Our analysis positively validated the use of SOFA score to predict unfavourable outcome and to limit misclassification into lower severity. However, qSOFA score had inadequate sensitivity for early risk assessment.

Substrate degradation and cell migration are key steps in cancer metastasis. Membrane-type 1-matrix metalloproteinase (MT1-MMP) has been linked with these processes. Using the fluorescein isothiocyanate (FITC)-labeled fibronectin degradation assay combined with the phagokinetic cell migration assay, structurefunction relationships of MT1-MMP were studied. Our data indicate that MT1-MMP initiates substrate degradation and enhances cell migration; cell migration occurs as a concurrent but independent event. Using recombinant DNA approaches, we demonstrated that the hemopexin-like domain and a nonenzymatic component of the catalytic domain of MT1-MMP are essential for MT1-MMP-mediated cell migration. Because the cytoplasmic domain of MT1-MMP was not required for MT1-MMP-mediated fibronectin degradation and cell migration, it is proposed that cross-talk between the hemopexin domain of MT1-MMP and adjacent cell surface molecules is responsible for outside-in signaling. Employing cDNAs encoding dominant negative mutations, we demonstrated that Rac1 participates in the MT1-MMP signal transduction pathway. These data demonstrated that each domain of MT1-MMP plays a distinct role in substrate degradation and cell migration.Cell migration and invasion are critical coordinated events in the cancer dissemination process (1, 2). Cell migration involves the locomotion of a cell over an extracellular matrix (ECM) 1 substratum (3). Extension of the leading edge is associated with adhesion, i.e. binding of integrins to their ECM ligands leading to subsequent migration and further invasion (4). Cancer cell invasion requires degradation of surrounding ECM and basement membrane by proteinases located at the leading edge of migrating cells. Extracellular proteolytic enzymes, i.e. matrix metalloproteinases (MMPs), serine and cysteine proteinases have long been implicated in cancer metastasis (1, 5).MMPs have been linked to the metastatic phenotype of tumor cells through both correlative and functional studies. Production and activation of MMPs in tumors are required for degradation of the ECM and dissemination of cancer cells to distant organs (2). MMPs also play an important role in tumor angiogenesis (6). The mechanism of activation of latent MMP-2 (pMMP-2) in tumors has been the focus of considerable recent interest based on the identification of a new category of intrinsic membrane-type MMPs (MT1, 2, 3, 4, 5, and 6-MMPs) (7).MT1-MMP is able to activate pMMP-2 on the surface of tumor cells by assembling a unique triplex with tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) and pMMP-2; a second MT1-MMP molecule then cleaves the propeptide of pMMP-2, thereby activating the enzyme at the cell surface (8 -10). Integrin receptors, ␣ 3 ␤ 1 and ␣ v ␤ 3 , participate in this response (11). Recombinant MT1-MMP hydrolyze collagen types I, II, and III and digests cartilage proteoglycan, fibronectin, fibrinogen, vitronectin, and laminin (12).It is now recognized that the actions of MMPs are not restricted to the simple breakdown of ECM...

The decade of the 1990s was ripe with enthusiasm for the use of MMPIs to treat cancer. Limitations to new cytotoxic chemotherapy approaches to treat solid cancers and a better understanding of tumor biology provided a strong impetus for alternative drug development. It is estimated that the pharmaceutical industry invested at least a billion dollars in this effort. Because MMPIs represent an entirely different therapeutic modality from proven anti-cancer agents, many of the therapeutic trials designed to test MMPIs in human patients with cancer bypassed traditional approaches to evaluate drug efficiency. The concept of systematic progression from small phase I (dose escalation to toxicity to examine drug safety), to phase II (drug treatment of patients with cancer types considered to be good candidates for the selected drug), to phase III (randomized trial of new drug versus best available therapy to determine drug efficacy) trials was modified. Much to the chagrin of everyone involved in these studies, the randomized trials of MMPIs in advanced cancer have, pretty much, flopped. This review article will attempt to dissect out aspects of previous human and animal studies that may be helpful in making decisions about the future of MMPI drug development for the treatment of cancer. The important questions to be addressed in this report are: What are the lessons that we have learned from preclinical (animal models) and clinical studies of MMPIs in cancer? Are we ready to abandon MMPIs as a therapeutic modality in cancer (termination of phase III trials) or do we need to have a better understanding of the myriad effects of MMPs in cancer before we proceed to develop different types of drugs that alter MMP activity in patients with cancer (beginning of new phase I trials)?

The PIK3CA gene is one of the most frequently mutated oncogenes in human cancers. It encodes p110α, the catalytic subunit of phosphatidylinositol 3-kinase alpha (PI3Kα), which activates signaling cascades leading to cell proliferation, survival, and cell growth. The most frequent mutation in PIK3CA is H1047R, which results in enzymatic overactivation. Understanding how the H1047R mutation causes the enhanced activity of the protein in atomic detail is central to developing mutant-specific therapeutics for cancer. To this end, Surface Plasmon Resonance (SPR) experiments and Molecular Dynamics (MD) simulations were carried out for both wild-type (WT) and H1047R mutant proteins. An expanded positive charge distribution on the membrane binding regions of the mutant with respect to the WT protein is observed through MD simulations, which justifies the increased ability of the mutated protein variant to bind to membranes rich in anionic lipids in our SPR experiments. Our results further support an auto-inhibitory role of the C-terminal tail in the WT protein, which is abolished in the mutant protein due to loss of crucial intermolecular interactions. Moreover, Functional Mode Analysis reveals that the H1047R mutation alters the twisting motion of the N-lobe of the kinase domain with respect to the C-lobe and shifts the position of the conserved P-loop residues in the vicinity of the active site. These findings demonstrate the dynamical and structural differences of the two proteins in atomic detail and propose a mechanism of overactivation for the mutant protein. The results may be further utilized for the design of mutant-specific PI3Kα inhibitors that exploit the altered mutant conformation.