[Show abstract][Hide abstract] ABSTRACT: Malignant pleural mesothelioma (MPM) is an aggressive disease with a poor prognosis. Studies have shown that both MET and its key downstream intracellular signaling partners, PI3K and mTOR, are overexpressed in MPM. Here we determined the combinatorial therapeutic efficacy of a new generation small molecule inhibitor of MET, ARQ 197, and dual PI3K/mTOR inhibitors NVP-BEZ235 and GDC-0980 in mesothelioma cell and mouse xenograft models. Cell viability results show that mesothelioma cell lines were sensitive to ARQ 197, NVP-BEZ235 and GDC-0980 inhibitors. The combined use of ARQ 197 with either NVP-BEZ235 or GDC-0980, was synergistic (CI<1). Significant delay in wound healing was observed with ARQ 197 (p<0.001) with no added advantage of combining it with either NVP-BEZ235 or GDC-0980. ARQ 197 alone mainly induced apoptosis (20±2.36%) that was preceded by suppression of MAPK activity, while all the three suppressed cell cycle progression. Both GDC-0980 and NVP-BEZ235 strongly inhibited activities of PI3K and mTOR as evidenced from the phosphorylation status of AKT and S6 kinase. The above observation was further substantiated by the finding that a majority of the MPM archival samples tested revealed highly active AKT. While the single use of ARQ 197 and GDC-0980 inhibited significantly the growth of MPM xenografts (p<0.05, p<0.001 respectively) in mice, the combination of the above two drugs was highly synergistic (p<0.001). Our results suggest that the combined use of ARQ 197/NVP-BEZ235 and ARQ 197/GDC-0980 is far more effective than the use of the drugs singly in suppressing MPM tumor growth and motility and therefore merit further translational studies.
PLoS ONE 09/2014; 9(9):e105919. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Non-small cell lung cancers (NSCLC) are highly heterogeneous at the molecular level and comprise 75% of all lung tumors. We have previously shown that the receptor tyrosine kinase (RTK) MET frequently suffers gain-of-function mutations that significantly promote lung tumorigenesis. Subsequent studies from our lab also revealed that PAX5 transcription factor is preferentially expressed in small cell lung cancer (SCLC) and promotes MET transcription. PAX8, however, is also expressed in NSCLC cell lines. We therefore investigated the role of PAX8 in NSCLC.
Using IHC analysis, PAX8 protein expression was determined in archival NSCLC tumor tissues (n = 254). In order to study the effects of PAX8 knockdown on NSCLC cellular functions such as apoptosis and motility, siRNA against PAX8 was used. Confocal fluorescence microscopy was used to monitor the localization of MET, RON and PAX8. The combinatorial effect of PAX8 knockdown and MET inhibition using SU11274 was investigated in NSCLC cell viability assay.
Relative levels of PAX8 protein were elevated (>= + 2 on a scale of 0-3) in adenocarcinoma (58/94), large cell carcinoma (50/85), squamous cell carcinoma (28/47), and metastatic NSCLC (17/28; lymph node). Utilizing early progenitors isolated from NSCLC cell lines and fresh tumor tissues, we observed robust overexpression of PAX8, MET, and RON. PAX8 knockdown A549 cells revealed abrogated PAX8 expression with a concomitant loss in MET and the related RON kinase expression. A dramatic colocalization between the active form of MET (also RON) and PAX8 upon challenging A549 cells with HGF was visualized. A similar colocalization of MET and EGL5 (PAX8 ortholog) proteins was found in embryos of C. elegans. Most importantly, knockdown of PAX8 in A549 cells resulted in enhanced apoptosis (~ 6 fold) and decreased cell motility (~45%), thereby making PAX8 a potential therapeutic target. However, the combinatorial approach of PAX8 knockdown and treatment with MET inhibitor, SU11274, had marginal additive effect on loss of NSCLC cell viability.
PAX8 provides signals for growth and motility of NSCLC cells and is necessary for MET and RON expression. Further investigations are necessary to investigate the therapeutic potential of PA8 in NSCLC.
