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1.  Regularized Multivariate Regression for Identifying Master Predictors with Application to Integrative Genomics Study of Breast Cancer 
In this paper, we propose a new method remMap — REgularized Multivariate regression for identifying MAster Predictors — for fitting multivariate response regression models under the high-dimension-low-sample-size setting. remMap is motivated by investigating the regulatory relationships among different biological molecules based on multiple types of high dimensional genomic data. Particularly, we are interested in studying the influence of DNA copy number alterations on RNA transcript levels. For this purpose, we model the dependence of the RNA expression levels on DNA copy numbers through multivariate linear regressions and utilize proper regularization to deal with the high dimensionality as well as to incorporate desired network structures. Criteria for selecting the tuning parameters are also discussed. The performance of the proposed method is illustrated through extensive simulation studies. Finally, remMap is applied to a breast cancer study, in which genome wide RNA transcript levels and DNA copy numbers were measured for 172 tumor samples. We identify a trans-hub region in cytoband 17q12–q21, whose amplification influences the RNA expression levels of more than 30 unlinked genes. These findings may lead to a better understanding of breast cancer pathology.
PMCID: PMC3905690  PMID: 24489618
sparse regression; MAP(MAster Predictor) penalty; DNA copy number alteration; RNA transcript level; v-fold cross validation
2.  The interface between biomarker discovery and clinical validation: The tar pit of the protein biomarker pipeline 
Proteomics. Clinical applications  2008;2(10-11):1386-1402.
The application of “omics” technologies to biological samples generates hundreds to thousands of biomarker candidates; however, a discouragingly small number make it through the pipeline to clinical use. This is in large part due to the incredible mismatch between the large numbers of biomarker candidates and the paucity of reliable assays and methods for validation studies. We desperately need a pipeline that relieves this bottleneck between biomarker discovery and validation. This paper reviews the requirements for technologies to adequately credential biomarker candidates for costly clinical validation and proposes methods and systems to verify biomarker candidates. Models involving pooling of clinical samples, where appropriate, are discussed. We conclude that current proteomic technologies are on the cusp of significantly affecting translation of molecular diagnostics into the clinic.
PMCID: PMC2957839  PMID: 20976028
Biomarker verification; Multiple reaction monitoring; Targeted proteomics
3.  Genomic Profiling Identifies GATA6 as a Candidate Oncogene Amplified in Pancreatobiliary Cancer 
PLoS Genetics  2008;4(5):e1000081.
Pancreatobiliary cancers have among the highest mortality rates of any cancer type. Discovering the full spectrum of molecular genetic alterations may suggest new avenues for therapy. To catalogue genomic alterations, we carried out array-based genomic profiling of 31 exocrine pancreatic cancers and 6 distal bile duct cancers, expanded as xenografts to enrich the tumor cell fraction. We identified numerous focal DNA amplifications and deletions, including in 19% of pancreatobiliary cases gain at cytoband 18q11.2, a locus uncommonly amplified in other tumor types. The smallest shared amplification at 18q11.2 included GATA6, a transcriptional regulator previously linked to normal pancreas development. When amplified, GATA6 was overexpressed at both the mRNA and protein levels, and strong immunostaining was observed in 25 of 54 (46%) primary pancreatic cancers compared to 0 of 33 normal pancreas specimens surveyed. GATA6 expression in xenografts was associated with specific microarray gene-expression patterns, enriched for GATA binding sites and mitochondrial oxidative phosphorylation activity. siRNA mediated knockdown of GATA6 in pancreatic cancer cell lines with amplification led to reduced cell proliferation, cell cycle progression, and colony formation. Our findings indicate that GATA6 amplification and overexpression contribute to the oncogenic phenotypes of pancreatic cancer cells, and identify GATA6 as a candidate lineage-specific oncogene in pancreatobiliary cancer, with implications for novel treatment strategies.
