Capital Structure of Innovative Companies in BRICS Countries

This article aims to identify the main business and economic determinants of capital structure in a sample of innovative companies from BRICS countries. We achieve this by presenting a comparative analysis of 1,437 high-tech and 1,485 non-innovative companies in the pharmaceuticals, electronics, IT, and telecommunications sectors between 2008 and 2015. We conduct a regression analysis using a significant number of variables, such as profitability, size, proportion of tangible assets, and growth potential. The highlighted parameters are then examined in order to identify the characteristic features displayed in the capital structure of innovative firms. Our results indicate that the following company characteristics are relevant in determining capital structure: information asymmetry costs (those which are associated with the unique activities of innovative companies), high growth potential generated by the availability of network effects, a high innovative applicability, low marginal and transport costs, and a high proportion of intangible assets. Moreover, we found that there is a distinct difference in the capital structure of companies as they vary in levels of innovation. An innovative company\u2019s proportion of intangible assets has a multidirectional effect on the debt amount. The potential for growth is also a significant factor which has a predominantly negative effect on the level of an innovative company\u2019s financial leverage. Levels of borrowing are overall lower for innovative firms. Our major conclusion, drawing from the results above, is that innovative companies in BRICS countries use relatively little debt in the case of high growth potential. This indicates a general need to overcome the information asymmetry challenge in order to increase the growth rates of individual companies. The scientific novelty of this analysis relates most strongly to the broadness of scope of our investigation, the focus on BRICS countries specifically, and the applicability of its conclusions in wider business and economic contexts. The breadth of data from a wide range of companies and sectors (both innovative and non-innovative), and the high number of companies utilized in the study, lend our evaluation an undeniable credibility within its scope, especially where it upholds similar conclusions in related literature of narrower focus. As a corollary to this, it may be conceivably asserted that these results are not merely applicable to individual companies, or even sectors of the economy, but due to their wide field of origin, they can have economy-wide implications on business and financial strategies

Air and water pollution over time and industries with stochastic dominance

We employ a stochastic dominance (SD) approach to analyze the components that contribute to environmental degradation over time. The variables include countries\u2019 greenhouse gas (GHG) emissions and water pollution. Our approach is based on pair-wise SD tests. First, we study the dynamic progress of each separate variable over time, from 1990 to 2005, within 5-year horizons. Then, pair-wise SD tests are used to study the major industry contributors to the overall GHG emissions and water pollution at any given time, to uncover the industry which contributes the most to total emissions and water pollution. While CO2 emissions increased in the first order SD sense over 15 years, water pollution increased in a second-order SD sense. Electricity and heat production were the major contributors to the CO2 emissions, while the food industry gradually became the major water polluting industry over time. SD sense over 15 years, water pollution increased in a second-order SD sense. Electricity and heat production were the major contributors to the CO2 emissions, while the food industry gradually

Tunable control of CAR T cell activity through tetracycline mediated disruption of protein-protein interaction

Chimeric antigen receptor (CAR) T cells are a promising form of cancer immunotherapy, although they are often associated with severe toxicities. Here, we present a split-CAR design incorporating separate antigen recognition and intracellular signaling domains. These exploit the binding between the tetracycline repressor protein and a small peptide sequence (TIP) to spontaneously assemble as a functional CAR. Addition of the FDA-approved, small molecule antibiotic minocycline, acts as an "off-switch" by displacing the signaling domain and down-tuning CAR T activity. Here we describe the optimization of this split-CAR approach to generate a CAR in which cytotoxicity, cytokine secretion and proliferation can be inhibited in a dose-dependent and reversible manner. Inhibition is effective during on-going CAR T cell activation and inhibits activation and tumor control in vivo. This work shows how optimization of split-CAR structure affects function and adds a novel design allowing easy CAR inhibition through an FDA-approved small molecule

Noninvasive diffusion magnetic resonance imaging of brain tumour cell size for the early detection of therapeutic response

