Search

Background The burden of chronic obstructive pulmonary disease (COPD) in the Asia-Pacific region is projected to increase. Data from other regions show bacterial and viral infections can trigger acute exacerbations of COPD (AECOPD). Methods This 1-year prospective epidemiological study (ClinicalTrials.gov identifier: NCT03151395) of patients with moderate to very severe COPD in Hong Kong, the Philippines, South Korea and Taiwan assessed the prevalence in sputum samples (by culture and PCR) of bacterial and viral pathogens during stable COPD and AECOPD. The odds of experiencing an exacerbation was evaluated for pathogen presence, acquisition and apparition. Health-related quality of life (HRQOL) was assessed. Results 197 patients provided 983 sputum samples, with 226 provided during exacerbation episodes. The mean yearly AECOPD incidence rate was 1.27 per patient. The most prevalent bacteria by PCR at exacerbation were Haemophilus influenzae (Hi) and Moraxella catarrhalis (Mcat); Mcat prevalence was higher at exacerbation than at stable state. Virus prevalence was low, other than for human rhinovirus (HRV) (8.1%, stable state; 16.6%, exacerbation). The odds ratio (95% CI) for an exacerbation (versus stable state) was statistically significant for the presence, acquisition and apparition of Hi (2.20, 1.26–3.89; 2.43, 1.11–5.35; 2.32, 1.20–4.46, respectively), Mcat (2.24, 1.30–3.88; 5.47, 2.16–13.86; 3.45, 1.71–6.98, respectively) and HRV (2.12, 1.15–3.91; 2.22, 1.09–4.54; 2.09, 1.11–3.91, respectively). HRQOL deteriorated according to the number of exacerbations experienced. Conclusion In patients with COPD in the Asia-Pacific region, the presence of Hi, Mcat or HRV in sputum samples significantly increased the odds of an exacerbation, providing further evidence of potential roles in triggering AECOPD.

Background/purpose: Patients with cancer are eligible for hospice care when their life expectancy is 180 days or shorter. This study investigated the prognostic factors of patients with cancer and sepsis who were admitted to an intensive care unit (ICU) to assist with clinical decisions of hospice care. Methods: A series of 279 patients admitted to the medical ICU with cancer and sepsis were included. Another series of 109 patients with cancer and sepsis admitted to the other medical ICU in the different branch of our hospital was included to verify the results. Results: Among 279 patients, the 30-, 90-, and 180-day mortality rates were 47.3%, 72.0%, and 81.0%, respectively. APACHE II score and the cancer control status (controlled or remission (CR), active newly diagnosed (AND) and active recurrent or progressive (ARP)) were significant predictors of 30- and 90-day mortality(30-day: AND(odds ratio: 5.66; 95% confidence interval: 2.12-15.15), ARP(6.24; 2.92-13.33), APACHE II( 1.07; 1.03-1.11); 90-day: AND(4.78; 1.91-11.99), ARP( 24.03; 11.11-51.99), APACHE II( 1.07; 1.02-1.19)) and were associated with a poor 180-day outcome. The 180-day mortality were significantly different among the patients with different cancer control status in the series of 279 patients (CR: 29.8%; AND: 69.4%; and ARP: 98.9 %) and that of 109 patients (46.4%; 96.8%; and 94.0%). Conclusion: APACHE II score and the cancer control status may be the prognostic factors for critically ill patients with cancer and sepsis, and they may be helpful for evaluating hospice care. Keywords: Cancer, Sepsis, Hospice care, Prognosis, ICU

