Factors influencing superior returns achieved through mergers & acquisitions of corporate spin-outs in the life sciences

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2009.Cataloged from PDF version of thesis.Includes bibliographical references (p. 68-69).Corporate spin-outs have become more frequent in the contemporary business environment as an alternate source of risk diversification and value creation for both the parent and external investors. Once established, corporate spin-outs are often perceived to be of higher quality than their counterparts in the industry; previous studies have shown that they tend to receive higher valuations in financing, faster financing and higher preference by prestigious Wall Street investment banks when they decide to go public. The primary objective of this thesis was to compare the net proceeds associated with successful liquidity events (IPO or M&A) for US based therapeutic-focused corporate spin-outs to industry averages and test the hypothesis that corporate spin-outs generate superior returns. A database containing information on 186 corporate spin-outs within the life sciences (founded from 1990 - present) was generated for the purpose of testing this hypothesis. Net proceeds from corporate spin-out liquidity events were compared to median net proceeds of all biotech/pharmaceutical liquidity events for a given vintage year and type of liquidity event (IPO vs. M&A). Liquidity events were observed with a(cont.) higher frequency than overall industry averages. Results indicated that net IPO proceeds were similar to industry averages, while M&A proceeds were above the median vintage year value for every case observed. When normalizing by the most advanced clinical stage program, a similar trend was observed in three of the five cases. In addition, internal rate of return (IRR) and cash on cash exit multiple for Series A investors was substantially higher in corporate spin-outs than industry averages. In order to understand why acquisitions of corporate spin-outs appeared to generate sizable excess returns relative to industry averages, qualitative interviews were conducted with former executives involved in these transactions. Key insights from these interviews indicate that a seasoned management team, prestige of parent company, high quality syndicate of investors, clinically proven technology and a clear regulatory path to approval are all elements that help drive excess valuations of corporate spin-outs in the life sciences. We conclude that corporate spin-outs do generate superior returns through M&A exits compared to venture-backed start ups, while proceeds from IPO's were similar to case controls.by Michael Robert Magnani.S.M

Human Calmodulin Methyltransferase: Expression, Activity on Calmodulin, and Hsp90 Dependence

Deletion of the first exon of calmodulin-lysine N-methyltransferase (CaM KMT, previously C2orf34) has been reported in two multigene deletion syndromes, but additional studies on the gene have not been reported. Here we show that in the cells from 2p21 deletion patients the loss of CaM KMT expression results in accumulation of hypomethylated calmodulin compared to normal controls, suggesting that CaM KMT is essential for calmodulin methylation and there are no compensatory mechanisms for CaM methylation in humans. We have further studied the expression of this gene at the transcript and protein levels. We have identified 2 additional transcripts in cells of the 2p21 deletion syndrome patients that start from alternative exons positioned outside the deletion region. One of them starts in the 2nd known exon, the other in a novel exon. The transcript starting from the novel exon was also identified in a variety of tissues from normal individuals. These new transcripts are not expected to produce proteins. Immunofluorescent localization of tagged CaM KMT in HeLa cells indicates that it is present in both the cytoplasm and nucleus of cells whereas the short isoform is localized to the Golgi apparatus. Using Western blot analysis we show that the CaM KMT protein is broadly expressed in mouse tissues. Finally we demonstrate that the CaM KMT interacts with the middle portion of the Hsp90 molecular chaperon and is probably a client protein since it is degraded upon treatment of cells with the Hsp90 inhibitor geldanamycin. These findings suggest that the CaM KMT is the major, possibly the single, methyltransferase of calmodulin in human cells with a wide tissue distribution and is a novel Hsp90 client protein. Thus our data provides basic information for a gene potentially contributing to the patient phenotype of two contiguous gene deletion syndromes

Rubisco in complex with Rubisco large subunit methyltransferase.

