Abstract: More than 2% of adults harbor a pancreatic cyst, a subset of which progress to invasive lesions with lethal consequences. To assess the genomic landscapes of neoplastic cysts of the pancreas, we determined the exomic sequences of DNA from the neoplastic epithelium of eight surgically resected cysts of each of the major neoplastic cyst types: serous cystadenomas (SCAs), intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs) and solid pseudo-papillary neoplasms (SPNs). SPNs are low-grade malignancies, and IPMNs and MCNs, but not SCAs, have the capacity to progress to cancer. We found that SCAs, IPMNs, MCNs, and SPNs contained 10=4.6, 27=12, 16=7.6, and 2.9=2.1 somatic mutations per tumor, respectively. Among the mutations identified, E3 ubiquitin ligase components were of particular note. Four of the eight SCAs contained mutations of VHL, a key component of the VHL ubiquitin ligase complex that has previously been associated both with renal cell carcinomas, SCAs, and other neoplasms.

Abstract: To help reveal the pathogenesis of these lesions, we purified the DNA from Intraductal Papillary Mucinous Neoplasm (IPMN) cyst fluids from 19 patients and searched for mutations in 169 genes commonly altered in human cancers. We identified recurrent mutations at codon 201 of GNAS. We found that GNAS mutations were present in 66% of IPMNs and that either KRAS or GNAS mutations could be identified in 96%. In eight cases, we could investigate invasive adenocarcinomas that developed in association with IPMNs containing GNAS mutations. In seven of these eight cases, the GNAS mutations present in the IPMNs were also found in the invasive lesion. GNAS mutations were not found in other types of cystic neoplasms of the pancreas or in invasive adenocarcinomas not associated with IPMNs. These data suggest that GNAS mutations can inform the diagnosis and management of patients with cystic pancreatic lesions.

Abstract: More than 2% of adults harbor a pancreatic cyst, a subset of which progress to invasive lesions with lethal consequences. To assess the genomic landscapes of neoplastic cysts of the pancreas, we determined the exomic sequences of DNA from the neoplastic epithelium of eight surgically resected cysts of each of the major neoplastic cyst types: serous cystadenomas (SCAs), intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs) and solid pseudo-papillary neoplasms (SPNs). SPNs are low-grade malignancies, and IPMNs and MCNs, but not SCAs, have the capacity to progress to cancer. We found that SCAs, IPMNs, MCNs, and SPNs contained 10=4.6, 27=12, 16=7.6, and 2.9=2.1 somatic mutations per tumor, respectively. Among the mutations identified, E3 ubiquitin ligase components were of particular note. Four of the eight SCAs contained mutations of VHL, a key component of the VHL ubiquitin ligase complex that has previously been associated both with renal cell carcinomas, SCAs, and other neoplasms.

Abstract: More than 2% of adults harbor a pancreatic cyst, a subset of which progress to invasive lesions with lethal consequences. To assess the genomic landscapes of neoplastic cysts of the pancreas, we determined the exomic sequences of DNA from the neoplastic epithelium of eight surgically resected cysts of each of the major neoplastic cyst types: serous cystadenomas (SCAs), intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs) and solid pseudo-papillary neoplasms (SPNs). SPNs are low-grade malignancies, and IPMNs and MCNs, but not SCAs, have the capacity to progress to cancer. We found that SCAs, IPMNs, MCNs, and SPNs contained 10=4.6, 27=12, 16=7.6, and 2.9=2.1 somatic mutations per tumor, respectively. Among the mutations identified, E3 ubiquitin ligase components were of particular note. Four of the eight SCAs contained mutations of VHL, a key component of the VHL ubiquitin ligase complex that has previously been associated both with renal cell carcinomas, SCAs, and other neoplasms.

Abstract: Provided are methods for treating cancer in a patient, comprising administering to a patient in need thereof a therapeutically effective regimen, the regimen comprising administering a gamma-secretase inhibitor, wherein the regimen results in a reduction in the cancer cell population in the patient. In some embodiments of the methods, the therapeutically effective regimen stabilizes, reduces or eliminates the cancer stem cell population. Also provided are compounds of the formula I or a pharmaceutically acceptable salt thereof, wherein R1, R2, and X are as herein described.

Abstract: To help reveal the pathogenesis of these lesions, we purified the DNA from Intraductal Papillary Mucinous Neoplasm (IPMN) cyst fluids from 19 patients and searched for mutations in 169 genes commonly altered in human cancers. We identified recurrent mutations at codon 201 of GNAS. We found that GNAS mutations were present in 66% of IPMNs and that either KRAS or GNAS mutations could be identified in 96%. In eight cases, we could investigate invasive adenocarcinomas that developed in association with IPMNs containing GNAS mutations. In seven of these eight cases, the GNAS mutations present in the IPMNs were also found in the invasive lesion. GNAS mutations were not found in other types of cystic neoplasms of the pancreas or in invasive adenocarcinomas not associated with IPMNs. These data suggest that GNAS mutations can inform the diagnosis and management of patients with cystic pancreatic lesions.

