Analysis Of The Relationship Between Economic Cycle Swings And Adoption Rate Models Of Financial Innovation Diffusion

The United States financial crisis, starting with the credit boom of 2007 and ending with the failure of Lehman Brothers in September 2008, has led to a loss of confidence in the United States financial system.  The Financial Crisis Inquiry Commission indicated that the financial crisis affected over 26 million Americans.  Many scholars have attributed the crisis to financial innovations, such as mortgage backed securities, adjustable rate mortgages and no-income verified loans, as key innovations that led to the market collapse.  Financial innovations have had both positive and negative impacts on the financial industry.  Providing a framework that describes the relationship between economic cycle swings and adoption rates of innovative financial instruments can provide greater stability and predictability in financial innovation diffusion, which can lead to more stable returns for shareholders and enhance the public interest through a healthy, innovative and more stable financial industry.  An abbreviated evidence-based systematic review was completed on financial innovations that led to the financial crisis of 2007. The research suggests that there is an equilibrium period of time that financial organizations can adopt innovation to avoid unintended consequences like the recent financial crisis.  Providing a framework of adoption time can demonstrate where financial innovations can be absorbed to provide the organization with the ability to financially innovate during pro and counter cyclical economic periods. Through an understanding of the timing of financial innovations as they occur in economic cycles, managers of financial organizations can choose the adoption period of time more carefully which could have averted the financial crisis that affected millions of Americans

Water and Wastewater Utility Affordability The Cape Coral Florida Experience

This study describes the trials and tribulations of a growing city involved in maintaining utility rates at an affordable level while completing a one billion dollar utility expansion. Emphasis is on the political and financial issues faced by management. This research deals exclusively with utility rate issues within the City of Cape Coral Florida during rapid growth and utility expansion. The analysis alludes to issues with affordability when the expansion is stopped, but bonds for a new water plant must be paid

Einfluss des Anbausystems auf Ertrag und Gesundheit von Winterweizen

In a long-term trial in central Switzerland, yield and health of winter wheat was examined under organic, extensive and intensive management. In the organic cropping system, soil was ploughed and fertilised with cattle dung. In the extensive system, soil was cultivated ploughless and dung was supplemented by mineral fertiliser. Herbicides were used, but no growth regulators or fungicides. In the intensive system, soil was ploughed and manure was based on cattle dung and mineral fertiliser with 20 % more nitrogen than in the extensive system. For plant protection, herbicides, growth regulators and fungicides were used. In the period from 2004 to 2007, average winter wheat yields of the intensive and the extensive crop management system exceeded those of the organic production by 21.3 % and 5.5 % respectively. This was probably due to the higher level of fertilisation and plant protection. In 2007, a year with frequent rain during the summer, the infestation of grains with Microdochium nivale and Fusarium graminearum was lowest in the organic wheat. In consequence, its germination capacity was higher and the deoxynivalenol content was lower compared with the other systems. The increased grain infestation with F. graminearum and the higher deoxynivalenol content of wheat grains in the extensive system can be explained by the ploughless tillage, with straw from the previous maize crop remaining on the soil surface

A conservative coupling algorithm between a compressible flow and a rigid body using an Embedded Boundary method

This paper deals with a new solid-fluid coupling algorithm between a rigid body and an unsteady compressible fluid flow, using an Embedded Boundary method. The coupling with a rigid body is a first step towards the coupling with a Discrete Element method. The flow is computed using a Finite Volume approach on a Cartesian grid. The expression of numerical fluxes does not affect the general coupling algorithm and we use a one-step high-order scheme proposed by Daru and Tenaud [Daru V,Tenaud C., J. Comput. Phys. 2004]. The Embedded Boundary method is used to integrate the presence of a solid boundary in the fluid. The coupling algorithm is totally explicit and ensures exact mass conservation and a balance of momentum and energy between the fluid and the solid. It is shown that the scheme preserves uniform movement of both fluid and solid and introduces no numerical boundary roughness. The effciency of the method is demonstrated on challenging one- and two-dimensional benchmarks

Wavelength-dependent effect of tetra(m-hydroxyphenyl)chlorin for photodynamic therapy in an ‘early' squamous cell carcinoma model