BMC Cancer 03/2014; 14(1):185. · 3.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Transthyretin (TTR) cardiac amyloidosis is characterized by deposition of either mutant or wild type TTR amyloid protein in the myocardium ultimately leading to progressive cardiomyopathy and heart failure. The most common TTR gene mutation that leads to TTR cardiac amyloidosis is the valine-to-isoleucine substitution at position 122 (V122I or Ile122). Currently, the only definitive treatment suggested for mutant TTR cardiac amyloidosis is the combined or sequential liver-heart transplantation in eligible patients, since liver is the source of TTR production. Here, we report a case of heterozygous Val122L mutated TTR-related cardiac amyloidosis treated with isolated heart transplantation with no recurrence of amyloid in the cardiac allograft and no systemic abnormalities 5 years after heart transplantation.AbbreviationsMMFmycophenolate mofetilNYHANew York Heart AssociationTTRtransthyretinVEminute ventilation
[Show abstract][Hide abstract] ABSTRACT: Small cell lung cancer (SCLC) is a devastating disease and current therapies have not greatly improved the 5-year survival rates. Topoisomerase (Top) inhibition is a treatment modality for SCLC; however, the response is short lived. Consequently, our research has focused on improving SCLC therapeutics through the identification of novel targets. Previously, we identified MET to be overexpressed and functional in SCLC. Herein, we investigated the therapeutic potential of combinatorial targeting of MET using SU11274 and Top1 using 7-ethyl-10-hydroxycamptothecin (SN-38). MET and TOP1 gene copy numbers and protein expression were determined in 29 patients with limited (n=11) and extensive (n=18) disease. MET gene copy number was significantly increased (>6 copies) in extensive disease compared to limited disease (p=0.015). Similar TOP1 gene copy numbers were detected in limited and extensive disease. Immunohistochemical staining revealed significantly higher Top1 nuclear expression in extensive (0.93) versus limited (0.15) disease (p=0.04). Interestingly, a significant positive correlation was detected between MET gene copy number and Top1 nuclear expression (r=0.5). In vitro stimulation of H82 cells revealed HGF-induced nuclear co-localization of p-MET and Top1. Furthermore, activation of the HGF/MET axis enhanced Top1 activity, which was abrogated by SU11274. Combination of SN-38 with SU11274 dramatically decreased SCLC growth as compared to either drug alone. Collectively, these findings suggest that combinatorial inhibition of MET and Top1 is a potentially efficacious treatment strategy for SCLC.
Molecular Cancer Therapeutics 12/2013; · 5.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lung cancer is a heterogeneous disease encompassing a wide array of genetic abnormalities. The MET receptor tyrosine kinase is altered in many lung cancers, especially non-small cell lung cancer (NSCLC), and clinical trials of MET inhibitors that are underway are documenting cases of acquired resistance. Based on evidence that the RON tyrosine kinase receptor can also be overexpressed in NSCLC, we evaluated the potent MET/RON dual kinase inhibitor LY2801653 in this setting. LY2801653 was more efficacious than the MET/ALK/RON/ROS inhibitor crizotinib with a distinct pattern of downstream signaling effects. Using the PamGene platform, we found that inhibition of MET and RON was associated with decreased phosphorylation of CBL, PI3K and STAT3. In classical and orthotopic mouse xenograft models of lung cancer, LY2801653 decreased tumor growth, dramatically inhibiting mitotic events and angiogenesis. Taken together, our results argued that specific targeting of the MET/RON kinases could provide robust inhibition of cell proliferation and tumor outgrowth in multiple in vitro and in vivo models of NSCLC. These findings offer a robust preclinical proof of concept for MET/RON targeting by LY2801653 as a promising small molecule modality to treat NSCLC.
