Zhijun Jie

Human Infection with a Novel Avian-Origin Influenza A (H7N9) Virus

BACKGROUND Infection of poultry with influenza A subtype H7 viruses occurs worldwide, but the introduction of this subtype to humans in Asia has not been observed previously. In March 2013, three urban residents of Shanghai or Anhui, China, presented with rapidly progressing lower respiratory tract infections and were found to be infected with a novel reassortant avian-origin influenza A (H7N9) virus. METHODS We obtained and analyzed clinical, epidemiologic, and virologic data from these patients. Respiratory specimens were tested for influenza and other respiratory viruses by means of real-time reverse-transcriptase-polymerase-chain-reaction assays, viral culturing, and sequence analyses. RESULTS A novel reassortant avian-origin influenza A (H7N9) virus was isolated from respiratory specimens obtained from all three patients and was identified as H7N9. Sequencing analyses revealed that all the genes from these three viruses were of avian origin, with six internal genes from avian influenza A (H9N2) viruses. Substitution Q226L (H3 numbering) at the 210-loop in the hemagglutinin (HA) gene was found in the A/Anhui/1/2013 and A/Shanghai/2/2013 virus but not in the A/Shanghai/1/2013 virus. A T160A mutation was identified at the 150-loop in the HA gene of all three viruses. A deletion of five amino acids in the neuraminidase (NA) stalk region was found in all three viruses. All three patients presented with fever, cough, and dyspnea. Two of the patients had a history of recent exposure to poultry. Chest radiography revealed diffuse opacities and consolidation. Complications included acute respiratory distress syndrome and multiorgan failure. All three patients died. CONCLUSIONS Novel reassortant H7N9 viruses were associated with severe and fatal respiratory disease in three patients. (Funded by the National Basic Research Program of China and others.).

The effects of Th2 cytokines on the expression of ADAM33 in allergen-induced chronic airway inflammation☆

A disintegrin and metalloprotease domain 33 (ADAM33) has been identified as an asthma susceptibility gene, which is associated with small-airway remodeling. However, the role of ADAM33 in the development of allergic airway inflammation is unclear. The present study used an established murine model of allergen-induced chronic airway inflammation, which was sensitized and then challenged by nebulized 2.5% ovalbumin (OVA) for 8 weeks (30 min/day, three times a week). The expression of ADAM33 mRNA detected by real time RT-PCR was significantly enhanced in the lung tissue of mice with OVA challenge, as compared with the group challenged with saline. This OVA-challenged model showed significant Th2-biased airway inflammation as well as airway remodeling with features of sub-epithelial fibrosis and mucus hyper-secretion. Furthermore, in vitro studies showed that IL-4 and IL-13 could significantly up-regulate the expression of ADAM33 mRNA in human fibroblasts in a concentration- and time-dependent manner as compared to normal controls. These results support the note that Th2 cytokines can up-regulate the expression of ADAM33 mRNA and ADAM33 may play an important role in the development of airway remodeling in allergen-induced chronic airway inflammation.

A Detailed Epidemiological and Clinical Description of 6 Human Cases of Avian-Origin Influenza A (H7N9) Virus Infection in Shanghai

Background The world’s first reported patient infected with avian influenza H7N9 was treated at the Fifth People’s Hospital of Shanghai. Shortly thereafter, several other cases emerged in the local area. Here, we describe the detailed epidemiological and clinical data of 6 cases of avian influenza H7N9. Methods and Findings We analyzed the epidemiologic and clinical data from clustered patients infected with H7N9 in the Minhang District of Shanghai during a 2-week period. Of the 6 patients, 2 were from a single family. In addition, 3 patients had a history of contact with poultry; however, all 6 patients lived in the proximity of 2 food markets where the H7N9 virus was detected in chickens and pigeons. The main symptoms were fever, cough, and hemoptysis. At onset, a decreased lymphocyte count and elevated creatine kinase, lactate dehydrogenase, procalcitonin, and C-reactive protein levels were observed. As the disease progressed, most patients developed dyspnea and hypoxemia. Imaging studies revealed lung consolidation and multiple ground-glass opacities in the early stage, rapidly extending bilaterally. All patients were treated with oseltamivir tablets beginning on days 3–8 after onset. The main complications were as follows: acute respiratory distress syndrome (ARDS; 83.3%), secondary bacterial infection (66.7%), pleural effusion (50%), left ventricular failure (33.3%), neuropsychiatric symptoms (33.3%), and rhabdomyolysis (16.7%). Of the 6 patients, 4 died of ARDS, with 2 patients recovering from the infection. Conclusions An outbreak of H7N9 infection occurred in the Minhang District of Shanghai that easily progressed to acute respiratory distress syndrome. Two cases showed family aggregation, which led us to identify the H7N9 virus and indicated that human transmission may be involved in the spread of this infection.

