Search

The 2030 Agenda and the SDGs respond to humanity’s challenge to live humanely, justly, sustainably and in peace on our interconnected globe. Pursuit of the Agenda is inevitably subject to forces that ‘shake and stir’ it. Correspondingly, our analytical frameworks need to be shaken and stirred too, to be more perceptive and responsive to emergent objective threats, subjective fears, and their impacts. A human security perspective offers an essential complement to the thinking and action underway for the SDGs, because insecurities arise in diverse and fluctuating forms in the daily lives of most people, produced by local, national, international and global forces. The worldwide ‘shake and stir’ triggered by COVID-19 is a reminder of how serious and all-encompassing such disruption can be. A human security perspective should be added in and/or to SDGs planning and implementation, at country level and in multilateral arenas. The perspective can draw together many available tools and stimulate their use focused on recognising and managing threats in people’s daily lives, not least by increasing human resilience. This paper presents the approach’s rationale, certain components, and its relevance to the SDGs Agenda, then presents two extended case studies: first, from almost 20 years of experience with human security-related thinking and practice in Latvia, and, second, from the COVID-19 pandemic and the resulting crises. It concludes with some suggestions for UN organizations, governments, and policy researchers.

Recently, we identified the microRNA-99 family as unfavorable prognostic factor in patients with pancreatic ductal adenocarcinoma (PDAC). The aim of this study is to evaluate its value as circulating biomarker for PDAC. Tissue and corresponding preoperative blood samples of 181 patients with PDAC UICC Stages I–IV (n = 90), intraductal papillary mucinous neoplasm (IPMN, n = 11), chronic pancreatitis (n = 40), pancreatic cystadenoma (n = 20), and age-matched healthy blood serum controls (n = 20) were collected between 2014 and 2017 prospectively. Expression of microRNA-21 as confirmatory marker and the microRNA-99 family, consisting of microRNA-99a, -99b, and -100, was analyzed by qRT-PCR. Target analysis of insulin-like growth factor 1 receptor (IGF1R) was performed using tissue array immunohistochemistry and Western blotting. Expression of microRNA-99 family members was significantly increased in macrodissected tumor tissue and corresponding blood serum samples (p

A key normative principle of transformative social policy is that it is rights-based. This implies that it be universal, as a right extended categorically to all persons in a defined situation, or to all citizens, or, in its most radical form, as applicable to all residents regardless of citizenship status. To be transformative, social policy also needs to tackle the root causes of inequalities and social injustices. In the recent past, approaches emerged in a number of countries in Southeast Asia and South Asia that pointed in the direction of universal, rights-based social policy. These suggest that a “social turn” took place – a shift to ideas and policies that prioritize social issues. In the cases under review (India, Myanmar, Nepal, Pakistan and Thailand), the trends towards a universal, rights-based approach to social services and social transfers were in each case politically driven and a result of changes in government – the social turns were the outcome of contestation. At present, these countries are experiencing political backlashes, with democratic processes and civil society under severe attack. This article seeks to make two points. First, a rights-based, transformative policy approach and a social turn do not come automatically: it is always the result of contestation, be it from the electorate and their interests groups, or from competition between political parties. Second, acquired rights and moves towards transformation can be dismantled. In the current global political rollback, there is a need to defend and fight for transformative and rights-based social policy.

This article explores some of the shared dimensions of fragility experienced by Myanmar and Nepal to illuminate the challenging contexts in which social protection policies and programmes have taken shape. Both countries have adopted a universalist, rights-based vision in their approaches to social protection, with social pensions and child benefits at the forefront of social protection programming. At the same time, both countries are employing incremental strategies to overcome political, social, and administrative obstacles, while demonstrating that fiscal space is available. The politics of social protection policy making are obvious, and consistent engagement by progressive social policy advocates in these countries will be necessary to seize opportunities, and to ensure continued investment in building inclusive, effective, and accountable social protection systems.

In 2016, the government of Myanmar began the implementation of the National Social Protection Strategy Plan (NSPSP). This is a significant step since it addresses social assistance for the majority of the population outside the formal sector for the first time in a systematic manner, moving beyond the few fragmented social transfers in place earlier. The adoption of the strategic plan was propelled by a combination of political factors. Technically, it builds on the life cycle approach of the International Labour Organization’s (ILO) Social Protection Floor Initiative (SPFI). It follows a universal, basic income security approach. This article offers cost calculations based on three different social protection transfer options: a social pension, an education grant and a combined mother and child benefit. The calculations conclude that such transfers can easily be covered from the government’s fiscal budget, and the fiscal and gross domestic product (GDP) shares would actually decrease over time, given population growth dynamics. This reinforces the political and social case for universal social protection in Myanmar.