[Show abstract][Hide abstract] ABSTRACT: GATA3 has been recognized as a promising marker for primary urothelial carcinoma (UC), consistently showing higher expression levels than urothelial markers thrombomodulin and uroplakin III. However, expression of GATA3 in comparison with UC-associated markers CK7 and p63 has not been systematically studied. Moreover, no studies have been conducted to establish GATA3 sensitivity in regional metastases. In this study, high-density tissue microarrays were constructed from 69 matched paired primary and metastatic bladder tumors including pure urothelial UCs with papillary (n=48) or flat phenotype (n=9), mixed tumors with micropapillary, glandular, small cell, squamous, giant cell, and plasmacytoid features (n=9), and 3 adenocarcinomas. GATA3 was expressed in 62/69 (90%) primary UC and 64/69 (93%) metastases, with significantly higher staining intensity in nodal metastases (P=0.03). In primary tumors, GATA3 was positive in 44/48 (92%) papillary UCs, 9/9 (100%) flat UCs, 8/9 (89%) mixed UCs, and 1/3 (33%) adenocarcinomas, whereas in metastases these numbers were 45/48 (94%), 9/9 (100%), 8/9 (89%), and 2/3 (67%), respectively. The majority of positive cases showed strong diffuse nuclear reactivity: 75% of primary UCs and 79% of metastases. GATA3 sensitivity in primary and metastatic UCs was comparable to that of CK7 and superior to that of p63 (P<0.05). GATA3 specificity was computed in comparison with its morphologic mimics expressing CK7 and p63, including 208 primary and 24 metastatic tumors from the lung, cervix, and head and neck regions. Strong GATA3 expression was present in 2/51 (4%) cervical carcinomas, whereas weak GATA3 expression was present in 7/51 (14%) cervical, 6/74 (8%) head and neck cancers, and 2/83 (3%) lung carcinomas. Remaining 191 primary and 24 metastatic tumors were GATA3 negative. Therefore, specificity of GATA3 calculated on the basis of morphologic and immunophenotypic UC mimics from lung, cervix, head and neck was 92%. Our findings demonstrate high sensitivity and specificity of the GATA3 diagnostic marker, with not only maintained but increased expression in regional metastases.
The American journal of surgical pathology 10/2013; · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Plexiform lesions (PLs), the hallmark of plexogenic pulmonary arterial hypertension (PAH) contain phenotypically altered, proliferative endothelial cells (ECs). The molecular mechanism that contributes to EC proliferation and formation of PLs is poorly understood. We now show that decrease of intersectin-1s (ITSN-1s) expression due to granzyme B (GrB) cleavage during inflammation associated with PAH and the high p38-Erk1/2(MAPK) activity ratio caused by the GrB/ITSN cleavage products lead to EC proliferation and selection of a proliferative/plexiform EC phenotype. We used human pulmonary artery ECs of PAH subjects (ECPAH), paraffin-embedded and frozen human lung tissue and animal models of PAH in conjunction with microscopy imaging, biochemical and molecular biology approaches to demonstrate that GrB cleaves ITSN-1s, a pro-survival protein of lung ECs, and generates two biologically active fragments: an N-terminal fragment (GrB-EHITSN) with EC proliferative potential and a C-terminal product with dominant negative effects on Ras/Erk1/2. The proliferative potential of GrB-EHITSN is mediated via sustained phosphorylation of p38(MAPK) and Elk-1 transcription factor and abolished by chemical inhibition of p38(MAPK). Moreover, lung tissue of PAH animal models and human specimens, as well as ECPAH, express lower levels of ITSN-1s compared to controls, and the GrB-EHITSN cleavage product. Moreover, GrB immuno-reactivity is associated with PLs in PAH lungs. The concurrent expression of the two cleavage products results in a high p38-Erk1/2(MAPK) activity ratio, critical for EC proliferation. Our findings identify a novel GrB-EHITSN-dependent pathogenic p38(MAPK)/Elk-1 signaling pathway involved in the poorly understood process of PLs formation in severe PAH.
Journal of Biological Chemistry 07/2013; · 4.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite progress in locoregional and systemic therapies, patient survival from lung cancer remains a challenge. Receptor tyrosine kinases are frequently implicated in lung cancer pathogenesis, and some tyrosine kinase inhibition strategies have been effective clinically. The EphB4 receptor tyrosine kinase has recently emerged as a potential target in several other cancers. We sought to systematically study the role of EphB4 in lung cancer. Here, we demonstrate that EphB4 is overexpressed 3-fold in lung tumors compared to paired normal tissues and frequently exhibits gene copy number increases in lung cancer. We also show that overexpression of EphB4 promotes cellular proliferation, colony formation, and motility, while EphB4 inhibition reduces cellular viability in vitro, halts the growth of established tumors in mouse xenograft models when used as a single-target strategy, and causes near-complete regression of established tumors when used in combination with paclitaxel. Taken together, these data suggest an important role for EphB4 as a potential novel therapeutic target in lung cancer. Clinical trials investigating the efficacy of anti-EphB4 therapies as well as combination therapy involving EphB4 inhibition may be warranted.
