Managing authenticity and performance in Gulag tourism, Kazakhstan

To date, there has been limited research concerning the methodology and approach to Gulag heritage and how it has been memorialised and commodified for tourism purposes. The recent cultural commodification of the Soviet past and the development of participatory visitor experiences at Gulag museums in Kazakhstan necessitate to advance understandings of the roles authenticity and performance play in the management of Gulag museum practices in the country. Using a qualitative case study research approach based on a combination of semi-structured interviews with stakeholders involved in the development of Gulag tourism including senior management of museums, museum guides, policy-makers, tourism operators, local NGOs and experts in Soviet Gulag heritage, direct observations and qualitative document analysis of two Gulag museums and sites in Kazakhstan, the commodification and management of Soviet Gulag heritage is explored. Results reveal that beyond objects on display and images regarded as interpretive illustrations that allow visitors to connect with the past and verify history, dioramas and staged performances re-enacting various elements of the Gulag life are used as immersive and emotional tools to accentuate the ‘dark’ atmosphere of the epoch and induce a more impactful and participatory visitor experience. The findings contribute to literature on authenticity and performance in Gulag tourism by examining the delicate question of the extent to which stakeholders involved in the management of the Gulag tragedy can offer meaningful visitor experiences that are historically accurate and protect the dignity of the victims while adapting to the dynamic roles of museums as heritage and education sites

A single dose of antibody-drug conjugate cures a stage 1 model of African trypanosomiasis.

Infections of humans and livestock with African trypanosomes are treated with drugs introduced decades ago that are not always fully effective and often have severe side effects. Here, the trypanosome haptoglobin-haemoglobin receptor (HpHbR) has been exploited as a route of uptake for an antibody-drug conjugate (ADC) that is completely effective against Trypanosoma brucei in the standard mouse model of infection. Recombinant human anti-HpHbR monoclonal antibodies were isolated and shown to be internalised in a receptor-dependent manner. Antibodies were conjugated to a pyrrolobenzodiazepine (PBD) toxin and killed T. brucei in vitro at picomolar concentrations. A single therapeutic dose (0.25 mg/kg) of a HpHbR antibody-PBD conjugate completely cured a T. brucei mouse infection within 2 days with no re-emergence of infection over a subsequent time course of 77 days. These experiments provide a demonstration of how ADCs can be exploited to treat protozoal diseases that desperately require new therapeutics

Oppilaitten eettinen toimijuus videotutkimuksessa

The rapid development of various recording technologies in recent years has created appealing opportunities for researchers to document and study science, technology, engineering, and mathematics (STEM) learning in ways which previously were either impossible, high-priced, or impractical. The potential access that low-cost and ever-smaller recorders provide us has been wisely tempered with cautions that researchers critically reflect on whether the benefits of the research outweigh the invasion of participants’ privacy, especially in research with children. These cautions rightfully place the burden of ethical deliberation on the researcher. However, by so doing they also direct attention away from the ethical work done by study participants and overshadow their agency in relation to the research. In effect, the cautions join and reinforce dominant narratives of participant, especially children’s, vulnerability in research and the researcher as the main ethical actor during the research process. This study seeks to balance such narratives by drawing attention to how children demonstrate their awareness of the audience of nearby recorders to each other and, through such actions, also create spaces for private, out-of-view interaction they do not wish to be recorded. With demonstrative vignettes from a yearlong ethnographic study of children’s learning in an alternative STEM learning infrastructure, the study argues that such moments highlight children’s ethical agency in research.The rapid development of various recording technologies in recent years has created appealing opportunities for researchers to document and study science, technology, engineering, and mathematics (STEM) learning in ways which previously were either impossible, high-priced, or impractical. The potential access that low-cost and ever-smaller recorders provide us has been wisely tempered with cautions that researchers critically reflect on whether the benefits of the research outweigh the invasion of participants’ privacy, especially in research with children. These cautions rightfully place the burden of ethical deliberation on the researcher. However, by so doing they also direct attention away from the ethical work done by study participants and overshadow their agency in relation to the research. In effect, the cautions join and reinforce dominant narratives of participants’, especially children’s, vulnerability in research and the researcher as the main ethical actor during the research process. This study seeks to balance such narratives by drawing attention to how children demonstrate their awareness of the audience of nearby recorders to each other and, through such actions, also create spaces for private, out-of-view interaction they do not wish to be recorded. With demonstrative vignettes from a yearlong ethnographic study of children’s learning in an alternative STEM learning infrastructure, the study argues that such moments highlight children’s ethical agency in research.Peer reviewe

