Aejaz Nasir

Moffitt Cancer Center, Tampa, Florida, United States

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Publications (50)123.64 Total impact

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    ABSTRACT: OBJECTIVES: Cytoplasmic clusterin (Clusterin), a ubiquitous multifunctional secretory sulfated glycoprotein, plays a role in apoptosis and is reportedly overexpressed in a variety of tumors. The role of Clusterin in pancreatic neuroendocrine tumors (PNETs) has not been investigated. In this study, Clusterin expression was evaluated in a subset of PNETs, and the results were correlated with the clinical-pathological features of the tumors. METHODS: Fifty-nine surgical cases were used to evaluate the immunohistochemical expression of Clusterin in PNETs. Using the avidin-biotin complex method, tissue sections from each case were stained with a rabbit anticlusterin antibody (Abcam, Cambridge, Mass). The immunohistochemical reactions were qualitatively and semiquantitatively evaluated by 2 pathologists. RESULTS: Strong Clusterin reactivity was identified in 36 (61%) of 59 PNETs. In 23 (39%) of 59 cases, the Clusterin score was 3 or less. Clusterin expression scores significantly associated with tumor size (P = 0.03) and with tumor stage (P = 0.02). The immunohistochemical score index did not correlate with tumor grade (P = 0.15). CONCLUSIONS: We report the expression of Clusterin in PNETs. The correlation of Clusterin with tumor size and stage suggests involvement of this molecule in pancreatic neuroendocrine tumor progression. Clusterin may represent a new target of therapy for PNETs.
    Pancreas 06/2013; · 2.95 Impact Factor
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    ABSTRACT: Palladin is a metastasis-associated gene regulating cell motility. The expression of palladin protein in pancreatic neuroendocrine tumors (PET) and carcinomas (PECA) is not known. A tissue microarray (TMA) of well-differentiated (WD) PETs/PECAs (AJCC 2010) and non-neoplastic, histologically normal pancreatic tissue/islets (HNPIs) was immunostained with palladin antibody and quantified using the Allred score. The results were correlated with the presence or absence of liver metastases. The retrospective study included 19 males and 19 females of age 27-79 years (mean 54). Tumor size was 0.9-11.5 cm (mean 3.8). Palladin expression was cytoplasmic and/or membranous. The tumors with high palladin expression were associated with liver metastasis (p<0.0001). All 14 primary PECA with hepatic metastases (MP-PECAs) exhibited palladin expression whereas 14 out of 24 (58%) clinically-localized primary PET (CLP-PETs) expressed palladin (p<0.01) with median Allred scores of 5 (range 3-7) and 2 (range 0-6) respectively (p<0.0001). The mean Allred score for the HNPIs in the MP-PECAs (N=6) was higher (4.2) as compared to that in the CLP-PETs (2.5,N=11) (p=0.23). Palladin may identify primary pancreatic endocrine neoplasms with a propensity to metastasize to the liver.
    Anticancer research 09/2011; 31(9):2957-62. · 1.71 Impact Factor
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    ABSTRACT: Because of clinicopathologic and genetic differences between left-sided colorectal cancer (LSCRC) and right-sided colon cancer (RSCC), cyclooxygenase-2(COX-2) and adenomatous polyposis coli (APC) expression may be of clinical relevance. Clinicopathologic information for 72 primary colon tumors, 44 left and 28 right, from 72 patients (34 F, 38 M) were analyzed. COX-2 and wild-type APC (W-APC) immunohistochemical expressions were determined for each case. The data were analyzed using the Chi-square test and exact binomial confidence intervals. Overall, 31 out of 44 (70%) LSCRC were W-COX-2 positive vs. 13 out of 28 (46%) RSCC (p-value=0.042). When evaluated independently of the anatomic location, COX-2 expression showed a borderline statistical correlation with the lack of W-APC protein (p-value=0.054). When considering location of tumors, the inverse correlation between COX-2 and W-APC expression became statistically significant (p-value=0.024). We report a strong inverse correlation between COX-2 and W-APC expression, with COX-2 being more frequently as expressed in LSCRC. These data may be useful to stratify colorectal cancer patients into right- and left-sided and COX-2 expressor and non-expressor subsets, when evaluating COX-2 inhibitor and other targeted therapies in colon cancer.