MicroRNA-141 promotes the proliferation of non-small cell lung cancer cells by regulating expression of PHLPP1 and PHLPP2

The dysregulation of microRNAs (miRNAs) is crucially implicated in the development of various cancers. In this study, we explored the biological role of miR‐141 in non‐small cell lung cancer (NSCLC). miR‐141 expression was significantly up‐regulated in NSCLC tissues, and its overexpression accelerated NSCLC cell proliferation in vitro and tumor growth in vivo. We subsequently identified the antagonists of PI3K/AKT signaling, PH domain leucine‐rich‐repeats protein phosphatase 1 (PHLPP1) and PHLPP2, as direct targets of miR‐141. Re‐introduction of PHLPP1 and PHLPP2 abrogated miR‐141‐induced proliferation of NSCLC cells. Together, the results of this study suggest that miR‐141 and its targets PHLPP1 and PHLPP2 play critical roles in NSCLC tumorigenesis, and provide potential therapeutic targets for NSCLC treatment.

ADAM33 Gene Polymorphisms Associate with Asthma Susceptibility and Severity in East China Han Population

Objective. Multiple genetic and environmental factors impact the pathogenesis of asthma. ADAM33 (a disintegrin and metalloproteinase domain 33) represents a novel susceptibility gene for asthma in several diverse populations. The aim of this study was to determine whether single nucleotide polymorphisms (SNPs) of the ADAM33 gene associate with asthma susceptibility and severity in the Chinese Han population. Methods. A total of 224 subjects were enrolled, including 74 normal controls and 150 asthmatic patients. The asthmatic enrollees were further categorized into high- or low-severity groups according to the percentage of forced expiratory volume in 1 second of predicted value, symptoms, nighttime awakening, requirement for short-acting β2-agonist, and interference with normal activities. Six SNPs (F + 1, ST + 4, S1, S2, T1, and T2) in ADAM33 were genotyped using the polymerase chain restriction fragment length polymorphism method. Results. Three SNPs (F + 1, T1, and T2) of ADAM33 were found to have significant associations with asthma in the study population (p = .0058−.0067). The allele frequencies of two SNPs (F + 1, T1) in both the low- and high-severity groups were significantly different from the allele frequency in the control group. The allelic frequency of the T2 SNP was significantly different from that of the control group only in the high-severity group (p = .0081). Haplotype analysis demonstrated that the frequency of 7575G, 12433T, and 12462C (GTC haplotype) is higher in healthy controls than amongst asthma patients (78.4% vs. 61.8%, p = .0004). Conclusions. Polymorphisms of the ADAM33 gene associate with asthma susceptibility in the east China Han population, and the genetic association is stronger in high-severity asthmatics.

Family Outbreak of Severe Pneumonia Induced by H7N9 Infection

monary function impairment. These findings from their patient cohort are consistent with the experience of the BAL guideline committee members in their clinical practice when BAL is used to evaluate patients with suspected ILD (1). Although significant complications have been associated with the performance of diagnostic BAL in patients with a suspected or established diagnosis of ILD (2, 3), such complications are rare. BAL not only has been widely used in patients with suspected ILD, but it can be used safely in patients with airway disorders (e.g., asthma or bronchiectasis) or lung transplant recipients when protocols are in place to ensure that adequate precautions are taken to maintain adequate monitoring throughout the procedure and during the post-procedure recovery period (4–6). It was our hope that the publication of this guideline would (1) enhance the safety and efficacy of BAL as a useful clinical tool for the evaluation of patients with suspected ILD, (2) lead to better standardization of the BAL procedure when performed in centers around the world, and (3) increase recognition of the potential for BAL cell analysis to enhance clinicians’ ability to make a confident diagnosis of specific forms of ILD in the appropriate clinical setting. When BAL is properly performed and analyzed, the BAL cell differential count can provide very useful diagnostic information when combined with clinical findings and appropriate thoracic high-resolution computed tomography imaging (1, 7). The study by Agarwal and colleagues nicely demonstrates that BAL can be performed safely with adequate retrieval of lavage fluid for subsequent analysis when a protocol consistent with the ATS clinical practice guideline is used.