PLoS ONE 07/2013; 8(7):e67668. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cytoskeletal and focal adhesion abnormalities are observed in several types of cancer, including lung cancer. We have previously reported that paxillin (PXN) was mutated, amplified and overexpressed in a significant number of lung cancer patient samples, that PXN protein was upregulated in more advanced stages of lung cancer compared with lower stages and that the PXN gene was also amplified in some pre-neoplastic lung lesions. Among the mutations investigated, we previously found that PXN variant A127T in lung cancer cells enhanced cell proliferation and focal adhesion formation and colocalized with the anti-apoptotic protein B Cell Lymphoma 2 (BCL-2), which is known to localize to the mitochondria, among other sites. To further explore the effects of activating mutations of PXN on mitochondrial function, we cloned and expressed wild-type PXN and variants containing the most commonly occurring PXN mutations (P46S, P52L, G105D, A127T, P233L, T255I, D399N, E423K, P487L and K506R) in a GFP tagged vector using HEK-293 human embryonic kidney cells. Utilizing live-cell imaging to systematically study the effects of wild-type PXN vs. mutants, we created a model that recapitulates the salient features of the measured dynamics and conclude that compared with wild-type, some mutant clones confer enhanced focal adhesion and lamellipodia formation (A127T, P233L, P487L) and some confer increased association with BCL-2, Dynamin-related Protein-1 (DRP-1) and Mitofusion-2 (MFN-2) proteins (P233L and D399N). Further, PXN mutants, through their interactions with BCL-2 and DRP-1, could regulate cisplatin drug resistance in human lung cancer cells. The data reported herein suggest that mutant PXN variants play a prominent role in mitochondrial dynamics with direct implications on lung cancer progression and hence, deserve further exploration as therapeutic targets.
Cancer biology & therapy 05/2013; 14(7). · 3.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract Introduction: Bronchial thermoplasty (BT) is an emerging therapy for patients with severe persistent asthma who remain poorly controlled despite standard maximal medical therapy. Thermoplasty elicits asthma control over time by applying thermal radiofrequency energy to airways to ablate underlying smooth muscle. While this therapy is suggested to eliminate such smooth muscle permanently, no human studies have examined the possibility of treatment failure. Case Report: We present a 62-year-old female with severe, refractory asthma symptoms who underwent BT without apparent complications. However, severe symptoms including multiple clinical exacerbations persisted despite BT treatment. Repeat endobronchial biopsy done six months after BT treatment demonstrated persistent smooth muscle hyperplasia in multiple airways that previously had been treated. The patient continued to have uncontrolled, refractory asthma despite multiple therapies. Conclusion: This case is the first to describe a failure of BT to reduce or eliminate airway smooth muscle in a patient with severe persistent asthma. It suggests the potential for treatment failure in the management of these patients after BT and highlights the need for further study of potential BT-refractory patients.
[Show abstract][Hide abstract] ABSTRACT: Objective Bronchial thermoplasty (BT) reduces airway smooth muscle in patients with severe asthma. We developed a novel standardized histologic grading system assessing inflammation and structural remodeling on endobronchial biopsy (EBBx) in severe persistent asthma and evaluated airway structure before and after BT. In addition, we correlated invasive and non-invasive inflammatory markers in severe persistent asthma. Methods Thirty-three patients with severe persistent asthma underwent bronchoscopy, including bronchoalveolar lavage and diagnostic EBBx. The control group (N=41) underwent EBBx for other clinical indications. Biopsies were graded for airway inflammation and epithelial and submucosal structural features. We also evaluated airway histology in three patients before and after BT. Results Compared to the control group, patients with severe persistent asthma more often had intraepithelial eosinophils and lymphocytes (67% vs. 17% and 61% vs. 27%; p<0.001 and p=0.005, respectively) and prominent smooth muscle and goblet cell hyperplasia (88% vs. 29% and 47% vs. 22%, p<0.001 and p=0.004, respectively). Other features including epithelial denudation and basement membrane thickening were not significantly different. Following BT, airway smooth muscle was no longer prominent due to partial replacement by fibrosis. Increased submucosal eosinophilic inflammation and bronchoalveolar lavage eosinophilia correlated with exhaled nitric oxide (eNO, p=0.05 for both). Conclusions We developed a clinically applicable standardized histologic grading system which identified structural but not inflammatory changes before and after bronchial thermoplasty in severe persistent asthmatics. Additionally, we demonstrate that eNO is representative of submucosal eosinophilia in this population. This semi-quantitative assessment will be useful for practicing pathologists assessing EBBx from severe persistent asthma patients for diagnostic and clinical research purposes.