The purpose of the present study was to correlate the wavelength of the irradiation source with the phototoxic activity of tetra(m-hydroxyphenyl)chlorin (mTHPC) in healthy and neoplastic mucosae. The hamster tumour model for early squamous cell carcinoma was used in these experiments. In vitro and in vivo studies have shown that mTHPC absorbs significantly at 652 nm (1, 2). This wavelength is used currently in clinical mTHPC photodynamic therapy (PDT) trials. In order to study the wavelength dependence of the phototoxic effect on normal and tumour tissues, irradiation tests were performed 4 days after injection of 0.5mg kg-1 mTHPC. An argon-ion pumped dye laser was used as the light source. The light dose of 12 J cm-2 was delivered at a light dose rate of 150 mW cm-2. The wavelength was varied between 642.5 and 665 nm at 2.5-nm increments. The PDT damage was evaluated in serial Haematoxylin and Eosin stained sections using a tissue-damage scale. Light between 647.5 and 652.5 nm induced the highest damage to both the healthy and tumour mucosae. At wavelengths equal to or below 645 nm, and equal to or above 655 nm, tissue damage decreased. Wavelengths below 642 nm and above 660 nm did not induce any visible tissue damage. These results suggest that the in vivo optimal wavelength range for PDT with mTHPC is between 647 and 652 nm. This information is essential for selecting an appropriate light sourc

Thermostable designed ankyrin repeat proteins (DARPins) as building blocks for innovative drugs

Designed ankyrin repeat proteins (DARPins) are antibody mimetics with high and mostly unexplored potential in drug development. By using in silico analysis and a rationally guided Ala scanning, we identified position 17 of the N-terminal capping repeat to play a key role in overall protein thermostability. The melting temperature of a DARPin domain with a single full-consensus internal repeat was increased by 8 °C to 10 °C when Asp17 was replaced by Leu, Val, Ile, Met, Ala, or Thr. We then transferred the Asp17Leu mutation to various backgrounds, including clinically validated DARPin domains, such as the vascular endothelial growth factor-binding domain of the DARPin abicipar pegol. In all cases, these proteins showed improvements in the thermostability on the order of 8 °C to 16 °C, suggesting the replacement of Asp17 could be generically applicable to this drug class. Molecular dynamics simulations showed that the Asp17Leu mutation reduces electrostatic repulsion and improves van-der-Waals packing, rendering the DARPin domain less flexible and more stable. Interestingly, this beneficial Asp17Leu mutation is present in the N-terminal caps of three of the five DARPin domains of ensovibep, a SARS-CoV-2 entry inhibitor currently in clinical development, indicating this mutation could be partly responsible for the very high melting temperature (>90 °C) of this promising anti-COVID-19 drug. Overall, such N-terminal capping repeats with increased thermostability seem to be beneficial for the development of innovative drugs based on DARPins. Keywords: DARPin; N-terminal capping repeat; abicipar pegol; designed ankyrin repeat protein; drug development; drug engineering; ensovibep; molecular dynamics; thermostabilit

Targeted alpha-radionuclide therapy of functionally critically located gliomas with 213Bi-DOTA-[Thi8,Met(O2)11]-substance P: a pilot trial

Purpose: Functionally critically located gliomas represent a challenging subgroup of intrinsic brain neoplasms. Standard therapeutic recommendations often cannot be applied, because radical treatment and preservation of neurological function are contrary goals. The successful targeting of gliomas with locally injected beta radiation-emitting 90Y-DOTAGA-substance P has been shown previously. However, in critically located tumours, the mean tissue range of 5mm of 90Y may seriously damage adjacent brain areas. In contrast, the alpha radiation-emitting radionuclide 213Bi with a mean tissue range of 81µm may have a more favourable toxicity profile. Therefore, we evaluated locally injected 213Bi-DOTA-substance P in patients with critically located gliomas as the primary therapeutic modality. Methods: In a pilot study, we included five patients with critically located gliomas (WHO grades II-IV). After diagnosis by biopsy, 213Bi-DOTA-substance P was locally injected, followed by serial SPECT/CT and MR imaging and blood sampling. Besides feasibility and toxicity, the functional outcome was evaluated. Results: Targeted radiopeptide therapy using 213Bi-DOTA-substance P was feasible and tolerated without additional neurological deficit. No local or systemic toxicity was observed. 213Bi-DOTA-substance P showed high retention at the target site. MR imaging was suggestive of radiation-induced necrosis and demarcation of the tumours, which was validated by subsequent resection. Conclusion: This study provides proof of concept that targeted local radiotherapy using 213Bi-DOTA-substance P is feasible and may represent an innovative and effective treatment for critically located gliomas. Primarily non-operable gliomas may become resectable with this treatment, thereby possibly improving the prognosi

An in-vitro screening assay for the detection of inhibitors of proinflammatory cytokine synthesis: a useful tool for the development of new antiarthritic and disease modifying drugs

