibliometric Study.

BACKGROUND: Social media platforms provide an easily accessible and time-saving communication approach for individuals with mental disorders compared to face-to-face meetings with medical providers. Recently, machine learning (ML)-based mental health exploration using large-scale social media data has attracted significant attention. OBJECTIVE: We aimed to provide a bibliometric analysis and discussion on research trends of ML for mental health in social media. METHODS: Publications addressing social media and ML in the field of mental health were retrieved from the Scopus and Web of Science databases. We analyzed the publication distribution to measure productivity on sources, countries, institutions, authors, and research subjects, and visualized the trends in this field using a keyword co-occurrence network. The research methodologies of previous studies with high citations are also thoroughly described. RESULTS: We obtained a total of 565 relevant papers published from 2015 to 2020. In the last 5 years, the number of publications has demonstrated continuous growth with Lecture Notes in Computer Science and Journal of Medical Internet Research as the two most productive sources based on Scopus and Web of Science records. In addition, notable methodological approaches with data resources presented in high-ranking publications were investigated. CONCLUSIONS: The results of this study highlight continuous growth in this research area. Moreover, we retrieved three main discussion points from a comprehensive overview of highly cited publications that provide new in-depth directions for both researchers and practitioners.

OSMI-1 Enhances TRAIL-Induced Apoptosis through ER Stress and NF-κB Signaling in Colon Cancer Cells.

Levels of O-GlcNAc transferase (OGT) and hyper-O-GlcNAcylation expression levels are associated with cancer pathogenesis. This study aimed to find conditions that maximize the therapeutic effect of cancer and minimize tissue damage by combining an OGT inhibitor (OSMI-1) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). We found that OSMI-1 treatment in HCT116 human colon cancer cells has a potent synergistic effect on TRAIL-induced apoptosis signaling. Interestingly, OSMI-1 significantly increased TRAIL-mediated apoptosis by increasing the expression of the cell surface receptor DR5. ROS-induced endoplasmic reticulum (ER) stress by OSMI-1 not only upregulated CHOP-DR5 signaling but also activated Jun-N-terminal kinase (JNK), resulting in a decrease in Bcl2 and the release of cytochrome c from mitochondria. TRAIL induced the activation of NF-κB and played a role in resistance as an antiapoptotic factor. During this process, O-GlcNAcylation of IκB kinase (IKK) and IκBα degradation occurred, followed by translocation of p65 into the nucleus. However, combination treatment with OSMI-1 counteracted the effect of TRAIL-mediated NF-κB signaling, resulting in a more synergistic effect on apoptosis. Therefore, the combined treatment of OSMI-1 and TRAIL synergistically increased TRAIL-induced apoptosis through caspase-8 activation. Conclusively, OSMI-1 potentially sensitizes TRAIL-induced cell death in HCT116 cells through the blockade of NF-κB signaling and activation of apoptosis through ER stress response.