Abstract TAR DNA‐binding protein 43 (TDP‐43) has been implicated in frontotemporal lobar degeneration with ubiquitin‐positive inclusions (FTLD‐TDP) and amyotrophic lateral sclerosis. Histone deacetylase 1 (HDAC1) is involved in DNA repair and neuroprotection in numerous neurodegenerative diseases. However, the pathological mechanisms of FTLD‐TDP underlying TDP‐43 proteinopathies are unclear, and the role of HDAC1 is also poorly understood. Here, we found that aberrant cell cycle activity and DNA damage are important pathogenic factors in FTLD‐TDP transgenic (Tg) mice, and we further identified these pathological features in the frontal cortices of patients with FTLD‐TDP. TDP‐43 proteinopathies contributed to pathogenesis by inducing cytosolic mislocalization of HDAC1 and reducing its activity. Pharmacological recovery of HDAC1 activity in FTLD‐TDP Tg mice ameliorated their cognitive and motor impairments, normalized their aberrant cell cycle activity, and attenuated their DNA damage and neuronal loss. Thus, HDAC1 deregulation is involved in the pathogenesis of TDP‐43 proteinopathies, and HDAC1 is a potential target for therapeutic interventions in FTLD‐TDP.

Interleukin (IL)-17 family members (IL-17A to IL-17F) are appearing to play key roles in host defense and inflammatory disease. Recently, several cytokines, such as IL-6, IL-10, IL-12, and transforming growth factor (TGF)-β1, were shown to have vital roles in severe sepsis. However, the influence of IL-17 on these cytokine responses from peripheral blood mononuclear cells (PBMCs) is unclear. Methods: Fifty-two patients who were admitted to our intensive care unit (ICU) because of severe sepsis were enrolled into this study. To validate experimental findings, 25 healthy controls were enrolled. Lipopolysaccharide-stimulated PBMCs with IL-17 or anti-IL-17 treatments were cultured for 24 hours. IL-6, IL-10, IL-12, and TGF-β1 levels in supernatants were measured. Results: The IL-12 production from stimulated PBMCs was increased after IL-17 treatment in both control and patient groups. Additional treatment of anti-IL-17 enhanced IL-10 production but decreased IL-12 production from stimulated PBMCs of healthy controls and patients with severe sepsis. Conclusion: IL-17 was helpful for inflammation in severe sepsis. Lack of IL-17 decreased IL-12 and enhanced IL-10 production from PBMCs, which resulted in immune imbalance.

Frontotemperal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are two common neurodegenerative diseases. TDP-43 is considered to be a major disease protein in FTLD/ALS, but it’s exact role in the pathogenesis and the effective treatments remains unknown. To address this question and to determine a potential treatment for FTLD/ALS, the disease animal models of TDP-43 proteinopathy have been established. TDP-43 proteinopathy is the histologic feature of FTLD/ALS and is associated with disease progression. Studies on the disease animal models with TDP-43 proteinopathy and their pre-clinical applications are reviewed and summarized. Through these disease animal models, parts of TDP-43 functions in physiological and pathological conditions will be better understood and possible treatments for FTLD/ALS with TDP-43 proteinopathy may be identified for possible clinical applications in the future.

Background. The risk factors for Staphylococcus aureus (S. aureus) pneumonia are not fully identified. The aim of this work was to find out the clinical characteristics associated with S. aureus infection in patients with healthcare-associated pneumonia (HCAP) and hospital-acquired pneumonia (HAP), which may be applicable for more appropriate selection of empiric antibiotic therapy. Methods. From July 2007 to June 2010, patients who were admitted to the intensive care unit with severe HCAP/HAP and severe sepsis were enrolled in this study. Lower respiratory tract sample was semiquantitatively cultured. Initial broad-spectrum antibiotics were chosen by Taiwan or American guidelines for pneumonia management. Standard bundle therapies were provided to all patients according to the guidelines of the Surviving Sepsis Campaign. Results. The most frequently isolated pathogens were Pseudomonas aeruginosa, S. aureus, Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli. Patients with positive isolation of S. aureus in culture had significantly higher history of liver cirrhosis and diabetes mellitus, with odds ratios of 3.098 and 1.899, respectively. The S. aureus pneumonia was not correlated with history of chronic obstructive pulmonary disease, hypertension, and hemodialysis. Conclusion. Liver cirrhosis and diabetes mellitus may be risk factors for S. aureus infection in patients with severe HCAP or HAP.