SET domain protein lysine methyltransferases (PKMT) are a structurally unique class of enzymes that catalyze the specific methylation of lysine residues in a number of different substrates. Especially histone-specific SET domain PKMTs have received widespread attention because of their roles in the regulation of epigenetic gene expression and the development of some cancers. Rubisco large subunit methyltransferase (RLSMT) is a chloroplast-localized SET domain PKMT responsible for the formation of trimethyl-lysine-14 in the large subunit of Rubisco, an essential photosynthetic enzyme. Here, we have used cryoelectron microscopy to produce an 11-A density map of the Rubisco-RLSMT complex. The atomic model of the complex, obtained by fitting crystal structures of Rubisco and RLSMT into the density map, shows that the extensive contact regions between the 2 proteins are mainly mediated by hydrophobic residues and leucine-rich repeats. It further provides insights into potential conformational changes that may occur during substrate binding and catalysis. This study presents the first structural analysis of a SET domain PKMT in complex with its intact polypeptide substrate

Calmodulin-Mediated Signal Transduction Pathways in \u3ci\u3eArabidopsis\u3c/i\u3e Are Fine-Tuned by Methylation

Calmodulin N-methyltransferase (CaM KMT) is an evolutionarily conserved enzyme in eukaryotes that transfers three methyl groups to a highly conserved lysyl residue at position 115 in calmodulin (CaM). We sought to elucidate whether the methylation status of CaM plays a role in CaM-mediated signaling pathways by gene expression analyses of CaM KMT and phenotypic characterization of Arabidopsis thaliana lines wherein CaM KMT was overexpressed (OX), partially silenced, or knocked out. CaM KMT was expressed in discreet spatial and tissue-specific patterns, most notably in root tips, floral buds, stamens, apical meristems, and germinating seeds. Analysis of transgenic plants with genetic dysfunction in CaM KMT revealed a link between the methylation status of CaM and root length. Plants with suppressed CaM methylation had longer roots and CaM KMT OX lines had shorter roots than wild type (Columbia-0). CaM KMT was also found to influence the root radial developmental program. Protein microarray analyses revealed a number of proteins with specificity for methylated forms of CaM, providing candidate functional intermediates between the observed phenotypes and the target pathways. This work demonstrates that the functionality of the large CaM family in plants is fine-tuned by an overarching methylation mechanism

Observation of erythrocyte dynamics in the retinal capillaries and choriocapillaris using ICG-loaded erythrocyte ghost cells.

Purpose To find evidence of retinal vasomotion and to examine the relationship between erythrocyte dynamics and previously observed high-frequency pulsatile blood flow through the choriocapillaris. Methods An osmotic shock technique was used to encapsulate indocyanine green (ICG) dye in erythrocyte ghost cells at a concentration that produced maximum cell fluorescence. By obviating the plasma staining that results from aqueous ICG's high affinity for plasma proteins, high contrast was maintained between reinjected ICG-loaded erythrocytes and their plasma background. High-speed, high-magnification ICG angiograms showing individual cell movement were recorded from the intact eyes of four monkeys and three rabbits for periods up to 30 seconds. Results In monkey retinal perifoveal capillaries, numerous erythrocytes were seen to pause for as long as 20 seconds and then resume transit. Similar pausing behavior was observed in the subfoveal choriocapillaris. Individual erythrocytes also were seen to pause in the rabbits' choriocapillaries below the medullary rays, where visualization of the cells was uninhibited by overlying retinal vasculature or dense pigment. Conclusions Reinjected ICG-loaded erythrocytes permit routine visualization of retinal capillary and choriocapillaris hemodynamics of the intact eye. It is speculated that erythrocyte-pausing in both microcirculations facilitates metabolic exchange across capillary walls. In retinal capillaries, pausing is presumed to result from vasomotion-which has been postulated as necessary for the inhibition of retinal edema-and in choriocapillaries, to result from the shifting distributions of local perfusion pressures within the network of capillary vessel segments that comprise each lobular area of the choriocapillaris vascular plexus

Financial Constraints and Small and Medium Enterprises: A review

We review the literature on financial constraints and the performance of small and medium enterprises (SMEs). We consider the important role that SMEs play in the economies of Australia and the Organisation for Economic Cooperation and Development. We examine the role of financial constraints in SME growth, with emphasis on business cycles and credit access. We discuss issues that SMEs face in accessing financial resources for expansion. We look at the literature that evaluates the impact of financial constraints on key outcomes: employment, productivity and wages. We review key policy debates and consider where government involvement might be appropriate