    Anticancer research 06/2011; 31(6):2191-5. · 1.71 Impact Factor
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    ABSTRACT: Using gene expression profiling on frozen primary pancreatic endocrine tumors (PETs), we discovered RUNX1T1 as a leading candidate progression gene. This study was designed (1) to validate the differential expression of RUNX1T1 protein on independent test sets of metastatic and nonmetastatic PETs and (2) to determine if RUNX1T1 underexpression in primary tumors was predictive of liver metastases. Immunohistochemical expression of RUNX1T1 protein was quantified using Allred scores on archival metastatic (n = 13) and nonmetastatic (n = 24) primary adult PET tissues using custom-designed tissue microarrays. Wilcoxon rank sum/Fisher exact tests and receiver operating characteristic curves were used in the data analysis. Median RUNX1T1 scores were 2 (2-7) and 6 (3-8) in metastatic versus nonmetastatic primaries (P < 0.0001). Eleven of 13 metastatic and 1 of 24 nonmetastatic primaries exhibited RUNX1T1-scores of 4 or less (P < 0.0001). Low RUNX1T1 expression was highly associated with hepatic metastases (P < 0.0001), whereas conventional histological criteria (Ki-67 index, mitotic rate, necrosis) were weakly associated with metastases (P = 0.08-0.15). Considering RUNX1T1 expression (Allred) score of 4 or less to be predictive, the sensitivity to predict hepatic metastases was 85%, with a specificity of 96%. RUNX1T1 protein is underexpressed in well-differentiated metastatic primary PETs relative to nonmetastatic primaries and emerges as a promising novel biomarker for prediction of liver metastases.
    Pancreas 05/2011; 40(4):627-33. · 2.95 Impact Factor
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    ABSTRACT: Temozolomide is an active agent in metastatic pancreatic endocrine carcinomas. In vitro data indicate that the combination of capecitabine and temozolomide is synergistic for induction of apoptosis in neuroendocrine tumor cell lines. The authors retrospectively evaluated the efficacy of capecitabine and temozolomide in 30 patients with metastatic pancreatic endocrine carcinomas to assess response rate, progression free survival (PFS), and overall survival (OS). Patients with metastatic, well, or moderately differentiated pancreatic endocrine carcinomas who had not received prior systemic chemotherapy were treated with capecitabine (750 mg/m² twice daily, days 1-14) and temozolomide (200 mg/m² once daily, days 10-14) every 28 days. Among 30 patients treated, 21 (70%) patients achieved an objective radiographic response. Median progression-free survival was 18 months. The rate of survival at two years was 92%. Only 4 patients (12%) experienced grade 3 or 4 adverse events. The combination of capecitabine and temozolomide is associated with an exceptionally high and durable response rate in metastatic endocrine carcinomas of the pancreas. Clinical endpoints, including response rate, survival, and toxicity, are superior to those observed with streptozocin-based regimens.
    Cancer 01/2011; 117(2):268-75. · 5.20 Impact Factor
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    ABSTRACT: To detect the molecular changes of malignancy in histologically normal breast (HNB) tissues, we recently developed a novel 117-gene-malignancy-signature. Here we report validation of our leading malignancy-risk-genes, topoisomerase-2-alpha (TOP2A), minichromosome-maintenance-protein-2 (MCM2) and "budding-uninhibited-by-benzimidazoles-1-homolog-beta" (BUB1B) at the protein level. Using our 117-gene malignancy-signature, we classified 18 fresh-frozen HNB tissues from 18 adult female breast cancer patients into HNB-tissues with low-grade (HNB-LGMA; N = 9) and high-grade molecular abnormality (HNB-HGMA; N = 9). Archival sections of additional HNB tissues from these patients, and invasive ductal carcinoma (IDC) tissues from six other patients were immunostained for these biomarkers. TOP2A/MCM2 expression was assessed as staining index (%) and BUB1B expression as H-scores (0-300). Increasing TOP2A, MCM2, and BUB1B protein expression from HNB-LGMA to HNB-HGMA tissues to IDCs validated our microarray-based molecular classification of HNB tissues by immunohistochemistry. We also demonstrated an increasing expression of TOP2A protein on an independent test set of HNB/benign/reductionmammoplasties, atypical-ductal-hyperplasia with and without synchronous breast cancer, DCIS and IDC tissues using a custom tissue microarray (TMA). In conclusion, TOP2A, MCM2, and BUB1B proteins are potential molecular biomarkers of malignancy in histologically normal and benign breast tissues. Larger-scale clinical validation studies are needed to further evaluate the clinical utility of these molecular biomarkers.