The article examines the approaches to poverty of the UN development decades, with a focus on the current 2030 Agenda for Sustainable Development. Using the “5 R” criteria of global social policy discourse, the article’s main point is that a coherent analysis of poverty is absent from the agenda. While the agenda does address redistribution, social rights, and resource consciousness, and makes important contributions to social protection and care policy, it makes only superficial reference to the need for regulating of the economy. The main lacuna of the agenda, however, is that it does not address the issue of relationality – the systemic asymmetries in economic, social and political power. As a result, it is weak on policy, and there is the risk that poverty eradication will remain an elusive goal, even beyond 2030, despite the agenda’s transformative remit.

The UN 2030 Agenda on Sustainable Development impresses with its ambition of transformation, and because it has succeeded in marrying economic, social and environmental goals. This article looks at two interrelated questions. It asks whether and to what extent the Agenda's goals are transformative, but finds numerous omissions and clashes. It also seeks to examine whether the Agenda refers to eco-social policy. Two schools of thought are examined. Both critical theory and sufficiency economics propose shifts in norms, policies and practice – and argue for a “hierarchy reversal”, whereby social and climate justice goals override the economic rationale. The article concludes with a case for instrumentalising the commitments of the 2030 Agenda, but complemented by a subversive approach – injecting radical thinking and action for economic, environmental and social justice. Whether this could succeed in light of political constellations is open, and requires an idealistic faith in the power of ideas.

This article examines the new agenda for sustainable development adopted by the United Nations, to see if it contains policies for gender equity and equality as well as for sustainable development in tune with planetary boundaries. It finds that the Sustainable Development Goals (SDGs) are not ambitious and lack a systematic policy approach. It therefore examines other internationally agreed conventions that address gender equality and sustainable development concerns, and contain policies. I examine the universe of policies needed to make sustainable gender equality real, for all women, going beyond the current economistic rationale. The article concentrates on several ‘domains’ widely considered to be core to the empowerment of women: namely work and incomes, access to health services, and the environment. I conclude by arguing that, by incorporating other, more progressive conventions and declarations, the SDGs can be used creatively and subversively, to move towards gender and climate justice.

Year 2015 is slated as a year of transformation to address unprecedented political, ecological, social, gender and economic inequities. UN negotiations are underway to produce new sustainable development goals (SDGs). The paper argues that ideas matter in the conceptualisation of development agendas, which in turn depend on power constellations within and between the first UN—the member states, the second UN—the UN secretariat and agencies, and the third UN—civil society. The paper tracks past development decades and examines whether the SDGs can and will be as visionary as the UN Charter adopted in 1945, which created moral pressure for institutional and policy change. Copyright © 2015 John Wiley & Sons, Ltd.

With the use of ChIP on microarray assays in primary leukemia samples, we report that acute myeloid leukemia (AML) blasts exhibit significant alterations in histone H3 acetylation (H3Ac) levels at > 1000 genomic loci compared with CD34+ progenitor cells. Importantly, core promoter regions tended to have lower H3Ac levels in AML compared with progenitor cells, which suggested that a large number of genes are epigenetically silenced in AML. Intriguingly, we identified peroxiredoxin 2 (PRDX2) as a novel potential tumor suppressor gene in AML. H3Ac was decreased at the PRDX2 gene promoter in AML, which correlated with low mRNA and protein expression. We also observed DNA hypermethylation at the PRDX2 promoter in AML. Low protein expression of the antioxidant PRDX2 gene was clinically associated with poor prognosis in patients with AML. Functionally, PRDX2 acted as inhibitor of myeloid cell growth by reducing levels of reactive oxygen species (ROS) generated in response to cytokines. Forced PRDX2 expression inhibited c-Myc–induced leukemogenesis in vivo on BM transplantation in mice. Taken together, epigenome-wide analyses of H3Ac in AML led to the identification of PRDX2 as an epigenetically silenced growth suppressor, suggesting a possible role of ROS in the malignant phenotype in AML.