The impact of life skills education on adolescent sexual risk behaviors

In response to the escalating HIV/AIDS epidemic, in 1998 the South African Ministry of Education mandated implementation of a comprehensive life skills education program in all secondary schools by 2005. The Life Skills Program aims to increase knowledge and develop skills to help youth protect themselves from HIV infection and to safeguard their reproductive health. Although it is too early to assess the long-term impact of this initiative, the phased implementation of life skills education provides an opportunity to assess short-term impact. To measure the effects of exposure to topics within the life skills curriculum on sexual and reproductive health knowledge and behaviors among youth, the University of Natal-Durban School of Development Studies, Horizons, The Population Council’s Policy Research Division, and Tulane University undertook a prospective study in KwaZulu Natal Province, South Africa, from 1999 to 2001. This brief considers the impact of the life skills program on a population-based sample of youth in two districts in the province

The impact of life skills education on adolescent sexual risk behaviors [Arabic]

In response to the escalating HIV/AIDS epidemic, in 1998 the South African Ministry of Education mandated implementation of a comprehensive life skills education program in all secondary schools by 2005. The Life Skills Program aims to increase knowledge and develop skills to help youth protect themselves from HIV infection and to safeguard their reproductive health. Although it is too early to assess the long-term impact of this initiative, the phased implementation of life skills education provides an opportunity to assess short-term impact. To measure the effects of exposure to topics within the life skills curriculum on sexual and reproductive health knowledge and behaviors among youth, the University of Natal-Durban School of Development Studies, Horizons, The Population Council’s Policy Research Division, and Tulane University undertook a prospective study in KwaZulu Natal Province, South Africa, from 1999 to 2001. This brief considers the impact of the life skills program on a population-based sample of youth in two districts in the province

Efficacy and safety of novel oral anticoagulants in patients with atrial fibrillation and heart failure: A meta-analysis

Objectives This study investigated the efficacy and safety of novel oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) and heart failure (HF) by a meta-analysis. Background AF is quite prevalent in patients with HF. Methods Four phase III clinical trials comparing NOACs to warfarin in patients with AF were included. Each patient was defined as affected by HF according to the criteria of the trial in which the patient was enrolled. Pre-specified outcomes were the composite of stroke/systemic embolism (SSE); major, intracranial, and any bleeding; and cardiovascular (CV) and all-cause death. Results A total of 55,011 patients were enrolled, 26,384 (48%) with HF, and 28,627 (52%) without HF; 27,518 receiving NOACs and 27,493 receiving warfarin (median, 70 years of age; 36% females; follow-up: 1.5 to 2.8 years). Rates of SSE (relative risk [RR]: 0.98; 95% confidence interval [CI]: 0.90 to 1.07]; p = 0.68) and major bleeding (RR: 0.95; 95% CI: 0.88 to 1.03; p = 0.21) were comparable in patients with and without HF. HF patients had reduced rates of any (RR: 0.86; 95% CI: 0.81 to 0.91; p 0.05 for each). Conclusions Patients with AF and HF had increased mortality but reduced rates of intracranial and any bleeding compared with the no-HF patients, with no differences in rates of SSE and major bleeding. NOACs significantly reduced SSE, major bleeding, and intracranial hemorrhage in HF patients. No interactions in efficacy and safety of NOACs were observed between AF patients with and without HF

Clipping and Gibberellin Treatments Promote Germination in Dormant Grape Seeds

‘Crimson Cabernet’ grape (Vitis vinifera) seeds showed physiological dormancy and germinated at ∼60% after 60 days of chilling stratification. Fresh seeds harvested after physiological maturity and sown without drying failed to germinate after 30 days when sown on agar. In agar-sown fresh seeds cut at the distal seed end or intact seeds treated with gibberellic acid (GA), the seeds germinated at ∼20% after 30 days. The highest germination percentages after 30 days were 63% to 83% in fresh, agar-sown seeds that were cut and treated with GA at 5000 mg⋅L–1 regardless of stratification time. Similar results were seen in seeds allowed to dry before sowing. Seeds cut and treated with GA at 5000 mg⋅L–1 germinated at 79% after 30 days. However, dry seeds sown on germination paper showed lower germination after cutting and GA treatment compared with agar-sown seeds. The highest germination percentages after 30 days in dry, cut seeds on germination paper treated with GA at 2000 and 5000 mg⋅L–1 were 33% and 55%, respectively, compared with agar-sown seeds, which germinated at 76% and 79%, with the same treatments. Results from this study provide a system that reduces the need for chilling stratification for grape seed germination by using partial seedcoat removal and GA treatment