The Incubation of Environmental Disasters: Case Study of the Rana Plaza collapse, Bangladesh

On April 24th, 2013 Rana Plaza, an eight story garment factory in Bangladesh collapsed killing one thousand one hundred and twenty nine workers and injuring many more. To date, the collapse of Rana Plaza is the worst industrial accident to take place in Bangladesh's ready-made garment sector. Factory collapses and factory fires are not an uncommon occurrence within the country's growing industry; the last decade alone has seen a number of fatalities and injuries to garment workers. Man-made/technological disasters are the result of human error, negligence, or failure of a human-made system which causes damage to property and the environment as well as injuries and/or loss of life. Yet environmental disasters are caused by more than one factor. They are the result of many events and interactions over a period of time. Therefore, in order to fully understand what caused a disaster such as the collapse of Rana Plaza the broader context of the disaster requires examination. In recognizing the importance of the broader context of a disaster, this major research paper aims to investigate the causes of the collapse of Rana Plaza. Using a sociological lens and primary and secondary documents this paper examines the political, economic, social, and corporate contexts which created the conditions for the collapse. This paper highlights weaknesses in the political, economic, corporate, and social structures involved and in doing so will provide recommendations for changes to remedy discrepancies that allow disasters to occur within Bangladesh's ready-made garment industry. Ideally learning from this disaster will help in preventing similar disasters from occurring; something garment industry workers in Bangladesh need and deserve

Current methods for the synthesis of homogeneous antibody–drug conjugates

AbstractDevelopment of efficient and safe cancer therapy is one of the major challenges of the modern medicine. Over the last few years antibody–drug conjugates (ADCs) have become a powerful tool in cancer treatment with two of them, Adcetris® (brentuximab vedotin) and Kadcyla® (ado-trastuzumab emtansine), having recently been approved by the Food and Drug Administration (FDA). Essentially, an ADC is a bioconjugate that comprises a monoclonal antibody that specifically binds tumor surface antigen and a highly potent drug, which is attached to the antibody via either cleavable or stable linker. This approach ensures specificity and efficacy in fighting cancer cells, while healthy tissues remain largely unaffected.Conventional ADCs, that employ cysteine or lysine residues as conjugation sites, are highly heterogeneous. This means that the species contain various populations of the ADCs with different drug-to-antibody ratios (DARs) and different drug load distributions. DAR and drug-load distribution are essential parameters of ADCs as they determine their stability and efficacy. Therefore, various drug-loaded forms of ADCs (usually from zero to eight conjugated molecules per antibody) may have distinct pharmacokinetics (PK) in vivo and may differ in clinical performance. Recently, a significant progress has been made in the field of site-specific conjugation which resulted in a number of strategies for synthesis of the homogeneous ADCs. This review describes newly-developed methods that ensure homogeneity of the ADCs including use of engineered reactive cysteine residues (THIOMAB), unnatural amino acids, aldehyde tags, enzymatic transglutaminase- and glycotransferase-based approaches and novel chemical methods. Furthermore, we briefly discuss the limitation of these methods emphasizing the need for further improvement in the ADC design and development

Methods for Calculating Coronary Perfusion Pressure During CPR

Coronary perfusion pressure (CPP) is a major indicator of the effectiveness of cardiopulmonary resuscitation in human and animal research studies; however methods for calculating CPP differ among research groups. Here we compare the 6 published methods for calculating CPP using the same data set of aortic (Ao) and right atrial (RA) blood pressures. CPP was computed using each of the 6 calculation methods in an anesthetized pig model, instrumented with catheters with Cobe pressure transducers. Aortic and right atrial pressures were recorded continuously during electrically induced ventricular fibrillation and standard CPR. CPP calculated from the same raw data set by the 6 calculation methods ranged from -1 (signifying retrograde blood flow) to 26 mmHg (mean ± SD of 15 ± 11 mmHg). The CPP achieved by standard closed chest CPR is typically reported as 10–20 mmHg. Within a single study the CPP values may be comparable; however, the CPP values for different studies may not be reliable indicators of the relative efficacies of different CPR methods. Electronically derived, true mean coronary perfusion pressure is arguably the gold standard metric for representing coronary perfusion pressure

Specific antibody fragment ligand traps blocking FGF1 activity

Fibroblast growth factor 1 (FGF1) and its receptors (FGFRs) regulate crucial biological processes such as cell proliferation and differentiation. Aberrant activation of FGFRs by their ligands can promote tumor growth and angiogenesis in many tumor types, including lung or breast cancer. The development of FGF1-targeting molecules with potential implications for the therapy of FGF1-driven tumors is recently being considered a promising approach in the treatment of cancer. In this study we have used phage display selection to find scFv antibody fragments selectively binding FGF1 and preventing it from binding to its receptor. Three identified scFv clones were expressed and characterized with regard to their binding to FGF1 and ability to interfere with FGF1-induced signaling cascades activation. In the next step the scFvs were cloned to scFv-Fc format, as dimeric Fc fusions prove beneficial in prospective therapeutic application. As expected, scFvs-Fc exhibited significantly increased affinity towards FGF1. We observed strong antiproliferative activity of the scFvs and scFvs-Fc in the in vitro cell models. Presented antibody fragments serve as novel FGF1 inhibitors and can be further utilized as powerful tools to use in the studies on the selective cancer therapy