Summary Myanmar is a country with a very low per capita income and distressing failures in nutrition, health, education, and others areas of social development. Currently, there appears to be some political softening, and in the realm of policymaking, a series of adaptations have been gradually introduced over the past three years. This paper examines vulnerability and poverty dynamics in the country and its evolving social protection framework. Building on pertinent regional examples, the paper makes the case for holistic social protection policy responses in the domains of social transfers for livelihood support and access to finance, education and health access, child protection, protection from exclusion, and as an emergency response. The outlook argues that comprehensive inclusive and ultimately transformative social protection needs to be introduced and could be within reach, as an integral part of deeper systemic reform in Myanmar.

This article argues that social transfers as such, are a ‘good thing’. They can alleviate the immediate economic impact of poverty and vulnerability. It cautions, however, that such transfers may be a ‘bad thing’, since they can divert attention from the real obstacles to equitable, inclusive development and social justice, and postpone actions for structural change. The article examines social transfers in the form of income supplements, employment guarantees, and transfers for affirmative action in Bangladesh, India, Nepal and Pakistan. It argues that additional factors are needed to render such social protection policy instruments genuinely transformative. These would include transparency of information and freedom of the press, among others. They would also include policies to address land reform, an industrial strategy to create decent work, progressive fiscal policy, policies for social inclusion and policies at the international level.

Summary Nepal, with a population of 27.6 million people, is a ‘least developed country’ in many ways. The country is characterised by significant socioeconomic insecurity, comprising structurally-generated income poverty, a politically and socially fragile post-conflict situation, threats to the environment, and deeply entrenched forms of social exclusion. At the same time, it is a country characterised by interesting socio-political policy innovations, triggered by the end of a ten-year violent conflict. Building on a discussion of the country's challenges, the paper explores the policy responses in the domain of social protection devised by the interim government to address the various dimensions of insecurity, and to show their novelty as well as their limitations. The final section offers some ideas on policy areas which would be needed to improve socioeconomic security.

Purpose EWS-ETS fusion genes are the driving force in Ewing's sarcoma pathogenesis. Because of the variable breakpoint locations in the involved genes, there is heterogeneity in fusion RNA and protein architecture. Since previous retrospective studies suggested prognostic differences among patients expressing different EWS-FLI1 fusion types, the impact of fusion RNA architecture on disease progression and relapse was studied prospectively within the Euro-E.W.I.N.G. 99 clinical trial. Patients and Methods Among 1,957 patients who registered before January 1, 2007, 703 primary tumors were accessible for the molecular biology study. Fusion type was assessed by polymerase chain reaction on frozen (n = 578) or paraffin-embedded materials (n = 125). The primary end point was the time to disease progression or relapse. Results After exclusion of noninformative patients, 565 patients were entered into the prognostic factor analysis comparing type 1 (n = 296), type 2 (n = 133), nontype 1/nontype 2 EWS-FLI1 (n = 91) and EWS-ERG fusions (n = 45). Median follow-up time was 4.5 years. The distribution of sex, age, tumor volume, tumor site, disease extension, or histologic response did not differ between the four fusion type groups. We did not observe any significant prognostic value of the fusion type on the risk of progression or relapse. The only slight difference was that the risk of progression or relapse associated with nontype 1/nontype 2 EWS-FLI1 fusions was 1.38 (95% CI, 0.96 to 2.0) times higher than risk associated with other fusion types, but it was not significant (P = .10). Conclusion In contrast to retrospective studies, the prospective evaluation did not confirm a prognostic benefit for type 1 EWS-FLI1 fusions.

Two hundred and fourteen patients with benign giant cell tumor of bone (GCTB), treated from 1980 to 2007 at the Department of Orthopedics of the University of Muenster (Germany), were analyzed in a retrospective study.The mean age was 33.3 years with a female-to-male ratio of 1.2 : 1. The mean follow up was 59.8 months. The recurrence rate of patients who received first treatment at our institution was 16.6%. The most common primary treatment was curettage (188 patients) usually followed by adjuvant local therapy. The effects of bone cement (PMMA), burring and hydrogen peroxide (H(2)O(2)) were statistically analyzed and the influence of a subchondral bone graft on the recurrence rate was evaluated.PMMA alone (n = 52) reduces the likelihood of recurrence by the factor 8.2, additional high-speed burring (n = 39) by the factor 3.9 (compared to PMMA only). H(2)O(2) (n = 42) seems to have an additional effect comparable to that of phenol although it did not reach statistical significance.The combination of all adjuncts (PMMA, burring, H(2)O(2) - n = 42) reduces the likelihood of recurrence by the factor 28.2 compared to curettage only and therefore should be recommended as a standard treatment. If the tumor reaches close to the articulating surface a subchondral bone graft (n = 42) can be performed without risking a higher recurrence rate. We add seven cases of pulmonary metastases and two cases of multicentricity to the literature. Bisphosphonates and interferon alpha may have a beneficial effect.