Author Summary
Pancreatic cancer is a devastating disease, having among the lowest survival rates of any cancer. A better understanding of the molecular basis of pancreatic cancer may lead to improved rationale therapies. We report here the discovery of amplification (i.e. extra copies) of the GATA6 gene in many human pancreatic cancers. GATA6 is a regulator of gene expression and functions in the development of the normal pancreas. Our findings indicate that its amplification and aberrant overexpression contribute to pancreatic cancer development. GATA6 joins a growing list of cancer genes with key roles in normal human development but pathogenic roles in cancer when aberrantly expressed. Our discovery of GATA6 amplification provides a new foothold into understanding the pathogenic mechanisms underlying pancreatic cancer, and suggests new strategies for therapy by targeting GATA6 or the genes it regulates.
PMCID: PMC2413204  PMID: 18535672
4.  Experimental study on operative methods of pancreaticojejunostomy with reference to anastomotic patency and postoperative pancreatic exocrine function 
AIM: To assess the patency of pancreaticoenterostomy and pancreatic exocrine function after three surgical methods.
METHODS: A pig model of pancreatic ductal dilation was made by ligating the main pancreatic duct. After 4 wk ligation, a total of 36 piglets were divided randomly into four groups. The piglets in the control group underwent laparotomy only; the others were treated by three anastomoses: (1) end-to-end pancreaticojejunostomy invagination (EEPJ); (2) end-to-side duct-to-mucosa sutured anastomosis (ESPJ); or (3) binding pancreaticojejunostomy (BPJ). Anastomotic patency was assessed after 8 wk by body weight gain, intrapancreatic ductal pressure, pancreatic exocrine function secretin test, pancreatography, and macroscopic and histologic features of the anastomotic site.
RESULTS: The EEPJ group had significantly slower weight gain than the ESPJ and BPJ groups on postoperative weeks 6 and 8 (P < 0.05). The animals in both the ESPJ and BPJ groups had a similar body weight gain. Intrapancreatic ductal pressure was similar in ESPJ and BPJ. However, pressure in EEPJ was significantly higher than that in ESPJ and BPJ (P < 0.05). All three functional parameters, the secretory volume, the flow rate of pancreatic juice, and bicarbonate concentration, were significantly higher in ESPJ and BPJ as compared to EEPJ (P < 0.05). However, the three parameters were similar in ESPJ and BPJ. Pancreatography performed after EEPJ revealed dilation and meandering of the main pancreatic duct, and the anastomotic site exhibited a variable degree of occlusion, and even blockage. Pancreatography of ESPJ and BPJ, however, showed normal ductal patency. Histopathology showed that the intestinal mucosa had fused with that of the pancreatic duct, with a gradual and continuous change from one to the other. For EEPJ, the portion of the pancreatic stump protruding into the jejunal lumen was largely replaced by cicatricial fibrous tissue.
CONCLUSION: A mucosa-to-mucosa pancreaticojejunostomy is the best choice for anastomotic patency when compared with EEPJ. BPJ can effectively maintain anastomotic patency and preserve pancreatic exocrine function as well as ESPJ.
PMCID: PMC2679134  PMID: 18200668
Pancreaticojejunostomy; Animal model; anastomotic patency; Pancreatic exocrine function; Histopathology; Pancreatography
5.  3,6-Dihydr­oxy-2′-[(2-hydr­oxy-1-naphth­yl)methyl­eneamino]xanthene-9-spiro-1′-isoindolin-3′-one acetonitrile solvate 
The title compound, C31H20N2O5·C2H3N, was synthesized by the reaction of fluorescein hydrazide and excess 2-hydr­oxy-1-naphthaldehyde in acetonitrile. The spirolactam ring is planar and is nearly at right angles to the two benzene rings of the xanthene system. The dihedral angle between the two benzene rings of the xanthene system is 9.92 (4)°. In the crystal structure, the mol­ecules are linked into extended two-dimensional networks by inter­molecular hydrogen bonding. Acetonitrile mol­ecules are located in the voids between the two-dimensional networks.
PMCID: PMC2960338  PMID: 21201469

Results 1-5 (5)