[Show abstract][Hide abstract] ABSTRACT: Background : In 2008 Wuhan University Medical School in China proposed to reform its curriculum by adapting the curriculum of the University of Chicago Medical School. Description : An assessment of Wuhan University Medical School's traditional curriculum conducted in 2009 informed the reform directions, which included course integration, use of clinical cases, improved relevance of basic sciences to clinical medicine, reduction of lecture time, increase in group and independent learning, and the use of formative assessments. Fifty student volunteers per year were chosen to participate in the reform, and the rest remained in the traditional curriculum. Evaluation : A student survey was conducted in 2011 to evaluate the reform by comparing the attitudes of those in the reform and standard curricula. Conclusions : The reform met the needs of the school, was generally well received, improved satisfaction in reform participants, and had a positive impact on students. Areas needing improvement were also identified.
Teaching and Learning in Medicine 04/2013; 25(2):148-54. · 1.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT BACKGROUND: Acute rejection remains a major source of morbidity after lung transplantation. Given the importance of this diagnosis, an international grading system was developed to standardize the diagnosis of acute lung allograft rejection. The reliability of this grading system has not been adequately assessed by previous studies. METHODS: We examined the level of agreement in grading transbronchial biopsies obtained from a large multicenter study (AIRSAC trial). Biopsies were initially graded for acute rejection and lymphocytic bronchiolitis by the site pathologist and subsequently graded by a central pathologist. Reliability of interobserver grading was evaluated using Cohen's kappa coefficients. RESULTS: A total of 481 transbronchial biopsies were graded by both the site and central pathologist. The overall concordance rate was 74% for Grade A biopsies and concordance rate for Grade B biopsies was 89%. When biopsies performed at different time points after transplantation were assessed, there was a higher level of agreement early (≤6 weeks) after transplant compared to later time points for acute rejection. However, there was still only moderate agreement for both Grade A (kappa score 0.479 (95% CI 0.29-0.67)) and Grade B (kappa score 0.465 (95% CI 0.08-0.85)) rejection. CONCLUSION: These results expand upon previous reports of interobserver variability in grading transbronchial biopsies after lung transplantation. Given the variability in the grading transbronchial biopsies, we advocate further education of the histopathologic findings in lung transplant biopsies as well as revisiting the current criteria for grading transbronchial biopsies in order to improve concordance among lung transplant pathologists.
[Show abstract][Hide abstract] ABSTRACT: Objective
Mesothelial hyperplasia (MH) and fibrosing pleuritis (FP) can be difficult to distinguish from epithelioid (MM-E) and sarcomatoid (MM-S) malignant pleural mesotheliomas. GLUT-1 has shown variable results regarding its sensitivity and specificity when used to evaluate mesothelial proliferations. We evaluated the utility of GLUT-1 immunostaining in differentiating MH and FP from MM-E and MM-S.
Materials and Methods
In this retrospective study, diagnostically well-characterized cases (MH = 31, FP = 29, MM-E = 41, MM-S = 29) were collected and manually stained for GLUT-1. All slides were visually scored by 2 pathologists; using the following system: 0%, 1+ 1-25%, 2+ 26-50% and 3+ > 51% cells staining.
All benign cases (n = 60) were negative for GLUT-1 while 45 of 78 (58%) MM [21 of 41 (50%) MM-E, 21 of 29 (72%) MM-S and 3 of 3 biphasic mesothelioma (100%)] had 1+ to 3+ staining. Of the MM-E, 10 had 1+, and 11 had 2+ staining; of the MM-S 3 had 1+, 15 had 2+ and 3 had 3+ staining. Both sarcomatoid and epithelioid components of the 3 biphasic mesotheliomas revealed 1+ staining. All 5 desmoplastic MM were negative.
Positive staining with GLUT-1 is helpful since it is present in half of MM-E and three-quarter of MM-S. Although all reactive mesothelial lesions were negative, the absence of immunoreactivity does not exclude the diagnosis of MM. As with all IHC stains used for diagnostic purposes, GLUT-1 has to be a part of a panel, and the results interpreted in the context of clinical, radiological and histological findings.