As the Millennium Development Goals pass their 2015 deadline and the international community is discussing the future of international development policy, Poverty and the Millennium Development Goals brings together leading experts to provide a much-needed critique of the prevailing development agenda. Examining the MDG efforts and results, it exposes the misleading measurements that have led official sources to routinely underestimate the scale of world poverty and hunger, even as the global distribution of income, wealth and access to health services becomes ever more imbalanced. Arguing that any post-2015 development agenda will be futile unless it addresses the fundamental structural flaws of the current system, this timely book suggests the relevance of an independent, transparent methodology to measure results and outlines a radically alternative approach to development, in which policy is informed by those who live in poverty and face economic and social exclusion. It offers innovative poverty analysis built not only on realistic, grassroots data but on confronting the issue of power head on. Poverty and the Millennium Development Goals represents a vital contribution towards a more equitable agenda for social, economic, political and ecological justice, which can point the way towards a more holistic theory and practice of development. Comparative Research Programme on Poverty (CROP) at the University of Bergen publishedVersion

Nitric oxide (NO) mediates fundamental physiological actions on skeletal muscle. The loss of NO synthase (NOS) from the sarcolemma was assumed to be associated with development of Duchenne muscular dystrophy (DMD). We have, however, recently reported that, in contrast to the commonly accepted view, NOS expression in DMD myofibres is up-regulated. This poses the question of the fibre type-specific NOS expression in DMD muscles and how the NOS expression is related to the regeneration or degeneration status. To address this issue, we examined localization of NOS isoforms I, II and III in skeletal muscles of DMD patients employing immunohistochemical labelling with tyramide signal amplification complemented with enzyme histochemistry. We found that NOS immunolabelling as well as metabolic enzyme activity in DMD muscles were heterogeneously distributed along the fibre length of DMD muscle fibres revealing regenerating and degenerate (hypercontracted) fibres as well as normal segments. Like in normal muscles, positive NOS immunoreactivity was found to be associated with fast-oxidative glycolytic (FOG) phenotype. The regeneration status of NOS-positive segments was deduced from the presence of neonatal and developmental myosin heavy chains. High NOS expression in regenerating DMD muscle fibres can be well reconciled with reports about the protective role of endogenous NO in inflammatory diseases and in muscle repair.

During successful chemotherapy of osteosarcomas tumour size does not diminish significantly because the therapy has limited impact on the mineralized matrix of the tumour. Treatment response is considered successful if, histologically, more than 90% of tumour cells show necrosis.To determine if osteosarcomas change their water diffusion during preoperative chemotherapy in relation to the amount of tumour necrosis.Eight patients (age 11-19 years) with histologically proven limb osteosarcoma underwent T1-weighted, fat-suppressed T2-weighted and contrast-enhanced T1-weighted spin-echo imaging together with diffusion-weighted EPI sequences (b = 700) at 1.5 T before and after five cycles of standard chemotherapy. Tumour volume and apparent diffusion coefficient (ADC) maps were calculated before and after chemotherapy. The degree of tumour necrosis after chemotherapy was assessed using the histological Salzer-Kuntschik classification (grades 1-6).During chemotherapy, the ADC values of osteosarcomas changed significantly. The ADC of untreated tumour was 2.1 +/- 0.4 x 10(-3) mm(2)/s (mean +/- SD) (95% CI 1.6-2.0). The ADC of chemotherapy-treated sarcomas was 2.5 +/- 0.4 x 10(-3) mm(2)/s (95% CI 1.8-2.2). Necrotic areas, which were confirmed by macroscopic examination, showed ADC values up to 2.7 x 10(-3) mm(2)/s. Four patients with little viable tumour tissue within the neoplasm (Salzer-Kuntschik grades 1-2) had an increase in ADC of 0.4 up to 0.7 x 10(-3) mm(2)/s. Four patients with larger areas of viable tumour (Salzer-Kuntschik grade 4) showed a lesser increase in ADC of 0.0 up to 0.3 x 10(-3) mm(2)/s. The differences in ADC values in tumour tissue before and after chemotherapy were highly significant (P = 0.01).During chemotherapy of osteosarcomas, tumour ADC changes are related to the degree of tumour necrosis.