Macrophage activation assisted by interferon-gamma (IFN-γ) is a primary mechanism by which Mycobacterium tuberculosis is killed, but IFN-γ (production is inhibited in tuberculosis (TB) patients. The production of IFN-γ is influenced by many factors, such as interleukin (IL)-10, IL-12, IL-18, and clinical diseases; but the relative importance of each factor is unclear. Methods: We evaluated the effects of these factors in 46 healthy individuals, 81 patients with TB, and 88 patients with non-TB pneumonia. The responses of IFN-γ, IL-10, IL-12 and IL-18 were determined from phytohemagglutinin-stimulated peripheral blood mononuclear cells (PBMCs). Results: General linear model analysis showed that disease status and IL-12 response were the independent factors associated with the IFN-γ response. The production of IFN-γ was not affected by IL-10 and IL-18. There was a significant relationship between the IFN-γ response and the IL-12 response among patients with non-TB pneumonia, patients with TB, and healthy participants (Pearson's correlation coefficients of 0.466, 0.483, and 0.464, respectively). Conclusion: Production of IFN-γ in PBMCs was associated with active pulmonary TB and IL-12 response.

SET7, serving as the only histone methyltransferase that monomethylates ‘Lys-4’ of histone H3, has been proved to function as a key regulator in diverse biological processes, such as cell proliferation, transcriptional network regulation in embryonic stem cell, cell cycle control, protein stability, heart morphogenesis and development. What′s more, SET7 is involved inthe pathogenesis of alopecia aerate, breast cancer, tumor and cancer progression, atherosclerosis in human carotid plaques, chronic renal diseases, diabetes, obesity, ovarian cancer, prostate cancer, hepatocellular carcinoma, and pulmonary fibrosis. Therefore, there is urgent need to develop novel SET7 inhibitors. In this paper, based on DC-S239 which has been previously reported in our group, we employed scaffold hopping- and 2D fingerprint-based similarity searches and identified DC-S285 as the new hit compound targeting SET7 (IC50 = 9.3 μM). Both radioactive tracing and NMR experiments validated the interactions between DC-S285 and SET7 followed by the second-round similarity search leading to the identification ofDC-S303 with the IC50 value of 1.1 μM. In cellular level, DC-S285 retarded tumor cell proliferation and showed selectivity against MCF7 (IC50 = 21.4 μM), Jurkat (IC50 = 2.2 μM), THP1 (IC50 = 3.5 μM), U937 (IC50 = 3.9 μM) cell lines. Docking calculations suggested that DC-S303 share similar binding mode with the parent compoundDC-S239. What′s more, it presented good selectivity against other epigenetic targets, including SETD1B, SETD8, G9a, SMYD2 and EZH2. DC-S303 can serve as a drug-like scaffold which may need further optimization for drug development, and can be used as chemical probe to help the community to better understand the SET7 biology.

Regulation of type-I interferon (IFN) production is essential to the balance between antimicrobial defence and autoimmune disorders. The human protein-coding gene ILRUN (inflammation and lipid regulator with UBA-like and NBR1-like domains, previously C6orf106) was recently characterised as an inhibitor of antiviral and proinflammatory cytokine (interferon-alpha/beta and tumor necrosis factor alpha) transcription. Currently there is a paucity of information about the molecular characteristics of ILRUN, despite it being associated with several diseases including virus infection, coronary artery disease, obesity and cancer. Here, we characterise ILRUN as a highly phylogenetically conserved protein containing UBA-like and a NBR1-like domains that are both essential for inhibition of type-I interferon and tumor necrosis factor alpha) transcription in human cells. We also solved the crystal structure of the NBR1-like domain, providing insights into its potential role in ILRUN function. This study provides critical information for future investigations into the role of ILRUN in health and disease.