Posttranslational modifications (PTM) of PD-L1 have emerged as important regulatory mechanisms that modulate immunosuppression in patients with cancer. In exposure to inflammatory cytokines, cancer ...cells and antigen-presenting cells, such as macrophages and dendritic cells, express PD-L1 to inhibit the activity of effector T cells through PD-1 engagement. Recent studies suggested that glycosylation, phosphorylation, ubiquitination, sumoylation, and acetylation play important roles in the regulation of PD-L1 protein stability and translocation and protein-protein interactions. Aberrant alterations of PTMs directly influence PD-L1-mediated immune resistance. On the basis of the newly identified regulatory signaling pathways of PD-L1 PTMs, researchers have investigated the cancer therapeutic potential of natural food compounds, small-molecule inhibitors, and mAbs by targeting PD-L1 PTMs. Results of these preclinical studies demonstrated that targeting PTMs of PD-L1 yields promising antitumor effects and that clinical translation of these therapeutic strategies is warranted.
.
The association between body mass index and mortality in patients with tuberculosis has not been extensively studied, and the existing evidence is inconsistent. This study aimed to investigate the ...impact of body mass index on timing of death in patients with tuberculosis.
All Taiwanese adults with tuberculosis in Taipei, Taiwan, were included in a retrospective cohort study in 2011-2012. Multinomial logistic regression was used to evaluate the association between body mass index and timing of death in patients with tuberculosis.
Among 1557 eligible patients, 84.1% (1310), 8.2% (128), and 7.6% (119) underwent successful treatment, early death, and late death, respectively. The mean age of the patients with tuberculosis was 64.2 years old, and 67.7% were male. After controlling for potential confounding variables, underweight with body mass index less than 18.5 kg/ m2 was significantly associated with elevated risk of all-cause mortality Adjusted odds ratio (AOR), 1.64; 95% confidence interval (CI), 1.17-2.30. Considering timing of death, underweight with body mass index less than 18.5 was significantly associated only with elevated risk of early mortality within the first 8 weeks of treatment onset (AOR, 2.22; 95% CI, 1.45-3.40).
For patients with tuberculosis infection, underweight with body mass index less than 18.5 kg/ m2 is an independent predictor for early mortality within the first 8 weeks of treatment.
The peripheral immune system plays a critical role in aging and in the response to brain injury. Emerging data suggest inflammatory responses are exacerbated in older animals following ischemic ...stroke; however, our understanding of these age-related changes is poor. In this work, we demonstrate marked differences in the composition of circulating and infiltrating leukocytes recruited to the ischemic brain of old male mice after stroke compared to young male mice. Blood neutrophilia and neutrophil invasion into the brain were increased in aged animals. Relative to infiltrating monocyte populations, brain-invading neutrophils had reduced phagocytic potential, and produced higher levels of reactive oxygen species and extracellular matrix-degrading enzymes (i.e., MMP-9), which were further exacerbated with age. Hemorrhagic transformation was more pronounced in aged versus young mice relative to infarct size. High numbers of myeloperoxidase-positive neutrophils were found in postmortem human brain samples of old (> 71 years) acute ischemic stroke subjects compared to non-ischemic controls. Many of these neutrophils were found in the brain parenchyma. A large proportion of these neutrophils expressed MMP-9 and positively correlated with hemorrhage and hyperemia. MMP-9 expression and hemorrhagic transformation after stroke increased with age. These changes in the myeloid response to stroke with age led us to hypothesize that the bone marrow response to stroke is altered with age, which could be important for the development of effective therapies targeting the immune response. We generated heterochronic bone marrow chimeras as a tool to determine the contribution of peripheral immune senescence to age- and stroke-induced inflammation. Old hosts that received young bone marrow (i.e., Young → Old) had attenuation of age-related reductions in bFGF and VEGF and showed improved locomotor activity and gait dynamics compared to isochronic (Old → Old) controls. Microglia in young heterochronic mice (Old → Young) developed a senescent-like phenotype. After stroke, aged animals reconstituted with young marrow had reduced behavioral deficits compared to isochronic controls, and had significantly fewer brain-infiltrating neutrophils. Increased rates of hemorrhagic transformation were seen in young mice reconstituted with aged bone marrow. This work suggests that age alters the immunological response to stroke, and that this can be reversed by manipulation of the peripheral immune cells in the bone marrow.
Glycosylation of immune receptors and ligands, such as T cell receptor and coinhibitory molecules, regulates immune signaling activation and immune surveillance. However, how oncogenic signaling ...initiates glycosylation of coinhibitory molecules to induce immunosuppression remains unclear. Here we show that IL-6-activated JAK1 phosphorylates programmed death-ligand 1 (PD-L1) Tyr112, which recruits the endoplasmic reticulum-associated N-glycosyltransferase STT3A to catalyze PD-L1 glycosylation and maintain PD-L1 stability. Targeting of IL-6 by IL-6 antibody induced synergistic T cell killing effects when combined with anti-T cell immunoglobulin mucin-3 (anti-Tim-3) therapy in animal models. A positive correlation between IL-6 and PD-L1 expression was also observed in hepatocellular carcinoma patient tumor tissues. These results identify a mechanism regulating PD-L1 glycosylation initiation and suggest the combination of anti-IL-6 and anti-Tim-3 as an effective marker-guided therapeutic strategy.