Nitric oxide (NO) mediates fundamental physiological actions on skeletal muscle. The neuronal NO synthase isoform (NOS1) was reported to be located exclusively in the sarcolemma. Its loss from the sarcolemma was associated with development of Duchenne muscular dystrophy (DMD). However, new studies evidence that all three NOS isoforms-NOS1, NOS2, and NOS3-are co-expressed in the sarcoplasm both in normal and in DMD skeletal muscles. To address this controversy, we assayed NOS expression in DMD myofibers in situ cytophotometrically and found NOS expression in DMD myofibers up-regulated. These results support the hypothesis that NO deficiency with consequent muscle degeneration in DMD results from NO scavenging by superoxides rather than from reduced NOS expression.

Purpose Precursor B-lymphoblastic lymphoma cells are indistinguishable by morphology, and immune phenotype from lymphoblasts in acute leukemia which in infancy is associated with MLL rearrangements and a poor prognosis. The role of MLL gene deregulation in rare cases of isolated lymphoblastic lymphoma in infants is obscure. We report the case of a 10-month-old child who presented with a cutaneous nodule on the left foot. Histological diagnosis was precursor B-lymphoblastic lymphoma. The young age of the patient motivated us to investigate the presence of an MLL rearrangement. Methods Cytogenetic analysis was performed by fluorescence in situ hybridization (FISH), and the genomic fusion partner of MLL was identified by long-distance inverse (LDI-)PCR and confirmed by direct PCR. Results Fluorescence in situ hybridization screening of paraffin-embedded formalin-fixed tissue indeed revealed the presence of an MLL rearrangement. The genomic fusion partner was identified as AF10 by DNA sequencing of the MLL breakpoint region. The MLL-AF10 fusion gene was further detected in cytologically normal pretreated bone marrow. Treatment was started with standard four-drug induction chemotherapy. Because of the unfavorable outcome associated with MLL rearrangements in infant leukemia, we intensified postremission treatment according to the Interfant-06 study protocol. The child is in continuous first remission 36 months after diagnosis. Conclusion This is the first report of submicroscopic bone marrow involvement in MLL-rearranged isolated cutaneous B-cell precursor lymphoma in an infant. To prospectively address the role of MLL rearrangements in extramedullary B-lymphoblastic malignancies in infants, we suggest to assess both tumors and non-infiltrated bone marrow for the presence of this genetic abnormality.

This book chapter was published in Development and Welfare Policy in South Asia [ ©2014 Taylor and Francis ] and the definite version is available at: http://doi.org/10.4324/9780203386255 The book website is at: http://www.tandfebooks.com/isbn/9780203386255

Chromosomal translocations between the EWS gene and members of the ETS gene family are characteristic molecular features of the Ewing sarcoma. The most common translocation t(11;22)(q24;q12) fuses the EWS gene to FLI1, and is present in 85–90% of Ewing sarcomas. In the present study, a specifically designed multiplex long-range PCR assay was applied to amplify genomic EWS-FLI1 fusion sites from as little as 100 ng template DNA. Characterization of the EWS-FLI1 fusion sites of 42 pediatric and young adult Ewing sarcoma patients and seven cell lines revealed a clustering in the 5′ region of the EWS-breakpoint cluster region (BCR), in contrast to random distribution of breakpoints in the FLI1-BCR. No association of breakpoints with various recombination-inducing sequence motifs was identified. The occurrence of small deletions and duplications at the genomic junction is characteristic of involvement of the non-homologous end-joining (NHEJ) repair system, similar to findings at chromosomal breakpoints in pediatric leukemia and lymphoma.

Background Periprosthetic osteolysis is a major cause of aseptic loosening in joint arthroplasty. This study investigates the impact of CT (calcitonin) deficiency and CT substitution under in-vivo circumstances on particle-induced osteolysis in Calca -/- mice. Methods We used the murine calvarial osteolysis model based on ultra-high molecular weight polyethylene (UHMWPE) particles in 10 C57BL/6J wild-type (WT) mice and twenty Calca -/- mice. The mice were divided into six groups: WT without UHMWPE particles (Group 1), WT with UHMWPE particles (Group 2), Calca -/- mice without UHMWPE particles (Group 3), Calca -/- mice with UHMWPE particles (Group 4), Calca -/- mice without UHMWPE particles and calcitonin substitution (Group 5), and Calca -/- mice with UHMWPE particle implantation and calcitonin substitution (Group 6). Analytes were extracted from serum and urine. Bone resorption was measured by bone histomorphometry. The number of osteoclasts was determined by counting the tartrate-resistant acid phosphatase (TRACP) + cells. Results Bone resorption was significantly increased in Calca -/- mice compared with their corresponding WT. The eroded surface in Calca -/- mice with particle implantation was reduced by 20.6% after CT substitution. Osteoclast numbers were significantly increased in Calca -/- mice after particle implantation. Serum OPG (osteoprotegerin) increased significantly after CT substitution. Conclusions As anticipated, Calca -/- mice show extensive osteolysis compared with wild-type mice, and CT substitution reduces particle-induced osteolysis.