Potential human transmission of amyloid β pathology: surveillance and risks

Studies in experimental animals show transmissibility of amyloidogenic proteins associated with prion diseases, Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases. Although these data raise potential concerns for public health, convincing evidence for human iatrogenic transmission only exists for prions and amyloid β after systemic injections of contaminated growth hormone extracts or dura mater grafts derived from cadavers. Even though these procedures are now obsolete, some reports raise the possibility of iatrogenic transmission of amyloid β through putatively contaminated neurosurgical equipment. Iatrogenic transmission of amyloid β might lead to amyloid deposition in the brain parenchyma and blood vessel walls, potentially resulting in cerebral amyloid angiopathy after several decades. Cerebral amyloid angiopathy can cause life-threatening brain haemorrhages; yet, there is no proof that the transmission of amyloid β can also lead to Alzheimer's dementia. Large, long-term epidemiological studies and sensitive, cost-efficient tools to detect amyloid are needed to better understand any potential routes of amyloid β transmission and to clarify whether other similar proteopathic seeds, such as tau or α-synuclein, can also be transferred iatrogenically

Intravenous apoptotic spleen cell infusion induces a TGF-beta-dependent regulatory T-cell expansion.: Apoptosis and regulatory T cells

International audienceApoptotic leukocytes are endowed with immunomodulatory properties that can be used to enhance hematopoietic engraftment and prevent graft-versus-host disease (GvHD). This apoptotic cell-induced tolerogenic effect is mediated by host macrophages and not recipient dendritic cells or donor phagocytes present in the bone marrow graft as evidenced by selective cell depletion and trafficking experiments. Furthermore, apoptotic cell infusion is associated with TGF-beta-dependent donor CD4+CD25+ T-cell expansion. Such cells have a regulatory phenotype (CD62L(high) and intracellular CTLA-4+), express high levels of forkhead-box transcription factor p3 (Foxp3) mRNA and exert ex vivo suppressive activity through a cell-to-cell contact mechanism. In vivo CD25 depletion after apoptotic cell infusion prevents the apoptotic cell-induced beneficial effects on engraftment and GvHD occurrence. This highlights the role of regulatory T cells in the tolerogenic effect of apoptotic cell infusion. This novel association between apoptosis and regulatory T-cell expansion may also contribute to preventing deleterious autoimmune responses during normal turnover

Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload tesirine

Synthetic pyrrolobenzodiazepine (PBD) dimers, where two PBD monomers are linked through their aromatic A-ring phenolic C8-positions via a flexible propyldioxy tether, are highly efficient DNA minor groove cross-linking agents with potent cytotoxicity. PBD dimer SG3199 is the released warhead component of the antibody-drug conjugate (ADC) payload tesirine (SG3249), currently being evaluated in several ADC clinical trials. SG3199 was potently cytotoxic against a panel of human solid tumour and haematological cancer cell lines with a mean GI50 of 151.5 pM. Cells defective in DNA repair protein ERCC1 or homologous recombination repair showed increased sensitivity to SG3199 and the drug was only moderately susceptible to multidrug resistance mechanisms. SG3199 was highly efficient at producing DNA interstrand cross-links in naked linear plasmid DNA and dose-dependent cross-linking was observed in cells. Cross-links formed rapidly in cells and persisted over 36 hours. Following intravenous (iv) administration to rats SG3199 showed a very rapid clearance with a half life as short as 8 minutes. These combined properties of cytotoxic potency, rapid formation and persistence of DNA interstrand cross-links and very short half-life contribute to the emerging success of SG3199 as a warhead in clinical stage ADCs

Comparison of the Hemostatic Efficacy of Pathogen-Reduced Platelets vs Untreated Platelets in Patients With Thrombocytopenia and Malignant Hematologic Diseases: A Randomized Clinical Trial