Abstract
Iron imbalance in the brain negatively affects brain function. With aging, iron levels increase in the brain and contribute to brain damage and neurological disorders. Changes in the ...cerebral vasculature with aging may enhance iron entry into the brain parenchyma, leading to iron overload and its deleterious consequences. Endothelial senescence has emerged as an important contributor to age‐related changes in the cerebral vasculature. Evidence indicates that iron overload may induce senescence in cultured cell lines. Importantly, cells derived from female human and mice generally show enhanced senescence‐associated phenotype, compared with males. Thus, we hypothesize that cerebral endothelial cells (CEC) derived from aged female mice are more susceptible to iron‐induced senescence, compared with CEC from aged males. We found that aged female mice, but not males, showed cognitive deficits when chronically treated with ferric citrate (FC), and their brains and the brain vasculature showed senescence‐associated phenotype. We also found that primary culture of CEC derived from aged female mice, but not male‐derived CEC, exhibited senescence‐associated phenotype when treated with FC. We identified that the transmembrane receptor
Robo4
was downregulated in the brain vasculature and in cultured primary CEC derived from aged female mice, compared with those from male mice. We discovered that
Robo4
downregulation contributed to enhanced vulnerability to FC‐induced senescence. Thus, our study identifies
Robo4
downregulation as a driver of senescence induced by iron overload in primary culture of CEC and a potential risk factor of brain vasculature impairment and brain dysfunction.
Although advance directives (AD) have been implemented for years in western countries, the concept of AD is not promoted extensively in eastern countries. In this study we evaluate a program to ...systematically conduct advance care planning (ACP) communication for hospitalized patients in Taiwan and identify the factors associated with AD completion.
In this retrospective evaluation of a clinical ACP program, we identified adult patients with chronic life-limiting illness admitted to Taipei City Hospital between April 2015 and January 2016. Trained healthcare providers held an ACP meeting to discuss patients' preference regarding end-of-life care and AD completion. A multiple logistic regression was performed to determine the factors associated with the AD completion.
A total of 2878 patients were determined to be eligible for ACP during the study, among which 1798 (62.5%) completed ACP and data was available for 1411 patients (49.1%). Of the 1411 patients who received ACP communication with complete data, the rate of AD completion was 82.6%. The overall mean (SD) age was 78.2 (14.4) years. Adjusting for other variables, AD completion was associated with patients aged ≥ 85 years adjusted odds ratio (AOR) = 1.80, 95% CI 1.21-2.67, critical illness (AOR = 1.17, 95% CI 1.06-1.30), and social workers participating in ACP meetings (AOR = 1.74, 95% CI 1.24-2.45).
The majority of inpatients with chronic life-limiting illness had ACP communication as part of this ACP program and over 80% completed an AD. Our study demonstrates the feasibility of implementing ACP discussion in East Asia and suggests that social workers may be an important component of ACP communication with patients.
Nonalcoholic fatty liver disease (NAFLD) can develop in prenatal stages and can be exacerbated by exposure to a postnatal high-fat (HF) diet. We investigated the protective effects of resveratrol on ...prenatal and postnatal HF diet-induced NAFLD.
Male Sprague-Dawley rat offspring were placed in five experimental groups (n = 10-12 per group): normal diet (VNF), maternal HF diet (ONF), postnatal HF diet (VHF), and maternal HF diet/postnatal HF diet (OHF). A therapeutic group with resveratrol for maternal HF diet/postnatal HF diet (OHFR) was used for comparison. Resveratrol (50 mg/kg/day) was dissolved in drinking water for offspring from post-weaning to postnatal day (PND) 120.
We found that HF/HF-induced NAFLD was prevented in adult offspring by the administration of resveratrol. Resveratrol administration mediated a protective effect on rats on HF/HF by regulating lipid metabolism, reducing oxidative stress and apoptosis, restoring nutrient-sensing pathways by increasing Sirt1 and leptin expression, and mediating the renin-angiotensin system (RAS) to decrease angiotensinogen, renin, ACE1, and AT1R levels and increased ACE2, AT2R and MAS1 levels compared to those in the OHF group.
Our results suggest that a maternal and post-weaning HF diet increases liver steatosis and apoptosis via the RAS. Resveratrol might serve as a therapeutic target by mediating protective actions against NAFLD in offspring exposed to a combination of maternal and postnatal HF diet.
