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1.  The Novel Human Influenza A(H7N9) Virus Is Naturally Adapted to Efficient Growth in Human Lung Tissue 
mBio  2013;4(5):e00601-13.
ABSTRACT
A novel influenza A virus (IAV) of the H7N9 subtype has been isolated from severely diseased patients with pneumonia and acute respiratory distress syndrome and, apparently, from healthy poultry in March 2013 in Eastern China. We evaluated replication, tropism, and cytokine induction of the A/Anhui/1/2013 (H7N9) virus isolated from a fatal human infection and two low-pathogenic avian H7 subtype viruses in a human lung organ culture system mimicking infection of the lower respiratory tract. The A(H7N9) patient isolate replicated similarly well as a seasonal IAV in explanted human lung tissue, whereas avian H7 subtype viruses propagated poorly. Interestingly, the avian H7 strains provoked a strong antiviral type I interferon (IFN-I) response, whereas the A(H7N9) virus induced only low IFN levels. Nevertheless, all viruses analyzed were detected predominantly in type II pneumocytes, indicating that the A(H7N9) virus does not differ in its cellular tropism from other avian or human influenza viruses. Tissue culture-based studies suggested that the low induction of the IFN-β promoter correlated with an efficient suppression by the viral NS1 protein. These findings demonstrate that the zoonotic A(H7N9) virus is unusually well adapted to efficient propagation in human alveolar tissue, which most likely contributes to the severity of lower respiratory tract disease seen in many patients.
IMPORTANCE
Humans are usually not infected by avian influenza A viruses (IAV), but this large group of viruses contributes to the emergence of human pandemic strains. Transmission of virulent avian IAV to humans is therefore an alarming event that requires assessment of the biology as well as pathogenic and pandemic potentials of the viruses in clinically relevant models. Here, we demonstrate that an early virus isolate from the recent A(H7N9) outbreak in Eastern China replicated as efficiently as human-adapted IAV in explanted human lung tissue, whereas avian H7 subtype viruses were unable to propagate. Robust replication of the H7N9 strain correlated with a low induction of antiviral beta interferon (IFN-β), and cell-based studies indicated that this is due to efficient suppression of the IFN response by the viral NS1 protein. Thus, explanted human lung tissue appears to be a useful experimental model to explore the determinants facilitating cross-species transmission of the H7N9 virus to humans.
doi:10.1128/mBio.00601-13
PMCID: PMC3791893  PMID: 24105764
2.  A case of mistaken identity: alcohol withdrawal, schizophrenia, or central pontine myelinolysis? 
Demyelination is a hallmark of central pontine myelinolysis (CPM). Neuropsychiatric manifestations of this condition include weakness, quadriplegia, pseudobulbar palsy, mood changes, psychosis, and cognitive disturbances. These psychiatric symptoms are also associated with schizophrenia and alcohol withdrawal. Thus, it is clinically relevant to differentiate between CPM, schizophrenia, and alcohol withdrawal as the treatment and prognostic outcomes for each diagnosis are distinct. We present a series of events that led to a misdiagnosis of a patient admitted to the medical emergency center presenting with confusion, psychomotor agitation, and delirium who was first diagnosed with schizophrenia and alcohol withdrawal by emergency medical physicians and later discovered by the psychiatric consult team to have CPM. With a thorough psychiatric evaluation, a review of the laboratory results first showing mild hyponatremia (127 mmol/L), subsequent hypernatremia (154 mmol/L), and magnetic resonance brain imaging, psychiatrists concluded that CPM was the primary diagnosis underlying the observed neuropsychopathology. This patient has mild impairments in mood, cognition, and motor skills that remain 12 months after her emergency-center admission. This case report reminds emergency clinicians that abnormal sodium metabolism can have long-term and devastating psychopathological and neurological consequences. Differentiating between CPM, schizophrenia, and alcohol withdrawal using neuroimaging techniques and preventing the risks for CPM using slow sodium correction are paramount.
doi:10.2147/NDT.S27634
PMCID: PMC3280106  PMID: 22347796
MRI; alcohol; schizophrenia; central pontine myelinolysis; hyponatremia
3.  Neoadjuvant Chemotherapy Compared With Surgery Alone for Locally Advanced Cancer of the Stomach and Cardia: European Organisation for Research and Treatment of Cancer Randomized Trial 40954 
Journal of Clinical Oncology  2010;28(35):5210-5218.
Purpose
Patients with locally advanced gastric cancer benefit from combined pre- and postoperative chemotherapy, although fewer than 50% could receive postoperative chemotherapy. We examined the value of purely preoperative chemotherapy in a phase III trial with strict preoperative staging and surgical resection guidelines.