Association between genetic polymorphisms in XPD and XRCC1 genes and risks of non-small cell lung cancer in East Chinese Han population.

Lung cancer is a multifactorial disease. Xeroderma pigmentosum group D (XPD) and X‐ray repair cross‐complementing 1 (XRCC1) genes are 2 important susceptibility genes related to lung cancer. In this study, we explored the correlation between genetic polymorphisms in XPD and XRCC1 and the risk of non‐small cell lung cancer (NSCLC) in the East Chinese Han population. We also investigated risk factors associated with non‐small cell lung cancer in this population.

Targeted blockade of TGF-β and IL-6/JAK2/STAT3 pathways inhibits lung cancer growth promoted by bone marrow-derived myofibroblasts

To investigate the role of TGF-β and IL-6 in myofibroblasts (MFs) — lung cancer cell interactions, lung cancer cells (Lewis and CTM-167 cell lines) were stimulated by IL-6, MF-conditioned medium (MF-CM) or MFs, with or without TGF-β signaling inhibitor — SB431542 and/or JAK2/STAT3 inhibitor — JSI-124. MFs were stimulated by TGF-β, cancer cell-CM or cancer cells, with or without SB431542 and JSI-124. Cell proliferation, the levels of cytokines, expression of mRNA and protein were determined. Mice bearing xenograft tumors were intraperitoneally treated with SB431542 or JSI-124 and monitored for up to 45 days. In co-culture systems, MFs secreted high levels of IL-6, while cancer cells produced high levels of TGF-β. Recombinant IL-6 and MF-CM activated STAT3 and upregulated TGF-β in cancer cells. In contrast, cancer cell-CM or TGF-β stimulated MFs to produce IL-6. Blockade of JAK2/STAT3 and TGF-β signaling by specific inhibitors significantly inhibited cell proliferation in vitro and tumor growth in vivo of lung cancer cells. Our study demontrated that the TGF-β and IL-6/JAK2/STAT3 signaling pathways form a positive feedback signaling loop that mediated the interactions between MFs and lung cancer cells. Targeted inhibiton of this signaling loop could be a new approach for lung cancer prevention and therapy.

IL‐17A and IL‐17F single nucleotide polymorphisms associated with lung cancer in Chinese population

Genetic predisposition and environmental factors impact the development of lung cancer. The aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) of the IL‐17A and IL‐17F genes with lung cancer risk in Chinese Han population.

Interleukin-23 facilitates Th1 and Th2 cell differentiation in vitro following respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) infection induces activation and imbalance of the immune system; however, the role of T helper 17 cells (Th17) in the response to RSV infection remains unclear. Interleukin‐23 (IL‐23) is a key cytokine in Th17 cell differentiation. The aim of this study was to explore the function of IL‐23 in determining the distribution of Th lymphocyte subsets (Th1, Th2, and Th17) after RSV infection in vitro. Human bronchial epithelial cell line BEAS‐2B was infected with mock or RSV at various multiplicities of infection (MOI) and transcript expression of IL‐6, IL‐23p19, and transforming growth factor (TGF‐β) was detected by real‐time polymerase chain reaction; IL‐6, IL‐23, and TGF‐β in the supernatant were measured by enzyme‐linked immunosorbent assay. The Th subset distribution in lymphocytes was determined by flow cytometry after co‐culture with supernatants from mock and 72‐hr RSV infection cultures. The role of IL‐23 in lymphocytes was assessed by specific receptor blockade (IL‐23R) prior to co‐culture with supernatants from RSV‐infected BEAS‐2B cells, followed by flow cytometry to analyze Th subset differentiation. Cytokine expression increased after RSV infection. IL‐23R blockade suppressed the differentiation of Th1, Th2, and Th17 cells in the presence of supernatants from RSV‐infected BEAS‐2B cells. RSV infection may induce cytokine secretion, thus inducing Th1, Th2, and Th17 differentiation via an IL‐23R‐dependent process. J. Med. Virol. 87:708–715, 2015.