Cancer cells differ in size from those of their host tissue and are known to change in size during the processes of cell death. A noninvasive method for monitoring cell size would be highly advantageous as a potential biomarker of malignancy and early therapeutic response. This need is particularly acute in brain tumours where biopsy is a highly invasive procedure. Here, diffusion MRI data were acquired in a GL261 glioma mouse model before and during treatment with Temozolomide. The biophysical model VERDICT (Vascular Extracellular and Restricted Diffusion for Cytometry in Tumours) was applied to the MRI data to quantify multi-compartmental parameters connected to the underlying tissue microstructure, which could potentially be useful clinical biomarkers. These parameters were compared to ADC and kurtosis diffusion models, and, measures from histology and optical projection tomography. MRI data was also acquired in patients to assess the feasibility of applying VERDICT in a range of different glioma subtypes. In the GL261 gliomas, cellular changes were detected according to the VERDICT model in advance of gross tumour volume changes as well as ADC and kurtosis models. VERDICT parameters in glioblastoma patients were most consistent with the GL261 mouse model, whilst displaying additional regions of localised tissue heterogeneity. The present VERDICT model was less appropriate for modelling more diffuse astrocytomas and oligodendrogliomas, but could be tuned to improve the representation of these tumour types. Biophysical modelling of the diffusion MRI signal permits monitoring of brain tumours without invasive intervention. VERDICT responds to microstructural changes induced by chemotherapy, is feasible within clinical scan times and could provide useful biomarkers of treatment response

AKT inhibition generates potent polyfunctional clinical grade AUTO1 CAR T-cells, enhancing function and survival

BACKGROUND: AUTO1 is a fast off-rate CD19-targeting chimeric antigen receptor (CAR), which has been successfully tested in adult lymphoblastic leukemia. Tscm/Tcm-enriched CAR-T populations confer the best expansion and persistence, but Tscm/Tcm numbers are poor in heavily pretreated adult patients. To improve this, we evaluate the use of AKT inhibitor (VIII) with the aim of uncoupling T-cell expansion from differentiation, to enrich Tscm/Tcm subsets. METHODS: VIII was incorporated into the AUTO1 manufacturing process based on the semiautomated the CliniMACS Prodigy platform at both small and cGMP scale. RESULTS: AUTO1 manufactured with VIII showed Tscm/Tcm enrichment, improved expansion and cytotoxicity in vitro and superior antitumor activity in vivo. Further, VIII induced AUTO1 Th1/Th17 skewing, increased polyfunctionality, and conferred a unique metabolic profile and a novel signature for autophagy to support enhanced expansion and cytotoxicity. We show that VIII-cultured AUTO1 products from B-ALL patients on the ALLCAR19 study possess superior phenotype, metabolism, and function than parallel control products and that VIII-based manufacture is scalable to cGMP. CONCLUSION: Ultimately, AUTO1 generated with VIII may begin to overcome the product specific factors contributing to CD19+relapse

Intratumoral IL-12 delivery empowers CAR-T cell immunotherapy in a pre-clinical model of glioblastoma

Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer, for which effective therapies are urgently needed. Chimeric antigen receptor (CAR)-based immunotherapy represents a promising therapeutic approach, but it is often impeded by highly immunosuppressive tumor microenvironments (TME). Here, in an immunocompetent, orthotopic GBM mouse model, we show that CAR-T cells targeting tumor-specific epidermal growth factor receptor variant III (EGFRvIII) alone fail to control fully established tumors but, when combined with a single, locally delivered dose of IL-12, achieve durable anti-tumor responses. IL-12 not only boosts cytotoxicity of CAR-T cells, but also reshapes the TME, driving increased infiltration of proinflammatory CD4+ T cells, decreased numbers of regulatory T cells (Treg), and activation of the myeloid compartment. Importantly, the immunotherapy-enabling benefits of IL-12 are achieved with minimal systemic effects. Our findings thus show that local delivery of IL-12 may be an effective adjuvant for CAR-T cell therapy for GBM

Clinical outcomes of fully and partially threaded zygomatic implants in a cohort of patients with minimum 7.5-year follow-up

OBJECTIVE: The aim of this retrospective case series report was to evaluate the results of oral rehabilitation with extra-sinus zygomatic implant surgery with a minimum follow-up of 7.5 years. PATIENTS AND METHODS: A total of 35 patients with 87 zygomatic implants were included. The mean follow-up period of the patients was 93 months. The zygomatic implant survival and complications were evaluated as criteria for success. RESULTS: There were no implant failures. Overall success rate without complications for zygomatic implant was 88.5%. Complications developed in 4 patients (1 cutaneous fistula and 3 mucositis). According to the results on an implant basis, patients with previously failed conventional implants had greater probability of complications. Patients with quad zygomatic implants had higher incidence of complications than those with two zygomatic implants. Fully threaded implant design was associated with higher incidence of mucositis than partially threaded design. No relation was found between implant success and smoking, prosthesis type, and antagonist dentition. When conducting the analysis using the patient as unit, only the antagonist dentition showed significant difference, the worst outcome being associated with the Toronto resin prosthesis. CONCLUSIONS: Zygomatic implants can be considered as a safe alternative to conventional implant insertions and bone grafting procedures in oral rehabilitation of patients with severely atrophic maxillary bone