AbstractObjective This work targets the development of a new tool to help develop new anticytokine drugs that prevent or reduce the progression of arthritic diseases. The specific aim of our study was to establish a fast and reliable in vitro screening assay of cytokine synthesis inhibitors (TNFα, IL-1β) which shows better correlation with enzyme assays than previously reported in vitro assays. The test system should be able to detect p38-MAP kinase inhibitors.Material and methods Human peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll density gradient centrifugation from human EDTA-potassium whole blood. Cells were adjusted at 1×106 cells/ml. PBMCs were stimulated with lipopolysaccharide (LPS; E. coli serotype 026:B6: 1μg/ml) in the presence of test compound (10−5–10−8M) for 4h at 37°C in a 5% CO2-incubator. Induced TNFα and IL-1β protein were measured by ELISA.Results The following are representative examples of inhibitors which effect cytokine synthesis. Corticoid Dexamethasone inhibits IL-1β and TNFα synthesis at IC50 of 38nM and 25nM, respectively. ERK1/ERK2 inhibitor U0126 effects cytokine synthesis at IC50 of 0.34μM for IL-1β production and 0.26μM for TNFα synthesis.p38-MAP kinase inhibitor SB 203580 inhibits IL-1β- and TNF-α-synthesis (IC50sof 0.052μM and 0.46μM) in the same degree as p38-MAP kinase activity (IC50: 0.34μM). Same results could be shown for SB 210313, which had same efficacy on IL-1β and TNFα biosynthesis (IC50's: 1.88μM and 1.01μM) and on p38-MAP kinase (IC50: 6.85μM). Also for SB 202190 this correlation in inhibition of IL-1β and TNFα synthesis (IC50's: 0.055μM and 1.01μM) and p38-MAP kinase inhibition (IC50: 0.088μM) could be shown.Conclusion This study shows the screening assay using PBMCs stimulated with LPS for IL-1β and TNFα synthesis is a reliable test system for the quantification of the effectiveness of new drugs modulating IL-1β and TNFα synthesis which is mainly mediated by p38-MAP Kinase. These assay allows fast detection of IL-1β and TNFα synthesis inhibitors with different modes of action, including p38-MAP kinase inhibitors. The results obtained with our in-vitro screening assay show good correlation with results from enzyme assays. Copyright 2002 OsteoArthritis Research Society International. Published by Elsevier Science Ltd. All rights reserved

Lutetium-labelled peptides for therapy of neuroendocrine tumours

Treatment with radiolabelled somatostatin analogues is a promising new tool in the management of patients with inoperable or metastasized neuroendocrine tumours. Symptomatic improvement may occur with 177Lu-labelled somatostatin analogues that have been used for peptide receptor radionuclide therapy (PRRT). The results obtained with 177Lu-[DOTA0,Tyr3]octreotate (DOTATATE) are very encouraging in terms of tumour regression. Dosimetry studies with 177Lu-DOTATATE as well as the limited side effects with additional cycles of 177Lu-DOTATATE suggest that more cycles of 177Lu-DOTATATE can be safely given. Also, if kidney-protective agents are used, the side effects of this therapy are few and mild and less than those from the use of 90Y-[DOTA0,Tyr3]octreotide (DOTATOC). Besides objective tumour responses, the median progression-free survival is more than 40 months. The patients' self-assessed quality of life increases significantly after treatment with 177Lu-DOTATATE. Lastly, compared to historical controls, there is a benefit in overall survival of several years from the time of diagnosis in patients treated with 177Lu-DOTATATE. These findings compare favourably with the limited number of alternative therapeutic approaches. If more widespread use of PRRT can be guaranteed, such therapy may well become the therapy of first choice in patients with metastasized or inoperable neuroendocrine tumours

Wavelength-dependent effect of tetra(m-hydroxyphenyl) chlorin for photodynamic therapy in an "early" squamous cell carcinoma model

The purpose of the present study was to correlate the wavelength of the irradiation source with the phototoxic activity of tetra(m-hydroxyphenyl)chlorin (mTHPC) in healthy and neoplastic mucosae. The hamster tumour model for early squamous cell carcinoma was used in these experiments. In vitro and in vivo studies have shown that mTHPC absorbs significantly at 652 nm (1, 2). This wavelength is used currently in clinical mTHPC photodynamic therapy (PDT) trials. In order to study the wavelength dependence of the phototoxic effect on normal and tumour tissues, irradiation tests were performed 4 days after injection of 0.5mg kg-1 mTHPC. An argon-ion pumped dye laser was used as the light source. The light dose of 12 J cm-2 was delivered at a light dose rate of 150 mW cm-2. The wavelength was varied between 642.5 and 665 nm at 2.5-nm increments. The PDT damage was evaluated in serial Haematoxylin and Eosin stained sections using a tissue-damage scale. Light between 647.5 and 652.5 nm induced the highest damage to both the healthy and tumour mucosae. At wavelengths equal to or below 645 nm, and equal to or above 655 nm, tissue damage decreased. Wavelengths below 642 nm and above 660 nm did not induce any visible tissue damage. These results suggest that the in vivo optimal wavelength range for PDT with mTHPC is between 647 and 652 nm. This information is essential for selecting an appropriate light source