    Pathology research international. 01/2011; 2011:489064.
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    ABSTRACT: Akt is a regulator of cell proliferation, tumorigenesis and apoptosis. This study evaluated the incidence of Akt activation in a subset of neuroendocrine tumors (NETs) and its correlation to clinical pathological parameters. A subset of 46 samples from patients with enteropancreatic NETs (26 male and 20 female) were selected for evaluation. The tissue slides were stained with a mouse monoclonal antiphospho-Akt antibody using the avidin-biotin-complex method. The tumors were from the small (n = 18) and large bowel (n = 9) and from the pancreas (n = 16). Activation of Akt was detected in 61% (28/46) of cases. No statistical correlation was found between the p-Akt score and tumor grade (p = 0.72), tumor size (p = 0.72) and the presence of metastases (p = 0.52). This study shows activation of Akt in a subset of enteropancreatic NET for the first time. This finding suggests a role of p-Akt in NET carcinogenesis.
    Anticancer research 12/2010; 30(12):5063-7. · 1.71 Impact Factor
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    ABSTRACT: Reaction monitoring mass spectrometry has emerged as a powerful tool for targeted detection and quantification of proteins in clinical samples. Here, we report the use of gel electrophoresis for protein fractionation and liquid chromatography coupled to multiple reaction monitoring mass spectrometry (LC-MRM) screening for quantitative analysis of components from the Wnt/beta-catenin signaling pathway, which contributes to colon tumor formation and progression. In silico tools are used to design LC-MRM screens for each target protein. Following successful peptide detection, stable isotope labeled peptides are synthesized and developed as internal standards. Then, the assays are implemented in colon cancer cell lines to achieve detection in minimal amounts of cells, compatible with direct translation to clinical specimens. Selected assays are compared with qualitative results from immunoblotting (Westerns) and translated to individual frozen colon tissue sections and laser capture microdissected tumor cells. This LC-MRM platform has been translated from in vitro models to clinical specimens, forming the basis for future experiments in patient assessment.
    Journal of Proteome Research 08/2010; 9(8):4215-27. · 5.06 Impact Factor
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    ABSTRACT: Identification of the site of origin for 'malignancy with unknown primary' remains a challenge for modern pathology. Correct diagnosis is critical to defining the most beneficial treatment for the patient. Standard pathological approaches combine morphology and immunohistochemical (IHC) studies to first subclassify cytokeratin-positive carcinomas into adenocarcinoma, squamous cell carcinoma, neuroendocrine carcinoma, and urothelial carcinoma. Subsequently, organ-specific IHC-markers, if available, are used to assign the tumor's primary site of origin. Previous gene expression classifiers have shown promise in tumor classification but cannot readily be integrated into standard practice because they ignore the algorithmic hierarchy used by pathologists. Here we present a novel hybrid approach integrating a hierarchy of gene expression classifiers into the algorithmic method used with IHC. In this method, a tumor is initially assigned to one of the carcinoma subclasses by the top tier classifier. Dependent on initial classification, one of three second-tier classifiers assign primary site resulting in both carcinoma subtype and primary site classification. First tier classifier accuracies were 89%, 88%, and 75% for cross-validation, independent, and institutional independent test sets, respectively. Second tier accuracies were 87%, 90%, and 87% for adenocarcinoma, squamous, and neuroendocrine carcinoma respectively. Therefore, we can successfully separate the four main subtypes of carcinoma and subsequently assign primary site by incorporation of gene expression-based classifiers into the standard algorithmic pathology approach.
