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2.  Y-chromosome status identification suggests a recipient origin of posttransplant non–small cell lung carcinomas: chromogenic in situ hybridization analysis☆,☆☆ 
Human pathology  2014;45(5):1065-1070.
Summary
Owing to the need of lifelong immunosuppression, solid-organ transplant recipients are known to have an increased risk of posttransplant malignancies including lung cancer. Posttransplant neoplastic transformation of donor-derived cells giving rise to hematopoietic malignancies, Kaposi sarcoma, and basal cell carcinoma in nongraft tissues has been reported. The goal of this study was to assess the cell origin (donor versus recipient derived) of posttransplant non–small cell lung carcinomas (NSCLCs) in kidney and heart transplant recipients. An institutional database search identified 2557 kidney and heart transplant recipients in 8 consecutive years. Among this cohort, 20 (0.8%) renal and 18 (0.7%) heart transplant recipients developed NSCLC. The study cohort comprised 6 of 38 NSCLCs arising in donor-recipient sex-mismatched transplant patients. The tumor cell origin was evaluated by chromogenic in situ hybridization with Y-chromosome probe on formalin-fixed, paraffin-embedded tissues. Y-chromosome was identified in 97% ± 1% (range from 92% to 99%) of all types of nucleated cells in male control tissues. In all 5 NSCLCs from male recipients of female donor organ, Y-chromosome was identified in 97% ± 2% (range from 92% to 100%) of tumor cells, statistically equivalent to normal control (P < .001). No Y-chromosome was identified in NSCLC cells from a female recipient of male kidney. These findings suggest a recipient derivation of NSCLC arising in kidney and heart transplant recipients. A combination of histologic evaluation and chromogenic in situ hybridization with Y-chromosome analysis allows reliable determination of tissue origin in sex-mismatched solid-organ transplant recipients and may aid in management of posttransplant malignancy in such cases.
doi:10.1016/j.humpath.2014.01.003
PMCID: PMC4271837  PMID: 24746212
Post–solid-organ transplantation lung cancer; Chromogenic in situ hybridization for Y-chromosome
3.  Elevated Positive End-Expiratory Pressure Decreases Cardiac Index in a Rhesus Monkey Model 
Rationale: Clinicians are often concerned that higher positive end-expiratory pressure (PEEP) will decrease cardiac index (CI). PEEP affects CI through multiple inter-related mechanisms. The adult Rhesus monkey is an excellent model to study cardiopulmonary interaction due to similar pulmonary and chest wall compliances to human infants.
Objective: Our goal was to examine the impact of increasing PEEP on CI in Rhesus monkeys as a model for critically ill children.
Methods: Prospective, experimental animal study. Nine healthy anesthetized, intubated Rhesus monkeys were allowed to breathe spontaneously at a PEEP of 0, 5, 10, and 15 cm H2O while CI was measured with an ultrasonic Doppler (USCOM).
Measurements and main results: Cardiac index decreased between PEEP levels of 5 and 15 cm H2O. The mean decrease in CI for the entire cohort of monkeys was 18% (p < 0.01) with a range of −11 to 49%. Stroke volume and oxygen delivery also decreased between PEEP levels of 5 and 15 cm H2O (p < 0.01).
Conclusion: Between PEEP levels of 5 and 15 cm H2O, there was a decrease in CI, stroke volume, and oxygen delivery in intubated Rhesus monkeys. A plausible mechanism is that over-distention of normally compliant lungs at increased PEEP resulted in decreased preload to the right ventricle, outweighing the potentially beneficial decrease in left ventricular afterload or pulmonary vascular resistance. Further investigation is warranted, particularly in children with lung injury, who have historically benefited from increased PEEP levels without over-distention.
doi:10.3389/fped.2014.00134
PMCID: PMC4253666  PMID: 25520944
positive end-expiratory pressure; cardiac index; oxygen transport; Macaca mulatta
4.  MicroRNA-31 predicts the presence of lymph node metastases and survival in lung adenocarcinoma patients 
Purpose
We performed genome-wide microRNA-sequencing (miRNA-seq) in primary cancer tissue from lung adenocarcinoma patients to identify markers for the presence of lymph node metastasis.
Experimental Design
Markers for lymph node metastasis identified by sequencing were validated in a separate cohort using QPCR. After additional validation in the TCGA dataset, functional characterization studies were performed in vitro.
Results
MiR-31 was upregulated in lung adenocarcinoma tissues from patients with lymph node metastases compared to those without lymph node metastases. We confirmed miR-31 to be up-regulated in lymph node positive patients in a separate patient cohort (p=0.009, t-test), and to be expressed higher in adenocarcinoma tissue than in matched normal adjacent lung tissues (p<0.0001, paired t-test). MiR-31 was then validated as a marker for lymph node metastasis in an external validation cohort of 233 lung adenocarcinoma cases of the TCGA (p=0.031, t-test). In vitro functional assays showed that miR-31 increases cell migration, invasion, and proliferation in an ERK1/2 signaling dependent manner. Of note, miR-31 was a significant predictor of survival in a multivariate cox regression model even when controlling for cancer staging. Exploratory in silico analysis showed that low expression of miR-31 is associated with excellent survival for T2N0 patients.
