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Thesis (Ph.D.)--Boston University / Functional competence of intact pancreas and neonatal pancreatic implants was determined in normal and alloxan diabetic Golden Hamsters by measurement of the ability to release insulin-like activity (ILA) in vitro and in vivo as bioassayed by the rat epididymal fat ped technique. Islets were determined to be functionally competent before birth. ILA was released in vitro prior to the second post-natal day when beta cells first showed definite granulation. By 30 days, beta cells showed mature granulation but with advancing age, they released less ILA. It is suggested that the corresponding development of exocrine pancreas results in proteolytic inactivation of ILA in vitro [TRUNCATED]

Digitized by Kansas Correctional Industries

Digitized by Kansas Correctional Industries

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of requirements for the degree of Master of Science. Johannesburg, 2015. / Over the decades, cancer has become a global burden with alarmingly high incidence and mortality rates in both economically developed and developing countries. Characteristically, tumour cells exhibit an over-expression of the 37kDa/67kDa laminin receptor (LRP/LR) in comparison to their normal cell counterparts, with this receptor being implicated in several tumourigenic processes – importantly for the present study, the maintenance of cellular viability and the evasion of apoptosis. This present study aimed to elucidate the role of LRP/LR on the cellular viability of pancreatic cancer (AsPC-1) and neuroblastoma (IMR-32) cells. Flow cytometry revealed that both of these tumourigenic cell lines exhibited LRP/LR on their surface, with further analysis using median fluorescence intensity values showing that IMR-32 cells contain about 70% more cell-surface LRP/LR than AsPC-1 cells. Additionally, Western blotting and densitometry suggested that IMR-32 cells contained about 63% more total LRP/LR than AsPC-1 cells. Western blot analysis also revealed that targeting the mRNA of the 37kDa LRP using a LRP-specific siRNA (siRNA-LAMR1) in AsPC-1 and IMR-32 cells led to significant down-regulation of 90% and 71% in LRP expression, respectively. Consequently, MTT assays showed that LRP knockdown led to reductions of 82% and 65% in the viability of AsPC-1 and IMR-32 cells, respectively. Moreover, use of an alternative LRP-specific siRNA (esiRNA-RPSA) confirmed the specificity and excluded an off-target effect of siRNA-LAMR1 for LRP. BrdU assays revealed that knockdown of LRP reduced the proliferation of AsPC-1 and IMR-32 cells by 76% and 44%, respectively. Confocal microscopy indicated nuclear morphological changes suggestive of apoptosis as the form of cell death occuring in both cell lines after LRP down-regulation. This observation was confirmed using Annexin-V assays, which revealed that AsPC-1 cells underwent 44% more apoptosis than IMR-32 cells post LRP knockdown. Furthermore, caspase-3 activity assays revealed that both cell lines experienced apoptotic induction after siRNA-mediated down-regulation of LRP. Caspase-8 and -9 activity assays suggested that post LRP knockdown, IMR-32 cells undergo apoptosis solely via the extrinsic pathway, whilst AsPC-1 cells use both the intrinsic and extrinsic apoptotic pathways, possibly through a retaliatory feedback loop. Overall, LRP/LR is critical for the maintenance of the tumour cellular viability, making the receptor a promising therapeutic target and proposing the potential use of siRNA technology for treatment of pancreatic cancer and neuroblastoma.