Fibroblast growth factor 2 conjugated with monomethyl auristatin E inhibits tumor growth in a mouse model

Worldwide, cancer is the second leading cause of death. Regardless of the continuous progress in medicine, we still do not have a fully effective anti-cancer therapy. Therefore, the search for new targeted anti-cancer drugs is still an unmet need. Here, we present novel protein–drug conjugates that inhibit tumor growth in a mouse model of human breast cancer. We developed conjugates based on fibroblast growth factor (FGF2) with improved biophysical and biological properties for the efficient killing of cancer cells overproducing fibroblast growth factor receptor 1 (FGFR1). We used hydrophilic and biocompatible PEG4 or PEG27 molecules as a spacer between FGF2 and the toxic agent monomethyl auristatin E. All conjugates exhibited a cytotoxic effect on FGFR1-positive cancer cell lines. The conjugate with the highest hydrodynamic size (42 kDa) and cytotoxicity was found to efficiently inhibit tumor growth in a mouse model of human breast cancer

Discovery of a Distinct Superfamily of Kunitz-Type Toxin (KTT) from Tarantulas

BACKGROUND: Kuntiz-type toxins (KTTs) have been found in the venom of animals such as snake, cone snail and sea anemone. The main ancestral function of Kunitz-type proteins was the inhibition of a diverse array of serine proteases, while toxic activities (such as ion-channel blocking) were developed under a variety of Darwinian selection pressures. How new functions were grafted onto an old protein scaffold and what effect Darwinian selection pressures had on KTT evolution remains a puzzle. PRINCIPAL FINDINGS: Here we report the presence of a new superfamily of ktts in spiders (TARANTULAS: Ornithoctonus huwena and Ornithoctonus hainana), which share low sequence similarity to known KTTs and is clustered in a distinct clade in the phylogenetic tree of KTT evolution. The representative molecule of spider KTTs, HWTX-XI, purified from the venom of O. huwena, is a bi-functional protein which is a very potent trypsin inhibitor (about 30-fold more strong than BPTI) as well as a weak Kv1.1 potassium channel blocker. Structural analysis of HWTX-XI in 3-D by NMR together with comparative function analysis of 18 expressed mutants of this toxin revealed two separate sites, corresponding to these two activities, located on the two ends of the cone-shape molecule of HWTX-XI. Comparison of non-synonymous/synonymous mutation ratios (omega) for each site in spider and snake KTTs, as well as PBTI like body Kunitz proteins revealed high Darwinian selection pressure on the binding sites for Kv channels and serine proteases in snake, while only on the proteases in spider and none detected in body proteins, suggesting different rates and patterns of evolution among them. The results also revealed a series of key events in the history of spider KTT evolution, including the formation of a novel KTT family (named sub-Kuntiz-type toxins) derived from the ancestral native KTTs with the loss of the second disulfide bridge accompanied by several dramatic sequence modifications. CONCLUSIONS/SIGNIFICANCE: These finding illustrate that the two activity sites of Kunitz-type toxins are functionally and evolutionally independent and provide new insights into effects of Darwinian selection pressures on KTT evolution, and mechanisms by which new functions can be grafted onto old protein scaffolds

SP-A binds alpha(1)-antitrypsin in vitro and reduces the association rate constant for neutrophil elastase

BACKGROUND: α1-antitrypsin and surfactant protein-A (SP-A) are major lung defense proteins. With the hypothesis that SP-A could bind α1-antitrypsin, we designed a series of in vitro experiments aimed at investigating the nature and consequences of such an interaction. METHODS AND RESULTS: At an α1-antitrypsin:SP-A molar ratio of 1:1, the interaction resulted in a calcium-dependent decrease of 84.6% in the association rate constant of α1-antitrypsin for neutrophil elastase. The findings were similar when SP-A was coupled with the Z variant of α1-antitrypsin. The carbohydrate recognition domain of SP-A appeared to be a major determinant of the interaction, by recognizing α1-antitrypsin carbohydrate chains. However, binding of SP-A carbohydrate chains to the α1-antitrypsin amino acid backbone and interaction between carbohydrates of both proteins are also possible. Gel filtration chromatography and turnover per inactivation experiments indicated that one part of SP-A binds several molar parts of α1-antitrypsin. CONCLUSION: We conclude that the binding of SP-A to α1-antitrypsin results in a decrease of the inhibition of neutrophil elastase. This interaction could have potential implications in the physiologic regulation of α1-antitrypsin activity, in the pathogenesis of pulmonary emphysema, and in the defense against infectious agents