Importance: Pathogen reduction of platelet concentrates may reduce transfusion-transmitted infections but is associated with qualitative impairment, which could have clinical significance with regard to platelet hemostatic capacity. Objective: To compare the effectiveness of platelets in additive solution treated with amotosalen-UV-A vs untreated platelets in plasma or in additive solution in patients with thrombocytopenia and hematologic malignancies. Design, Setting, and Participants: The Evaluation of the Efficacy of Platelets Treated With Pathogen Reduction Process (EFFIPAP) study was a randomized, noninferiority, 3-arm clinical trial performed from May 16, 2013, through January 21, 2016, at 13 French tertiary university hospitals. Clinical signs of bleeding were assessed daily until the end of aplasia, transfer to another department, need for a specific platelet product, or 30 days after enrollment. Consecutive adult patients with bone marrow aplasia, expected hospital stay of more than 10 days, and expected need of platelet transfusions were included. Interventions: At least 1 transfusion of platelets in additive solution with amotosalen-UV-A treatment, in plasma, or in additive solution. Main Outcomes and Measures: The proportion of patients with grade 2 or higher bleeding as defined by World Health Organization criteria. Results: Among 790 evaluable patients (mean [SD] age, 55 [13.4] years; 458 men [58.0%]), the primary end point was observed in 126 receiving pathogen-reduced platelets in additive solution (47.9%; 95% CI, 41.9%-54.0%), 114 receiving platelets in plasma (43.5%; 95% CI, 37.5%-49.5%), and 120 receiving platelets in additive solution (45.3%; 95% CI, 39.3%-51.3%). With a per-protocol population with a prespecified margin of 12.5%, noninferiority was not achieved when pathogen-reduced platelets in additive solution were compared with platelets in plasma (4.4%; 95% CI, -4.1% to 12.9%) but was achieved when the pathogen-reduced platelets were compared with platelets in additive solution (2.6%; 95% CI, -5.9% to 11.1%). The proportion of patients with grade 3 or 4 bleeding was not different among treatment arms. Conclusions and Relevance: Although the hemostatic efficacy of pathogen-reduced platelets in thrombopenic patients with hematologic malignancies was noninferior to platelets in additive solution, such noninferiority was not achieved when comparing pathogen-reduced platelets with platelets in plasma. Trial Registration: clinicaltrials.gov Identifier: NCT01789762

Industrial associations as ideational platforms : why Japan resisted American-style shareholder capitalism

Significant wage and treatment differentials between regular workers in long-term employment and precarious non-regular workers have been a major political issue in Japan since the mid-1990s. I argue this phenomenon was caused by Japanese society’s resistance to American neoliberal hegemony. Why has Japan resisted it, and how has the resistance resulted in the rapid increase in the working poor? I contend anti-liberal, anti-free market norms of Japanese society centred on ‘systemic support’ have bolstered resistance to convergence in order to prevent capitalist dominance from severing long-term social ties, such as management-labour cooperation. My broadened definition of systemic support incorporates dominant elites’ support and protection of subordinates in exchange for their loyalty and obedience. This paper will explore reasons for the resistance to convergence by examining an ideational conflict within Japanese elites between the market liberalisation and anti-free market camps, particularly between two major industrial associations, Keidanren and Keizai Doyukai, which have played a key role as ‘ideational platforms’ for Japanese corporate society. Under the Hashimoto (1996-8) and Koizumi (2001-6) administrations, the market liberalisation camp gained influence, but since 2006, both the anti-free market camp and its subordinates (e.g. regular workers) have driven anti-neoliberal backlash

ADCT-402, a PBD dimer-containing antibody drug conjugate targeting CD19-expressing malignancies

Human CD19 antigen is a 95-kDa type I membrane glycoprotein in the immunoglobulin superfamily whose expression is limited to the various stages of B-cell development and differentiation and is maintained in the majority of B-cell malignancies, including leukemias and non-Hodgkin lymphomas of B-cell origin. Coupled with its differential and favourable expression profile, CD19 has rapid internalization kinetics and it is not shed into the circulation, making it an ideal target for the development of antibody-drug conjugates (ADCs) to treat B-cell malignancies. ADCT-402 (loncastuximab tesirine) is a novel CD19-targeted ADC delivering SG3199, a highly cytotoxic DNA minor groove interstrand cross-linking pyrrolobenzodiazepine (PBD) dimer warhead. It showed potent and highly targeted in vitro cytotoxicity in CD19-expressing human cell lines. ADCT-402 was specifically bound, internalized and trafficked to lysosomes in CD19-expressing cells and following release of warhead, resulted in formation of DNA cross-links which persisted for 36 h. Bystander killing of CD19-negative cells by ADCT-402 was also observed. In vivo, single doses of ADCT-402 resulted in highly potent, dose-dependent anti-tumor activity in several subcutaneous and disseminated human tumor models with marked superiority to comparator ADCs delivering tubulin inhibitors. Dose-dependent DNA cross-links and γ-H2AX DNA damage response were measured in tumors by 24 h after single dose administration, while matched PBMCs showed no evidence of DNA damage. Pharmacokinetic analysis in rat and cynomolgus monkey showed excellent stability and tolerability of ADCT-402 in vivo. Together, these impressive data were used to support the clinical testing of this novel ADC in patients with CD19-expressing B-cell malignancies