Conclusions
We applied microRNA-seq to study microRNomes in lung adenocarcinoma tissue samples for the first time and identified potentially a microRNA predicting the presence of lymph node metastasis and survival outcomes in lung adenocarcinoma patients.
doi:10.1158/1078-0432.CCR-13-0320
PMCID: PMC3823052  PMID: 23946296
miRNA-seq; lung adenocarcinoma; metastasis; nodal stage; biomarker
5.  Synthesis and biochemical evaluation of triazole/tetrazole-containing sulfonamides against thrombin and related serine proteases 
A small library of 25 triazole/tetrazole-based sulfonamides have been synthesized and further evaluated for their inhibitory activity against thrombin, trypsin, tryptase and chymase. In general, the triazole-based sulfonamides inhibited thrombin more efficiently than the tetrazole counterparts. Particularly, compound 26 showed strong thrombin inhibition (Ki =880 nM) and significant selectivity against other human related serine proteases like trypsin (Ki =729 µM). Thrombin binding affinity of the same compound was determined by ITC and demonstrated that the binding of this new triazole-based scaffold is enthalpically driven, making it a good candidate for further development.
doi:10.1016/j.bmcl.2011.07.023
PMCID: PMC3159800  PMID: 21807511
Thrombosis or Thrombin inhibition; Sulfonamide synthesis; Isothermal titration calorimetry; Trypsin selectivity; Triazole and tetrazole scaffolds
6.  Developmental Changes in Emotion Recognition from Full-Light and Point-Light Displays of Body Movement 
PLoS ONE  2012;7(9):e44815.
To date, research on the development of emotion recognition has been dominated by studies on facial expression interpretation; very little is known about children's ability to recognize affective meaning from body movements. In the present study, we acquired simultaneous video and motion capture recordings of two actors portraying four basic emotions (Happiness Sadness, Fear and Anger). One hundred and seven primary and secondary school children (aged 4–17) and 14 adult volunteers participated in the study. Each participant viewed the full-light and point-light video clips and was asked to make a forced-choice as to which emotion was being portrayed. As a group, children performed worse than adults for both point-light and full-light conditions. Linear regression showed that both age and lighting condition were significant predictors of performance in children. Using piecewise regression, we found that a bilinear model with a steep improvement in performance until 8.5 years of age, followed by a much slower improvement rate through late childhood and adolescence best explained the data. These findings confirm that, like for facial expression, adolescents' recognition of basic emotions from body language is not fully mature and seems to follow a non-linear development. This is in line with observations of non-linear developmental trajectories for different aspects of human stimuli processing (voices and faces), perhaps suggesting a shift from one perceptual or cognitive strategy to another during adolescence. These results have important implications to understanding the maturation of social cognition.
doi:10.1371/journal.pone.0044815
PMCID: PMC3438163  PMID: 22970310
7.  Histological spectrum of pulmonary manifestations in kidney transplant recipients on sirolimus inclusive immunosuppressive regimens 
Diagnostic Pathology  2012;7:25.
Background
After the introduction of novel effective immunosuppressive therapies, kidney transplantation became the treatment of choice for end stage renal disease. While these new therapies lead to better graft survival, they can also cause a variety of complications. Only small series or case reports describe pulmonary pathology in renal allograft recipients on mTOR inhibitor inclusive therapies. The goal of this study was to provide a systematic review of thoracic biopsies in kidney transplant recipients for possible association between a type of immunosuppressive regimen and pulmonary complications.
Methods
A laboratory database search revealed 28 of 2140 renal allograft recipients (18 males and 10 females, 25 to 77 years old, mean age 53 years) who required a biopsy for respiratory symptoms. The histological features were correlated with clinical findings including immunosuppressive medications.
Results
The incidence of neoplasia on lung biopsy was 0.4% (9 cases), which included 3 squamous cell carcinomas, 2 adenocarcinomas, 1 diffuse large B-cell lymphoma, 1 lymphomatoid granulomatosis, and 2 post transplant B-cell lymphoproliferative disorders. Diffuse parenchymal lung disease was identified in 0.4% (9 cases), and included 5 cases of pulmonary hemorrhage, 3 cases of organizing pneumonia and 1 case of pulmonary alveolar proteinosis. Five (0.2%) cases showed histological features indicative of a localized infectious process. Patients on sirolimus had neoplasia less frequently than patients on other immunosuppressive combinations (12.5% vs. 58.3%, p = 0.03). Lung biopsies in 4 of 5 patients with clinically suspected sirolimus toxicity revealed pulmonary hemorrhage as the sole histological finding or in combination with other patterns.