    The Journal of molecular diagnostics: JMD 07/2010; 12(4):476-86. · 3.48 Impact Factor
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    ABSTRACT: Angiolymphoid hyperplasia with eosinophilia (AHE) of the colon is a rare entity. Since 1997, to our knowledge only 2 similar cases have been documented in the literature. Here, we report a third case that presented as a transverse colonic mass mimicking cancer both clinically and radiologically. Microscopically classic morphologic criteria of this entity were observed, which consisted of both a vascular proliferation and an inflammatory component rich in eosinophils without any malignant features. Whether AHE is a reactive process or a neoplastic process (either a benign vascular neoplasm or a T-cell lymphoproliferative disorder) is still under debate. However, it is important to recognize this entity as a cause of colonic mass to avoid a misdiagnosis of malignancy.
    Clinical Colorectal Cancer 07/2010; 9(3):179-82. · 1.80 Impact Factor
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    ABSTRACT: An abstract is unavailable. This article is available as HTML full text and PDF.
    Pancreas 02/2010; 39(2):276-277. · 2.95 Impact Factor
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    ABSTRACT: An abstract is unavailable. This article is available as HTML full text and PDF.
    Pancreas 02/2010; 39(2):276. · 2.95 Impact Factor
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    ABSTRACT: An abstract is unavailable. This article is available as HTML full text and PDF.
    Pancreas 02/2010; 39(2):277-278. · 2.95 Impact Factor
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    ABSTRACT: An abstract is unavailable. This article is available as HTML full text and PDF.
    Pancreas 02/2010; 39(2):277. · 2.95 Impact Factor
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    ABSTRACT: An abstract is unavailable. This article is available as HTML full text and PDF.
    Pancreas 02/2010; 39(2):280. · 2.95 Impact Factor
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    ABSTRACT: Mcl-1 inhibits apoptosis in well-differentiated cells by sequestering BAD, BID, and BAX and other apoptotic molecules. pAKT blocks apoptotsis by facilitating the interaction of BAD with BCL-XL. Expression of pAKT and Mcl-1 have been described in colon cancer, however, the relationship between pAKT and Mcl-1 has not. Mcl-1 and pAKT immunohistochemistry was performed using colorectal cancer tissue microarray (TMA). The Holm step-down method was used to adjust for multiple testing. Mcl-1 and pAKT scores, stage, and grade were compared using Spearman's correlation coefficient. Metastasis and no metastasis groups were compared using the Wilcoxon rank sum test. Mcl-1 and pAKT scores were compared for normal colorectal mucosa (NR), adenoma (AD), and colorectal cancer (CRC) cohorts. The mean (SD) pAKT expression in NR (14) was 2.0 (1.4), in AD (8) was 3.0 (1.7), and in CRC (101) was 5.6 (2.4). These differences were statistically significant. For Mcl-1 the mean (SD) expression was 4.1 (1.7) in NR, 3.2 (1.2) in AD, and 3.3 (2.6) in CRC. Mcl-1 and pAKT scores were directly correlated during various stages of colon car-cinogenesis (p = 0.04). Mcl-1 showed direct correlation with tumor grade (p = 0.001) and tumor stage (p = 0.02) and with presence of metastasis (p = 0.008). We report the correlation of Mcl-1 protein expression with higher grade and stage in colorectal cancer. Mcl-1 correlated also with pAKT expression. We also report the up regulation of pAKT during the transition from NR to CRC.
    International journal of clinical and experimental pathology 01/2010; 3(8):768-74. · 2.24 Impact Factor
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    ABSTRACT: Primary lymphoepithelioma-like carcinomas (LELC) of the hepatobiliary tract are quite rare and the majority are associated with the Epstein-Barr virus (EBV). Here we report an unusual case of intrahepatic cholangiocarcinoma (ICC), admixed with LELC in a 63 year-old Filipino woman who presented clinically with right flank and back pain. Histologically, the tumor showed a dense lymphocytic infiltrate, predominantly composed of CD3 (+) T cells, and two components: an undifferentiated carcinoma, morphologically similar to nasopharyngeal carcinoma, and a poorly differentiated ICC intimately admixed. Immunohistochemical studies revealed that both components were immunoreactive for AE1/AE3, cytokeratin 7 and, focally, for monoclonal CEA. Both components were negative for cytokeratin 20 and HePar 1. EBER-1 in situ hybridization was uniformly positive in the tumor cells. The presence of EBV in ICC and LELC suggests that the virus may be linked to the pathogenesis of both components of the tumor. The mechanism of virus-driven neoplastic transformation needs further study.