Although the recurrence rate of giant cell tumors of bone (GCTB) is relatively high exact data on treatment options for the recurrent cases is lacking. The possible surgical procedures range from repeated intralesional curettage to wide resection. Two hundred and fourteen patients with histologically certified GCTB have been treated at the authors department from 1980 to 2007. Sixty-seven patients with at least one local recurrence were included in this study. The mean follow-up was 77.3 months. The data was evaluated according the re-recurrence rate with regard to the surgical procedure for the recurrence. The mean time until the first local recurrence was 22.0 months; the mean number of recurrences per patient was 1.4. The recurrence occurred in 69.7% (46 out of 66 patients) within the first 2 years. If after intralesional procedures (curettage or intralesional resection) no adjunct was used the re-recurrence rate was 58.8% (10 out of 17 patients) and decreased to 21.7% (5 out of 23 patients) if a combination of all adjuncts (PMMA + burring) was used. The likelihood of re-recurrence was reduced by the factor 5.508 which was clearly significant (P = 0.016). In case of wide resection no re-recurrence occurred. Seven patients (10.5%) developed pulmonary metastases. Fourteen patients (20.9%) finally received an endoprosthesis; 12 due to tumor recurrence, 2 due to secondary arthritis. Recurrent GCTB can be treated by further curettage with additional burring and cementing with an acceptable re-recurrence rate of 21.7%. The rate of patients finally needing an endoprosthesis is 20.9%. Due to the high rate of pulmonary metastases recurrent GCTB may be considered as a severe disease.

In patients with sepsis, hemodynamic support is often complicated by a tachyphylaxis against conventional vasopressor agents. Bolus infusion of terlipressin, a vasopressin analog, has been reported to increase mean arterial pressure in patients with catecholamine-resistant septic shock. However, bolus infusion of terlipressin may be associated with severe side effects, including pulmonary vasoconstriction and impairment of oxygen delivery. We hypothesized that continuous low-dose infusion of terlipressin may reverse sepsis-related systemic arterial hypotension with reduced side effects as compared with the traditional concept of bolus administration. Twenty-seven adult sheep were instrumented for chronic study. After a baseline measurement, Salmonella typhosa endotoxin (10 ng.kg-1.min-1) was continuously administered for the next 40 h. After 16 h of endotoxemia, the surviving sheep (n = 24) were randomly assigned to be treated with either a continuous infusion of terlipressin (2 mg for 24 h), bolus injections of terlipressin (1 mg every 6 h), or placebo (normal saline; each n = 8). Continuous infusion of terlipressin permanently reversed endotoxin-induced systemic arterial hypotension (P < 0.001) and improved left ventricular stroke work index in all sheep (P < 0.05). Intermittent bolus injections of terlipressin were linked to decreases in heart rate and cardiac index and increases in pulmonary vascular resistance index (each, P < 0.001). These unwanted side effects were prevented by continuous low-dose infusion of the drug. In conclusion, continuous infusion of terlipressin stabilized hemodynamics and improved myocardial performance in endotoxemic ewes without obvious side effects. Continuous low-dose terlipressin infusion may represent a useful alternative treatment of arterial hypotension related to sepsis and systemic inflammatory response syndrome.

Duchenne and Becker muscular dystrophies (DMD and BMD) are associated with decreased total nitric oxide (NO). However, mechanisms leading to NO deficiency with consequent muscle-cell degeneration remain unknown. To address this issue, we examined skeletal muscles of DMD and BMD patients for co-expression of NO synthase (NOS) with nitrotyrosine and transcription factor CREB, as well as with enzymes engaged in NO signaling. Employing immunocytochemical labeling, Western blotting and RT-PCR, we found that, in contrast to the most commonly accepted view, neuronal NOS was not restricted to the sarcolemma and that muscles of DMD and BMD patients retained all three NOS isoforms with an up-regulation of the inducible NOS isoform, CREB and nitrotyrosine. We suggest that enhanced nitrotyrosine immunostaining in muscle fibers as well as in the vasculature of DMD and BMD specimens reflects massive oxidative stress, resulting in withdrawal of NO from its regular physiological course via the scavenging actions of superoxides.