Abstract: Polymeric nanoparticles with a hydrophobic core and a hydrophilic shell are formed from: 1) N-isopropylacrylamide (NIPAAM), at a molar ratio of about 50% to about 90%, and preferably 60% for specific delivery routes such as oral or parenteral; either water-soluble vinyl derivatives like vinylpryolidone (VP) or vinyl acetate (VA), or water insoluble vinyl derivatives like methyl methacrylate (MMA) or styrene (ST), at a molar ratio of about 10% to about 30%; and acrylic acid (AA), at a molar ration of about 10% to about 30%.

Abstract: Polymeric nanoparticles with a hydrophobic core that encapsulates curcumin and a hydrophilic shell with one or more chemotherapeutic agents (e.g., doxorubicin) associated with the shell surface are formed from N-isopropylacryl amide (NEPAAM), acrylic acid (AA), and at least one vinyl monomer selected from the group consisting of vinyl acetate, 4-vinyl benzoic acid, methylmethacrylate, vinylmethacrylate, N-vinylpyrrolidone, N-vinyl piperidone, N-vinyl caprolacum, N-vinyl carbazole, and styrene, where the NIPAAM, the AA, and the vinyl monomer are present at molar ratios of 50-70:10-30:10-30 for NIPAAM:AA:vinyl monomer. These nanoparticles effectively overcome multidrug resistance and ameliorate cardiomyopathy in vivo.

Abstract: Polymeric nanoparticles with a hydrophobic core and a hydrophilic shell are formed from: 1) N-isopropylacrylamide (NIPAAM), at a molar ratio of about 50% to about 90%, and preferably 60% for specific delivery routes such as oral or parenteral; either water-soluble vinyl derivatives like vinylpryolidone (VP) or vinyl acetate (VA), or water insoluble vinyl derivaties like methyl methacrylate (MMA) or styrene (ST), at a molar ratio of about 10% to about 30%; and acrylic acid (AA), at a molar ration of about 10% to about 30%.

Abstract: Polymeric nanoparticles with a hydrophobic core and a hydrophilic shell are formed from: 1) N-isopropyl acrylamide (NIPAAM), at a molar ratio of about 50% to about 90%, and preferably 60% for specific delivery routes such as oral or parenteral; either water-soluble vinyl derivatives like vinylpyrolidone (VP) or vinyl acetate (VA), or water insoluble vinyl derivatives like methyl methacrylate (MMA) or styrene (ST), at a molar ratio of about 10% to about 30%; and acrylic acid (AA), at a molar ratio of about 10% to about 30%. The formed nanoparticles may be optionally surface functionalized using reactive groups present in AA, including PEGylation, or conjugation of moieties such as chemotherapeutics, contrasting agents, antibodies, radionucleides, ligands, and sugars, for diagnostic, therapeutic, and imaging purposes. The polymeric nanoparticles are preferably dispersed in aqueous solutions.

Abstract: Provided are methods for treating cancer in a patient, comprising administering to a patient in need thereof a therapeutically effective regimen, the regimen comprising administering a gamma-secretase inhibitor, wherein the regimen results in a reduction in the cancer cell population in the patient. In some embodiments of the methods, the therapeutically effective regimen stabilizes, reduces or eliminates the cancer stem cell population. Also provided are compounds of the formula I or a pharmaceutically acceptable salt thereof, wherein R1, R2, and X are as herein described.

Abstract: The present invention provides compositions and methods featuring microRNA polynucleotides for the diagnosis, treatment or prevention of neoplasia.

Abstract: Elevated Hedgehog (Hh) pathway activity, including ligand stimulated Hh pathway activity, was detected in digestive tract cancers, including esophagus, stomach, biliary tract, and pancreatic cancer, and determined to be associated with growth and proliferation of the cancer cells. Accordingly, methods are provided for treating a digestive tract cancer associated with elevated Hh pathway activity by reducing or inhibiting the Hh pathway activity. Also provided are methods of determining the responsiveness of a digestive tract tumor to treatment with an Hh pathway antagonist.

Abstract: Provided are methods for treating cancer in a patient, comprising administering to a patient in need thereof a therapeutically effective regimen, the regimen comprising administering a gamma-secretase inhibitor, wherein the regimen results in a reduction in the cancer cell population in the patient. In some embodiments of the methods, the therapeutically effective regimen stabilizes, reduces or eliminates the cancer stem cell population. Also provided are compounds of the formula I or a pharmaceutically acceptable salt thereof, wherein R1, R2, and X are as herein described.

Abstract: Methods for diagnosing pancreatic endocrine neoplasms are provided. Methods include obtaining a nucleic acid sample from the subject; contacting nucleic acids of the sample with an array comprising a plurality of DNAs under conditions to form one or more hybridization complexes; detecting the hybridization complexes; and comparing the levels of the hybridization complexes detected with the level of hybridization complexes detected in a non-diseased sample, wherein an altered level of hybridization complexes detected compared with the level of hybridization complexes of a non-diseased sample correlates with the presence of PEN in the subject. Nearly 200 differentially expressed genes identified in well-differentiated PENs versus enriched normal islet cells are provided, and a subset of these genes was validated at the protein level using PEN tissue microarrays.

Abstract: The present invention includes methods and systems for identification (diagnosis) of abnormal cell growth by analysis of a patient sample, particularly the presence of a pancreatic cancer or susceptibility to a pancreatic cancer. The invention also includes therapeutic agents for treating pancreatic cancers as well as methods for identifying candidate agents for treatment of pancreatic cancers.