Patients and Methods
Patients with locally advanced adenocarcinoma of the stomach or esophagogastric junction (AEG II and III) were randomly assigned to preoperative chemotherapy followed by surgery or to surgery alone. To detect with 80% power an improvement in median survival from 17 months with surgery alone to 24 months with neoadjuvant, 282 events were required.
Results
This trial was stopped for poor accrual after 144 patients were randomly assigned (72:72); 52.8% patients had tumors located in the proximal third of the stomach, including AEG type II and III. The International Union Against Cancer R0 resection rate was 81.9% after neoadjuvant chemotherapy as compared with 66.7% with surgery alone (P = .036). The surgery-only group had more lymph node metastases than the neoadjuvant group (76.5% v 61.4%; P = .018). Postoperative complications were more frequent in the neoadjuvant arm (27.1% v 16.2%; P = .09). After a median follow-up of 4.4 years and 67 deaths, a survival benefit could not be shown (hazard ratio, 0.84; 95% CI, 0.52 to 1.35; P = .466).
Conclusion
This trial showed a significantly increased R0 resection rate but failed to demonstrate a survival benefit. Possible explanations are low statistical power, a high rate of proximal gastric cancer including AEG and/or a better outcome than expected after radical surgery alone due to the high quality of surgery with resections of regional lymph nodes outside the perigastic area (celiac trunc, hepatic ligament, lymph node at a. lienalis; D2).
doi:10.1200/JCO.2009.26.6114
PMCID: PMC3020693  PMID: 21060024
4.  Beyond Field Effect: Analysis of Shrunken Centroids in Normal Esophageal Epithelia Detects Concomitant Esophageal Adenocarcinoma 
Background and Aims:
Because of the extremely low neoplastic progression rate in Barrett’s esophagus, it is difficult to diagnose patients with concomitant adenocarcinoma early in their disease course. If biomarkers existed in normal squamous esophageal epithelium to identify patients with concomitant esophageal adenocarcinoma, potential applications would be far-reaching. The aim of the current study was to identify global gene expression patterns in normal esophageal epithelium capable of revealing simultaneous esophageal adenocarcinoma, even located remotely in the esophagus.
Methods:
Tissues comprised normal esophageal epithelia from 9 patients with esophageal adenocarcinoma, 8 patients lacking esophageal adenocarcinoma or Barrett’s, and 6 patients with Barrett’s esophagus alone. cDNA microarrays were performed, and pattern recognition in each of these subgroups was achieved using shrunken nearest centroid predictors.
Results:
Our method accurately discriminated normal esophageal epithelia of 8/8 patients without esophageal adenocarcinoma or Barrett’s esophagus and of 6/6 patients with Barrett’s esophagus alone from normal esophageal epithelia of 9/9 patients with Barrett’s esophagus and concomitant esophageal adenocarcinoma. Moreover, we identified genes differentially expressed between the above subgroups. Thus, based on their corresponding normal esophageal epithelia alone, our method accurately diagnosed patients who had concomitant esophageal adenocarcinoma.
Conclusions:
These global gene expression patterns, along with individual genes culled from them, represent potential biomarkers for the early diagnosis of esophageal adenocarcinoma from normal esophageal epithelia. Genes discovered in normal esophagus that are differentially expressed in patients with vs. without esophageal adenocarcinoma merit further pursuit in molecular genetic, functional, and therapeutic interventional studies.
PMCID: PMC2323355  PMID: 18425214
5.  Prognostic Significance and Clinicopathological Associations of COX-2 SNP in Patients with Nonsmall Cell Lung Cancer 
Journal of Oncology  2009;2009:139590.
Background. To further improve the screening, diagnosis, and therapy of patients with nonsmall cell lung cancer (NSCLC) additional diagnostic tools are urgently needed. Gene expression of Cyclooxygenase-2 (COX-2) has been linked to prognosis in patients with NSCLC. The role of the COX-2 926G>C Single Nucleotide Polymorphism (SNP) in patients with NSCLC remains unclear. The aim of this study was to investigate the potential of the COX-2 926G>C SNP as a molecular marker in this disease. Methods. COX-2 926G>C SNP was analyzed in surgically resected tumor tissue of 85 patients with NSCLC using a PCR-based RFLP technique. Results. The COX-2 926G>C SNP genotypes were detected with the following frequencies: GG n = 62 (73%), GC n = 20 (23%), CC n = 3 (4%). There were no associations between COX-2 SNP genotype and histology, grading or gender detectable. COX-2 SNP was significantly associated with tumor stage (P = .032) and lymph node status (P = .016, Chi-square test). With a median followup of 85.9 months, the median survival was 59.7 months. There were no associations seen between the COX-2 SNP genotype and patients prognosis. Conclusions. The COX-2 926G>C SNP is detectable at a high frequency in patients with NSCLC. The COX-2 926G>C SNP genotype is not a prognostic molecular marker in this disease. However, patients with the GC or CC genotype seem more susceptible to lymph node metastases and higher tumor stage than patients with the GG genotype. The results suggest COX-2 926G>C SNP as a molecular marker for lymph node involvement in this disease.