This study intended to examine if the immune response to a cognitive task as a variant of psychological stress in MS patients is distinct from healthy controls. The experiment was part of a larger study on mechanisms and measurements of MS fatigue. Patients (n =23) and controls (n =25) participated in a cognitive task lasting 40 minutes, in which the heart rate was continuously monitored. Blood samples were taken at baseline and directly after the stress-inducing task Whole blood stimulated cytokine production representative of the TH-1 (i.e. IFNgamma, TNFalpha) and TH-2 paradigm (i.e. IL-10) was evaluated in relation to disability, fatigue, cognitive deficit, and anxiety. Patients scored high on a disease specific fatigue score compared to controls, whereas baseline cytokine patterns did not differ between the groups. MS patients displayed a blunted response of IFNgamma (P =0.03) whereas TNFalpha and IL-10 responses did not change. Additionally MS patients showed a significantly lower heart rate increase after the task (P0.001). Cognitive impairment was associated with a decreased heart rate reactivity (P =0.02) while depressive symptoms correlated with stronger IL-10 responses (P =0.05). Overall, cognitive stress induces IFNgamma production in healthy controls but not in MS patients with fatigue. Furthermore, a reduced cardiac response might indicate an autonomic dysfunction in this group of patients.

A high serum level of beta human chorionic gonadotropin (hCG) normally indicates pregnancy in healthy women. We were confused by this finding in one of our patients. This 18-year-old girl presented with amenorrhoea of 1-month duration, a positive pregnancy test and a high beta-hCG serum level although taking contraceptives. Pregnancy was excluded by ultrasound. Three years previously, she had had an osteosarcoma of the humerus. The tumour initially had been wide resected and had shown a good response to neoadjuvant chemotherapy with COSS-96-protocol. We reviewed the original histological result and the literature about possible similar findings. We analysed therapeutic options and the value of beta-hCG levels as a therapy monitor. During examination we detected a recurrent osteosarcoma of the left humerus. The local relapse evidently expressed beta-hCG which, retrospectively, could only sparsely be shown in the primary resectate. After intralesional surgery, chemotherapy and radiotherapy levels of beta-hCG normalised. Osteosarcoma very rarely is able to produce a paraneoplastic syndrome by high levels of beta-hCG. This may well be of diagnostic value and offer an additional monitoring tool. It can indicate tumour recurrrence and dedifferentiation.

To evaluate fluorine 18 (18F) dopa positron emission tomography (PET) in comparison with established imaging procedures in gastrointestinal carcinoid tumors.After evaluation of the normal distribution of 18F dopa, 17 patients with histologically confirmed tumors were examined with 18F dopa PET. Results of 2-[fluorine 18]fluoro-2-deoxy-D-glucose (FDG) PET, somatostatin-receptor scintigraphy, and morphologic imaging (computed tomography and/or magnetic resonance imaging) were available for all patients. Results of the procedures were evaluated by two radiologists and two nuclear medicine specialists, whose consensus based on all available histologic, imaging, and follow-up findings was used as the reference standard.Ninety-two tumors were diagnosed: eight primary tumors, 47 lymph node metastases, and 37 organ metastases. 18F dopa PET led to 60 true-positive findings (seven primary tumors, 41 lymph node metastases, 12 organ metastases); FDG PET, 27 (two primary tumors, 14 lymph node metastases, 11 organ metastases); somatostatin-receptor scintigraphy, 52 (four primary tumors, 27 lymph node metastases, 21 organ metastases); and morphologic imaging, 67 (two primary tumors, 29 lymph node metastases, 36 organ metastases). This resulted in the following overall sensitivities: 18F dopa PET, 65% (60 of 92); FDG PET, 29% (27 of 92); somatostatin-receptor scintigraphy, 57% (52 of 92); morphologic procedures, 73% (67 of 92). Although the morphologic procedures were most sensitive for organ metastases, 18F dopa PET enabled best localization of primary tumors and lymph node staging.18F dopa PET is a promising procedure and useful supplement to morphologic methods in diagnostic imaging of gastrointestinal carcinoid tumors.