The intuitive assessment of palliative care (PC) needs and Palliative Care Screening Tool (PCST) are the assessment tools used in the early detection of patients requiring PC. However, the comparison ...of their prognostic accuracies has not been extensively studied. This cohort study aimed to compare the validity of intuitive assessment and PCST in terms of recognizing patients nearing end-of-life (EOL) and those appropriate for PC. All adult patients admitted to Taipei City Hospital from 2016 through 2019 were included in this prospective study. We used both the intuitive assessment of PC and PCST to predict patients' 6-month mortality and identified those appropriate for PC. The c-statistic value was calculated to indicate the predictive accuracies of the intuition and PCST. Of 111,483 patients, 4.5% needed PC by the healthcare workers' intuitive assessment, and 6.7% had a PCST score ≥ 4. After controlling for other covariates, a positive response 'yes' to intuitive assessment of PC needs adjusted odds ratio (AOR) = 9.89; 95% confidence interval (CI) 914-10.71 and a PCST score ≥ 4 (AOR = 6.59; 95%CI 6.17-7.00) were the independent predictors of 6-month mortality. Kappa statistics showed moderate concordance between intuitive assessment and PCST in predicting patients' 6-month mortality (k = 0.49). The c-statistic values of the PCST at recognizing patients' 6-month mortality was significantly higher than intuition (0.723 vs. 0.679; p < 0.001). As early identification of patients in need of PC could improve the quality of EOL care, our results suggest that it is imperative to screen patients' palliative needs by using a highly accurate screening tool of PCST.
Abstract
Immunotherapies targeting programmed cell death protein 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) immune checkpoints represent a major breakthrough in cancer treatment. PD-1 is ...an inhibitory receptor expressed on the surface of activated T cells that dampens T-cell receptor (TCR)/CD28 signaling by engaging with its ligand PD-L1 expressed on cancer cells. Despite the clinical success of PD-1 blockade using mAbs, most patients do not respond to the treatment, and the underlying regulatory mechanisms of PD-1 remain incompletely defined. Here we show that PD-1 is extensively N-glycosylated in T cells and the intensities of its specific glycoforms are altered upon TCR activation. Glycosylation was critical for maintaining PD-1 protein stability and cell surface localization. Glycosylation of PD-1, especially at the N58 site, was essential for mediating its interaction with PD-L1. The mAb STM418 specifically targeted glycosylated PD-1, exhibiting higher binding affinity to PD-1 than FDA-approved PD-1 antibodies, potently inhibiting PD-L1/PD-1 binding, and enhancing antitumor immunity. Together, these findings provide novel insights into the functional significance of PD-1 glycosylation and offer a rationale for targeting glycosylated PD-1 as a potential strategy for immunotherapy.
Significance:
These findings demonstrate that glycosylation of PD-1 is functionally significant and targeting glycosylated PD-1 may serve as a means to improve immunotherapy response.
Inhibitors of MET have not produced satisfactory outcomes in trials of patients with liver cancer. We investigated the mechanisms of liver tumor resistance to MET inhibitors in mice.
We tested the ...effects of MET inhibitors tivantinib and capmatinib in the mouse hepatocellular carcinoma (HCC) cell line HCA-1 and in immune-competent and immunodeficient mice with subcutaneous tumors grown from this cell line. Tumors were collected from mice and tumor cells were analyzed by time-of-flight mass cytometry. We used short hairpin RNAs to weaken expression of MET in Hep3B, SK-HEP-1, HA59T, and HA22T liver cancer cell lines and analyzed cells by immunoblot, immunofluorescence, and immunoprecipitation assays. Mass spectrometry was used to assess interactions between MET and glycogen synthase kinase 3β (GSK3B), and GSK3B phosphorylation, in liver cancer cell lines. C57/BL6 mice with orthotopic tumors grown from Hep1-6 cells were given combinations of capmatinib or tivantinib and antibodies against programmed cell death 1 (PDCD1; also called PD1); tumors were collected and analyzed by immunofluorescence. We analyzed 268 HCCsamples in a tissue microarray by immunohistochemistry.
Exposure of liver cancer cell lines to MET inhibitors increased their expression of PD ligand 1 (PDL1) and inactivated cocultured T cells. MET phosphorylated and activated GSK3B at tyrosine 56, which decreased the expression of PDL1 by liver cancer cells. In orthotopic tumors grown in immune-competent mice, MET inhibitors decreased the antitumor activity of T cells. However, addition of anti-PD1 decreased orthotopic tumor growth and prolonged survival of mice compared with anti-PD1 or MET inhibitors alone. Tissue microarray analysis of HCC samples showed an inverse correlation between levels of MET and PDL1 and a positive correlation between levels of MET and phosphorylated GSK3B.
In studies of liver cancer cell lines and mice with orthotopic tumors, MET mediated phosphorylation and activated GSK3B, leading to decreased expression of PDL1. Combined with a MET inhibitor, anti-PD1 and anti-PDL1 produced additive effect to slow growth of HCCs in mice.
PDF