doi:10.1155/2009/139590
PMCID: PMC2793422  PMID: 20016751
6.  Circulating Tumor Cells in Gastrointestinal Malignancies: Current Techniques and Clinical Implications 
Journal of Oncology  2009;2010:392652.
Since their introduction more than 50 years by Engell, circulating tumor cells (CTCs) have been evaluated in cancer patients and their detection has been correlated with clinical outcome, in esophageal, gastric, and colorectal cancer. With the availability of refined technologies, the identification of CTCs from peripheral blood is emerging as a useful tool for the detection of malignancy, monitoring disease progression, and measuring response to therapy. However, increasing evidence suggests a variety of factors to be responsible for disease progression. The analysis of a single CTC marker is therefore unlikely to accurately predict progression of disease with sufficient resolution and reproducibility. Here we discuss the current concept of CTCs, summarize the available techniques for their detection and characterization, and aim to provide a comprehensive update on the clinical implications of CTCs in gastrointestinal (GI) malignancies.
doi:10.1155/2010/392652
PMCID: PMC2774472  PMID: 19902005
7.  Breast pseudotumoral radionecrosis as a late radiation-induced injury: a case report 
Introduction
New therapies and treatment protocols have led to improved survival rates in many cancers. The improved rates are such that patients are now living long enough to experience some negative long-term side effects of the initial therapy.
Case presentation
We report the case of a 65-year-old Caucasian woman who presented with a rare case of pseudotumoral radionecrosis, a late radiation-induced injury, after combined surgical and cobalt radiation therapy for the treatment of adenocarcinoma of the right breast. The patient underwent resection of this benign, yet progressively growing and painful tumor. A cosmetically satisfying result was achieved by reconstruction of the thoracic wall with a polypropylene mesh and a latissimus dorsi muscle flap.
Conclusion
With improved overall survival, new management strategies for late side effects of therapy are becoming of crucial importance for affected patients. In the future, improving toxicity-free survival will be as important as achieving disease-free survival or local tumor control.
doi:10.1186/1752-1947-3-71
PMCID: PMC2783070  PMID: 19946547
8.  Beyond Field Effect: Analysis of Shrunken Centroids in Normal Esophageal Epithelia Detects Concomitant Esophageal Adenocarcinoma 
Background and Aims
Because of the extremely low neoplastic progression rate in Barrett’s esophagus, it is difficult to diagnose patients with concomitant adenocarcinoma early in their disease course. If biomarkers existed in normal squamous esophageal epithelium to identify patients with concomitant esophageal adenocarcinoma, potential applications would be far-reaching. The aim of the current study was to identify global gene expression patterns in normal esophageal epithelium capable of revealing simultaneous esophageal adenocarcinoma, even located remotely in the esophagus.
Methods
Tissues comprised normal esophageal epithelia from 9 patients with esophageal adenocarcinoma, 8 patients lacking esophageal adenocarcinoma or Barrett’s, and 6 patients with Barrett’s esophagus alone. cDNA microarrays were performed, and pattern recognition in each of these subgroups was achieved using shrunken nearest centroid predictors.
Results
Our method accurately discriminated normal esophageal epithelia of 8/8 patients without esophageal adenocarcinoma or Barrett’s esophagus and of 6/6 patients with Barrett’s esophagus alone from normal esophageal epithelia of 9/9 patients with Barrett’s esophagus and concomitant esophageal adenocarcinoma. Moreover, we identified genes differentially expressed between the above subgroups. Thus, based on their corresponding normal esophageal epithelia alone, our method accurately diagnosed patients who had concomitant esophageal adenocarcinoma.
Conclusions
These global gene expression patterns, along with individual genes culled from them, represent potential biomarkers for the early diagnosis of esophageal adenocarcinoma from normal esophageal epithelia. Genes discovered in normal esophagus that are differentially expressed in patients with vs. without esophageal adenocarcinoma merit further pursuit in molecular genetic, functional, and therapeutic interventional studies.
PMCID: PMC2323355  PMID: 18425214

Results 1-8 (8)