    International journal of clinical and experimental pathology 01/2010; 3(7):736-41. · 2.24 Impact Factor
  • Pancreas 01/2010; 39(2). · 2.95 Impact Factor
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    ABSTRACT: Evidence is rapidly accumulating to allow construction of a working hypothesis of the pathogenesis of PENs. Many studies have contributed significantly to our current understanding of PEN tumorigenesis and progression. We have learned, mainly through the study of β-cell regulation, that neogenesis and transdifferentiation, replication, hypertrophy, and apoptosis work together to control endocrine cell mass. However, the pluripotent stem cells thought to play a role in the neogenesis and transdifferentiation aree yet to be discovered. Studies have found many of the same mechanisms that operate during pancreatic development in the embryo, also regulate β-cell mass in adults. One could imagine how deregulation of these processes could lead to oncogenesis. All of these processes are steered by cell regulators such as glucose, c-Myc, P13K-AKT/PKB, PDX-1, Ngn-3, and others. Many of the members of these complex molecular pathways have been implicated in the pathogenesis of PENs. Genetic syndromes, which include PENs as one of their components, allow for the identification of genes associated with the genesis of PENs, including the MEN1 gene, vHL gene, NF-1 gene, TSC1 and TSC2 genes. Advanced molecular testing, is currently making it more feasible to pursue newer lines of genetic studies to unravel an increasing number of chromosomal aberrations associated with PENs. Multiple molecular alterations, involving migratory, cell cycle, and angiogenic functions, have been found to promote PEN development, growth, invasion, and metastases. As a result of these studies, phase III trials of novel therapies targeting cell regulators such as mTOR, VEGF and other targets are in progress. Focused investigation of various mediators/mechanisms implicated in the tumorigenesis of PENs will contribute to novel diagnostic, therapeutic, and preventive stratagies, as well as facilitate the development of prognostic and predictive markers, while continuing to advance our understanding of the pathogenesis of PENs.
    01/2010;
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    ABSTRACT: Several cutting-edge strategies are being used to evaluate candidate genetic risk factors for breast cancer. These include linkage analysis for mapping out BRCA1 and BRCA2, mutational screening of candidate risk genes like CHEK2, ATM, BRIP1 and PALB2, which are associated with an intermediate level of breast cancer risk. Genome-wide association studies have revealed several low-penetrance breast cancer risk alleles. The predisposition factors are associated with different levels of breast cancer risk. Relative to control population, the risk in patients harboring high-risk BRCA1 and 2 mutations is over 10-fold, with intermediate penetrance genes 2 to 4-fold and with low penetrance alleles less than 1.5-fold. Overall, these factors account for about 25% of the genetic risk for breast cancer. In the remainder, genetic factors to contribute to the risk of breast cancer remain unknown and are a subject of current investigation. With discovery and validation of newer and clinically relevant predisposition factors, additional breast cancer risk categories may be recognized. BRCA1 and BRCA2 mutation testing allows identification of individuals at increased risk of breast cancer who are offered risk-reducing interventions. Targeted therapies are being developed that may refine management of patients with BRCA1 and BRCA2 mutations. Further genome-wide studies are required to identify clinically relevant molecular factors that will allow more accurate and widely applicable genetic risk stratification. Current efforts in discovery, validation and qualification of molecular markers of breast cancer risk offer considerable promise in the future to develop more accurate breast cancer risk assessment along with development of more effective chemopreventive and therapeutic strategies.
    Minerva endocrinologica 12/2009; 34(4):295-309. · 1.40 Impact Factor

Publication Stats

426 Citations
125 Downloads
123.64 Total Impact Points

Institutions

  • 2006–2011
    • Moffitt Cancer Center
      Tampa, Florida, United States
  • 2003–2008
    • University of South Florida
      • Morsani College of Medicine
      Tampa, Florida, United States
  • 2000
    • George Washington University
      • Department of Pathology
      Washington, D. C., DC, United States
    • National Institutes of Health
      Maryland, United States