A NOVEL PRO-OXIDANT ROLE OF GELSOLIN IN CANCER CELL INVASION

Ph.DDOCTOR OF PHILOSOPH

Acute kidney injury in obstetrics: a five-year study in a tertiary centre

Background: Pregnancy Related Acute Kidney Injury (PRAKI) is a major cause of maternal and foetal morbidity and mortality in developing countries. The incidence has declined due to improvements in reproductive health but it is still associated with significant perinatal mortality and maternal morbidity. It may be due to decrease in renal perfusion or ischemic tubular necrosis from a variety of conditions encountered during pregnancy. Our study aims at determining the predisposing factors and causes of AKI during pregnancy and its impact on maternal and foetal outcome.Methods: A retrospective cohort study over a period of 5 years was conducted on pregnant women with AKI as per inclusion and exclusion criteria. The detailed history, events, mode of delivery, cause leading to AKI, management, hospital stay, maternal and foetal outcome were studied in detail and evaluated. These patients were classified according to RIFLE criteria and were followed up for hospital stay and residual morbidities.Results: The incidence of PRAKI in the study was 0.07% (36 out of 50,735 deliveries) and among obstetric ICU patients, it was 6.8%. Most of the majority of the cases were unbooked (66.7%) and multipara (61.1%). Maternal morbidity was seen in 66.7% and mortality was 27.8%. Poor foetal outcome was seen in 44.4%.Conclusions: Haemorrhage is the most common cause of PRAKI, followed by toxaemia of pregnancy and sepsis. Early detection and meticulous management of haemorrhage, hypertension and sepsis reduce the incidence of PRAKI and associated maternal mortality

Gelsolin induces colorectal tumor cell invasion via modulation of the urokinase-type plasminogen activator cascade

Gelsolin is a cytoskeletal protein which participates in actin filament dynamics and promotes cell motility and plasticity. Although initially regarded as a tumor suppressor, gelsolin expression in certain tumors correlates with poor prognosis and therapy-resistance. In vitro, gelsolin has anti-apoptotic and pro-migratory functions and is critical for invasion of some types of tumor cells. We found that gelsolin was highly expressed at tumor borders infiltrating into adjacent liver tissues, as examined by immunohistochemistry. Although gelsolin contributes to lamellipodia formation in migrating cells, the mechanisms by which it induces tumor invasion are unclear. Gelsolin’s influence on the invasive activity of colorectal cancer cells was investigated using overexpression and small interfering RNA knockdown. We show that gelsolin is required for invasion of colorectal cancer cells through matrigel. Microarray analysis and quantitative PCR indicate that gelsolin overexpression induces the upregulation of invasion-promoting genes in colorectal cancer cells, including the matrix-degrading urokinase-type plasminogen activator (uPA). Conversely, gelsolin knockdown reduces uPA levels, as well as uPA secretion. The enhanced invasiveness of gelsolin-overexpressing cells was attenuated by treatment with function-blocking antibodies to either uPA or its receptor uPAR, indicating that uPA/uPAR activity is crucial for gelsolin-dependent invasion. In summary, our data reveals novel functions of gelsolin in colorectal tumor cell invasion through its modulation of the uPA/uPAR cascade, with potentially important roles in colorectal tumor dissemination to metastatic sites

Redox regulation of cancer cell migration and invasion

Cancer cell migration and invasion are the initial steps in metastasis. Through a series of cellular events, including cytoskeletal remodeling resulting in phenotype changes and degradation of the extracellular matrix, cells are able to detach from the primary tumor and metastasize to distant sites. These changes occur in response to intracellular signaling mechanisms triggered via cell surface receptor stimulation or signal amplification within the cell. Amongst the active molecules that participate in relaying cellular signals are the reactive oxygen species (ROS). Initially identified to participate in defense mechanisms to ward off invading pathogens, ROS are now considered to have important roles in several other biological processes including cancer development. In this report, we review recent evidence pointing towards the involvement of ROS in tumor progression. We discuss the biology of ROS and their roles at different stages during the process of cancer cell migration and invasion. © 2012 Elsevier B.V. and Mitochondria Research Society