Conclusions
Our study documents a spectrum of neoplastic and non-neoplastic lesions in renal allograft recipients on current immunosuppressive therapies. Sirolimus inclusive regimens are associated with increased risk of pulmonary toxicity but may be beneficial in cases of posttransplant neoplasia.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3320012126569395.
doi:10.1186/1746-1596-7-25
PMCID: PMC3344684  PMID: 22416975
Kidney transplantation; Pulmonary neoplasia; Pulmonary hemorrhage; Mammalian target of rapamycin (mTOR) inhibitors; Sirolimus
8.  Gene Expression Profiling Identifies MMP-12 and ADAMDEC1 as Potential Pathogenic Mediators of Pulmonary Sarcoidosis 
Rationale: Little is known about the genetic regulation of granulomatous inflammation in sarcoidosis.
Objectives: To determine if tissue gene array analysis would identify novel genes engaged in inflammation and lung remodeling in patients with sarcoidosis.
Methods: Gene expression analysis was performed on tissues obtained from patients with sarcoidosis at the time of diagnosis (untreated) (n = 6) compared with normal lung tissue (n = 6). Expression of select genes was further confirmed in lung tissue from a second series of patients with sarcoidosis and disease-free control subjects (n = 11 per group) by semi-quantitative RT-PCR. Interactive gene networks were identified in patients with sarcoidosis using Ingenuity Pathway Analysis (Ingenuity Systems, Inc., Redwood, CA) software. The expression of proteins corresponding to selected overexpressed genes was determined using fluorokine multiplex analysis, and immunohistochemistry. Selected genes and proteins were then analyzed in bronchoalveolar lavage fluid in an independent series of patients with sarcoidosis (n = 36) and control subjects (n = 12).
Measurements and Main Results: A gene network engaged in Th1-type responses was most significantly overexpressed in the sarcoidosis lung tissues, including genes not previously reported in the context of sarcoidosis (e.g., IL-7). MMP-12 and ADAMDEC1 transcripts were most highly expressed (> 25-fold) in sarcoidosis lung tissues, corresponding with increased protein expression by immunohistochemistry. MMP-12 and ADAMDEC1 gene and protein expression were increased in bronchoalveolar lavage samples from patients with sarcoidosis, correlating with disease severity.
Conclusions: Tissue gene expression analyses provide novel insights into the pathogenesis of pulmonary sarcoidosis. MMP-12 and ADAMDEC1 emerge as likely mediators of lung damage and/or remodeling and may serve as markers of disease activity.
doi:10.1164/rccm.200803-490OC
PMCID: PMC2684019  PMID: 19218196
genetic; gene array; granuloma; lung; BAL
9.  Mediastinal abscess after endobronchial ultrasound with transbronchial needle aspiration: a case report 
Endobronchial ultrasound (EBUS) with transbronchial needle aspiration is now becoming widely accepted as a preferred staging technique. It has been perceived as a non-invasive and well tolerated procedure with minimal complications. We report the development and treatment of a severe complication that developed 2 weeks after the initial procedure in the form of a complex mediastinal abscess. EBUS although useful in its non-invasive application for diagnosing mediastinal or hilar disease, must be regarded with caution since the potential exists to develop severe complications.
doi:10.1186/1749-8090-5-33
PMCID: PMC2880312  PMID: 20444284
10.  Global Methylation Profiling of Lung Cancer Identifies Novel Methylated Genes1 
Neoplasia (New York, N.Y.)  2001;3(4):314-323.
Abstract
Epigenetic changes, including DNA methylation, are a common finding in cancer. In lung cancers methylation of cytosine residues may affect tumor initiation and progression in several ways, including the silencing of tumor suppressor genes through promoter methylation and by providing the targets for adduct formation of polycyclic aromatic hydrocarbons present in combustion products of cigarette smoke. Although the importance of aberrant DNA methylation is well established, the extent of DNA methylation in lung cancers has never been determined. Restriction landmark genomic scanning (RLGS) is a highly reproducible two-dimensional gel electrophoresis that allows the determination of the methylation status of up to 2000 promoter sequences in a single gel. We selected 1184 CpG islands for RLGS analysis and determined their methylation status in 16 primary non-small cell lung cancers. Some tumors did not show methylation whereas others showed up to 5.3% methylation in all CpG islands of the profile. Cloning of 21 methylated loci identified 11 genes and 6 ESTs. We demonstrate that methylation is part of the silencing process of BMP3B in primary tumors and lung cancer cell lines.
PMCID: PMC1505864  PMID: 11571631
non-small cell lung cancer; DNA methylation; RLGS; genome scanning; epigenetic

Results 1-10 (10)