Lung cancer (Amsterdam, Netherlands) 01/2013; · 3.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: World-wide, esophageal cancer is a growing epidemic and patients frequently present with advanced disease that is surgically inoperable. Hence, chemotherapy is the predominate treatment. Cytotoxic platinum compounds are mostly used, but their efficacy is only moderate. Newer alkylating agents have shown promise in other tumor types, but little is known about their utility in esophageal cancer.
We utilized archived human esophageal cancer samples and esophageal cancer cell lines to evaluate O-6-methylguanine-deoxyribonucleic acid methyltransferase (MGMT) hypermethylation status and determined sensitivity to the alkylating drug temozolomide (TMZ). Immunoblot analysis was performed to determine MGMT protein expression in cell lines. To assess and confirm the effect of TMZ treatment in a methylated esophageal cancer cell line in vivo, a mouse flank xenograft tumor model was utilized.
Nearly 71% (12/17) of adenocarcinoma and 38% (3/8) of squamous cell carcinoma (SCC) patient samples were MGMT hypermethylated. Out of four adenocarcinoma and nine SCC cell lines tested, one of each histology was hypermethylated. Immunoblot analyses confirmed that hypermethylated cell lines did not express the MGMT protein. In vitro cell viability assays showed the methylated Kyse-140 and FLO cells to be sensitive to TMZ at an IC50 of 52-420 μM, whereas unmethylated cells Kyse-410 and SKGT-4 did not respond. In an in vivo xenograft tumor model with Kyse-140 cells, which are MGMT hypermethylated, TMZ treatment abrogated tumor growth by more than 60%.
MGMT methylation may be an important biomarker in subsets of esophageal cancers and targeting by TMZ may be utilized to successfully treat these patients.
[Show abstract][Hide abstract] ABSTRACT: Esophageal cancer incidence is rising and has few treatment options. In studying receptor tyrosine kinases associated with esophageal cancers, we have identified EPHB4 to be robustly over expressed in cell lines and primary tumor tissues. In total, 94 squamous cell carcinoma (SCC), 82 adenocarcinoma, 25 dysplasia, 13 Barrett's esophagus and 25 adjacent or unrelated normal esophageal tissues were evaluated by IHC. EPHB4 expression was significantly higher in all the different histologic categories compared to adjacent normal tissues. In 13 esophageal cancer cell lines, three of the nine SCC cell lines and one of the four adenocarcinomas expressed very high levels of EPHB4. An increased gene copy number ranging from 4-20 copies was identified in a subset of the overexpressing patient samples and cell lines. We have developed a novel 4-NQO induced mouse model of esophageal cancer that recapitulates the EPHB4 expression in humans. A specific small molecule inhibitorof EPHB4 decreased cell viability in a time and dose dependent manner in three of the four cell lines tested. The small molecule inhibitor and an EPHB4 siRNA also decreased cell migration (12-40% closure in treated vs. 60-80% in untreated), with decreased phosphorylation of various tyrosyl containing proteins, EphB4 and its downstream target p125FAK. Finally, in a xenograft tumor model, an EPHB4 inhibitor abrogated tumor growth by approximately 60% compared to untreated control. EphB4 is robustly expressed and potentially serves as a novel biomarker for targeted therapy in esophageal cancers.
[Show abstract][Hide abstract] ABSTRACT: Usual interstitial pneumonia (UIP) is a common chronic interstitial pneumonitis. It can occur idiopathically (I-UIP) or in the setting of systemic connective tissue disease (CTD-UIP). Some studies suggest that CTD-UIP has a better prognosis than I-UIP. The histologic differences between CTD-UIP and I-UIP are not clearly defined.
The purpose of this study was to evaluate histologic criteria that may differentiate CTD-UIP from I-UIP, including fibroblastic foci (FFs), lymphoid aggregates (LAs), and the presence of nonspecific interstitial pneumonia pattern.
Thirty-five patients with histologic diagnoses of UIP were identified (27 biopsies [77%]; 8 explants [23%]). Biopsy slides were scanned and analyzed quantitatively for FF size, FF area, LA size, and LA area. Biopsy and explant slides were examined qualitatively for the presence of a nonspecific interstitial pneumonia pattern in areas away from UIP fibrosis. Results.-Of 27 biopsies, the number and size of FFs in CTD-UIP were smaller than they were in I-UIP. The number and size of LAs were larger in patients with rheumatoid arthritis than they were in patients with I-UIP. There was no interobserver variability among 3 pathologists using this quantitative system. Of 35 biopsies and explants, there was a higher prevalence of the nonspecific interstitial pneumonia pattern among patients with CTD-UIP than there was among patients with I-UIP (P = .005).
