Tape archiving using the time capsule file system

Thesis (M. Eng.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 1995.Includes bibliographical references (p. 40).by Brian K. Zuzga.M.Eng

MIT SchMUSE: Class-Based Remote Delegation in a Capricious Distributed Environment

MIT SchMUSE (pronounced "shmooz") is a concurrent, distributed, delegation-based object-oriented interactive environment with persistent storage. It is designed to run in a "capricious" network environment, where servers can migrate from site to site and can regularly become unavailable. Our design introduces a new form of unique identifiers called "globally unique tickets" that provide globally unique time/space stamps for objects and classes without being location specific. Object location is achieved by a distributed hierarchical lazy lookup mechanism that we call "realm resolution." We also introduce a novel mechanism called "message deferral" for enhanced reliability in the face of remote delegation. We conclude with a comparison to related work and a projection of future work on MIT SchMUSE

Tumor Epithelial Cell Matrix Metalloproteinase 9 (MMP-9) is a Prognostic Marker in Colorectal Cancer

Presented at American Association Cancer Research in 2008 Zuzga D.S., Gibbons A.V., Li P., Lubbe W.J., Chervoneva I., Pitari G.M. “Tumor epithelial cell MMP-9 is a prognostic marker in colorectal cancer”. In: American Association for Cancer Research Special Conference, Molecular Diagnostics in Cancer Therapeutic Development: Proceedings; 2008 Sept 22-25; Philadelphia, PA. Abstract A40. Colorectal cancer is the second leading cause of cancer-related mortality indeveloped nations. Mortality from colon cancer largely reflects metastasis, thespread of the disease to distant sites. Early diagnosis of pre-metastatic diseaseand accurate stratification of patients with metastasis is pivotal to decreasemortality rates from colon cancer by effectively administering surgery alone orwith chemotherapy. However, specific pathological markers of colorectal cancermetastasis have not emerged. Matrix metalloproteinase 9 (MMP-9) is a keyregulator of metastasis and a therapeutic target in colon cancer. Here, MMP-9overexpression in pure tumor epithelial, but nor stromal, cell populations frompatients was associated with metastatic colorectal cancer progression as definedby RT-PCR and confirmed by immunostaining. Thus, tumors with increasedMMP-9 expression compared to matched normal adjacent tissues alwaysexhibited metastatic dissemination. In particular, MMP-9 overexpression in tumorepithelial cells, compared to normal epithelial cells, specifically predicted lymphnode involvement. Importantly, patients with relative increase of MMP-9 levels intumor epithelial cells were characterized by more advanced disease stages, withsignificantly higher proportion of regional lymph nodes harboring metastasis,compared to patients with a relative decrease in MMP-9 expression. Together,these observations suggest tumor epithelial cell MMP-9 is a novel prognosticmarker that may be exploited for more efficient disease stage stratification andtherapeutic regimen selection in patients with colorectal cancer

Phosphorylation of vasodilator-stimulated phosphoprotein Ser239 suppresses filopodia and invadopodia in colon cancer.

In colorectal cancer, the antitumorigenic guanylyl cyclase C (GCC) signalome is defective reflecting ligand deprivation from downregulation of endogenous hormone expression. Although the proximal intracellular mediators of that signal transduction system, including cyclic guanosine monophosphate (cGMP) and cGMP-dependent protein kinase (PKG), are well characterized, the functional significance of its distal effectors remain vague. Dysregulation of ligand-dependent GCC signaling through vasodilator-stimulated phosphoprotein (VASP), an actin-binding protein implicated in membrane protrusion dynamics, drastically reduced cGMP-dependent VASP phosphorylation levels in colorectal tumors from patients. Restoration of cGMP-dependent VASP phosphorylation by GCC agonists suppressed the number and length of locomotory (filopodia) and invasive (invadopodia) actin-based organelles in human colon cancer cells. Membrane organelle disassembly reflected specific phosphorylation of VASP Ser239, the cGMP/PKG preferred site, and rapid VASP removal from tumor cell protrusions. Importantly, VASP Ser239 phosphorylation inhibited the proteolytic function of invadopodia, reflected by suppression of the cancer cell ability to digest DQ-collagen IV embedded in Matrigel. These results demonstrate a previously unrecognized role for VASP Ser239 phosphorylation, a single intracellular biochemical reaction, as an effective mechanism which opposes tumor cell shape promoting colon cancer invasion and metastasis. Reconstitution of physiological cGMP circuitry through VASP, in turn, represents an attractive targeted approach for patients with colorectal cancer

Overexpression of matrix metalloproteinase 9 in tumor epithelial cells correlates with colorectal cancer metastasis.

Colorectal cancer mortality largely reflects metastasis, the spread of the disease to distant organs. Matrix metalloproteinase 9 (MMP-9) is a key regulator of metastasis and a target for anticancer strategies in colon cancer. Here, the overexpression of MMP-9 in pure tumor epithelial, but nor stromal, cell populations was associated with metastatic progression of colorectal cancer, as defined by reverse transcriptase-polymerase chain reaction (qRT-PCR) and confirmed by immunostaining. Thus, cancer cell MMP-9 represents a novel, selective prognostic and predictive factor that may be exploited for more effective disease stage stratification and therapeutic regimen selection in patients with colorectal cancer

PKA-regulated VASP phosphorylation promotes extrusion of transformed cells from the epithelium

At the early stages of carcinogenesis, transformation occurs in single cells within tissues. In an epithelial monolayer, such mutated cells are recognized by their normal neighbors and are often apically extruded. The apical extrusion requires cytoskeletal reorganization and changes in cell shape, but the molecular switches involved in the regulation of these processes are poorly understood. Here, using stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative mass spectrometry, we have identified proteins that are modulated in transformed cells upon their interaction with normal cells. Phosphorylation of VASP at serine 239 is specifically upregulated in RasV12-transformed cells when they are surrounded by normal cells. VASP phosphorylation is required for the cell shape changes and apical extrusion of Ras-transformed cells. Furthermore, PKA is activated in Ras-transformed cells that are surrounded by normal cells, leading to VASP phosphorylation. These results indicate that the PKA-VASP pathway is a crucial regulator of tumor cell extrusion from the epithelium, and they shed light on the events occurring at the early stage of carcinogenesis