Patients with CTD-UIP had fewer, smaller FFs than did patients with I-UIP, and patients with rheumatoid arthritis-UIP had more, larger LAs than did patients with I-UIP. Of importance, the coexistence of UIP and the nonspecific interstitial pneumonia patterns was one of the most salient features in distinguishing CTD-UIP from I-UIP because CTD-UIP demonstrated an increased prevalence of multilobar, cellular, nonspecific interstitial pneumonia patterns in areas away from the UIP fibrosis.
Archives of pathology & laboratory medicine 10/2012; 136(10):1253-8. · 2.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Malignant pleural mesothelioma (MPM) is a devastating disease with an overall poor prognosis. Despite the recent advances in targeted molecular therapies, there is a clear and urgent need for the identification of novel mesothelioma targets for the development of highly efficacious therapeutics.
In this study, we report that the expression of Sphingosine Kinase 1 (SphK1) protein was preferentially elevated in MPM tumor tissues (49 epithelioid and 13 sarcomatoid) compared to normal tissue (n = 13). In addition, we also observed significantly elevated levels of SphK1 and SphK2 mRNA and SphK1 protein expression in MPM cell lines such as H2691, H513 and H2461 compared to the non-malignant mesothelial Met5 cells. The underlying mechanism appears to be mediated by SphK1 induced upregulation of select gene transcription programs such as that of CBP/p300 and PCAF, two histone acetyl transferases (HAT), and the down regulation of cell cycle dependent kinase inhibitor genes such as p27Kip1 and p21Cip1. In addition, using immunoprecipitates of anti-acetylated histone antibody from SphK inhibitor, SphK-I2 treated Met5A and H2691 cell lysates, we also showed activation of other cell proliferation related genes, such as Top2A (DNA replication), AKB (chromosome remodeling and mitotic spindle formation), and suppression of p21 CIP1 and p27KIP1. The CDK2, HAT1 and MYST2 were, however, unaffected in the above study. Using SphK inhibitor and specific siRNA targeting either SphK1 or SphK2, we also unequivocally established that SphK1, but not SphK2, promotes H2691 mesothelioma cell proliferation. Using a multi-walled carbon nanotubes induced peritoneal mesothelioma mouse model, we showed that the SphK1-/- null mice exhibited significantly less inflammation and granulamatous nodules compared to their wild type counterparts.
The lipid kinase SphK1 plays a positive and essential role in the growth and development of malignant mesothelioma and is therefore a likely therapeutic target.
PLoS ONE 09/2012; 7(9):e45330. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The International Society for Heart and Lung Transplantation (ISHLT) guidelines on the interpretation of lung rejection in pulmonary allograft biopsy specimens were revised most recently in 2007. The goal of our study was to determine how these revisions, along with nuances in the interpretation and application of the guidelines, affect patient care.
A Web-based survey was e-mailed to pathologists and pulmonologists identified as being part of the lung transplant team at institutions in the United States with active lung transplant programs as determined from the Organ Procurement and Transplantation Network Web site (http://optn.transplant.hrsa.gov/members/directory.asp).
Grades B1 and B2 in asymptomatic patients would fall into the same treatment group under the 2007 classification, which combines B1 and B2 into B1R. Also, some pulmonologists would not interpret a pathologic diagnosis of lymphocytic bronchiolitis as grade B rejection, resulting in under-treatment of these patients. Regarding bronchiolitis obliterans, most pulmonologists would treat the patient differently if there were an active mononuclear inflammatory infiltrate, and most pathologists would comment on the presence of such an infiltrate, contrary to the 2007 guidelines, which discourage reporting this infiltrate. We also found discrepancies among pathologists in their interpretation of airway lymphocytic infiltrates, whether eosinophils can be present in bronchial-associated lymphoid tissue, and whether airway inflammation represents rejection or bacterial infection.
The issue of grading and treating airway inflammation in pulmonary allograft biopsy specimens continues to be problematic, despite revised ISHLT guidelines. Clarification of guidelines for pathologists and pulmonologists using evidence-based criteria could lead to improved communication and patient care.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 09/2012; 31(9):972-9. · 5.61 Impact Factor