Abstract 4693 Loss of Structural Maintenance of Chromosomes 1A Protein Expression is Associated with a Poor Prognosis in Acute Myeloid Leukemia Utz Krug, Claudia Hömme, Nicola Tidow, Horst Bürger, Gabriele Köhler, Achim Heinecke, Thomas Büchner, Wolfgang E. Berdel, Steffen Koschmieder, Carsten Müller-Tidow Introduction Acute myelogenous leukemia is a genetically heterogenous disease with many risk factors for a poor prognosis. One of the most important independent risk factor in AML is the age at diagnosis. Older patients with AML generally have a poor prognosis which suggests that the biology of AML in elderly patients differs from AML in younger patients. Methods Gene expression profiling was carried out to identify age related changes in AML blasts of 67 AML patients of different age (range: 17 to 80 years). Among the genes that correlated with age, SMC1A was selected for protein expression studies. A tissue array was created containing bone marrow histology samples of 135 patients with newly diagnosed AML of different ages and probed with an antibody against SMC1A and protein expression was quantified by the DAKO score. Results 131 genes showed a significant correlation between mRNA expression levels and patient age. Increasing age was associated with significantly decreased mRNA levels of SMC1A. 116 patient samples were evaluable for SMC1A protein expression and expression of SMC1A protein was low or absent in 74 out of 116 AML specimens. SMC1A protein expression did not show a correlation with patients' age at diagnosis. Both event free survival (2.6 months vs. 10.3 months, p=0.003, see figure) and overall survival (10.4 months vs. 22.6 months, p=0.015, see figure) were significantly worse in patients with low or absent SMC1A protein expression. In a multivariate analysis, SMC1A protein expression level remained a significant prognostic factor for event free survival (p=0.014) with a borderline significance for overall survival (p=0.066). Conclusions We identified 131 genes with putative age-dependent microarray mRNA expression and identified low levels of SMC1A protein expression as a marker for poor prognosis in patients with newly diagnosed acute myeloid leukemia. Disclosures: No relevant conflicts of interest to declare.

Activating mutations in Flt3, N- and K-Ras have been reported in all AML subtypes and represent common molecular defects in de novo AML. We have previously shown that these mutations lead to constitutive AKT phosphorylation and activation. As a consequence, Akt phosphorylation is found in myeloid blasts of the majority of AML patients. We reasoned that constitutively active AKT may contribute to leukemia development, and therefore we assessed the contribution of AKT in oncogenic transformation in vivo. For this purpose, we established an inducible mouse model expressing myristylated AKT1 under the control of the scl-3′ enhancer (MyrAKT1). This system restricts activated AKT1 to endothelium, hematopoietic stem cells and myeloid lineage cells at a low but detectable level. About 40% of induced mice developed a myeloproliferative disorder after latencies of 7 to 22 months. Onset of disease was frequently associated with hemangioma formation, due to endothelial MyrAKT1 expression. The myeloproliferative disorder was associated with splenomegaly with increased extramedullary hematopoiesis, while the peripheral blood contained mature granulocytes. Furthermore, the stem cell and progenitor cell compartment in spleens and bone marrow of these mice was altered compared to control mice. Colony formation assays with MyrAKT1-expressing bone marrow suggested that overactivation of AKT1 enhanced proliferation. The AKT1-induced disease was transplantable by both bone marrow and spleen cells. These findings highlight the oncogenic capacity of constitutively activated AKT1 in vivo and indicate that AKT is an attractive target for therapeutic intervention in AML.

Cell cycle progression is driven by the kinase activity of cyclin/CDK complexes. Dysregulation of the cell cycle leads to altered cell growth and contributes to tumorigenesis. Recently, we identified p26INCA1 as novel interaction partner of Cyclin A1/CDK2. Here, we characterize the phenotype of Inca1-null mice to uncover the cellular and molecular function of Inca1. Inca1-knockout mice were viable and fertile. FACS analyses revealed that aging mutant animals harbored an increased hematopoietic stem cell (HSC) pool. Bone marrow cells of young mice exhibited enhanced clonogenic replating efficiency in colony formation assays as compared to wildtype mice. Weekly administration of the myeloablative agent 5-fluorouracil (5-FU) led to a significantly shorter life span of Inca1−/ − mice compared to wildtype littermates. The increased 5-FU toxicity might thus be related to a higher number of cycling HSC in Inca1−/ − bone marrow. Analysis of the impact of Inca1 on cell cycle regulation demonstrated that the fraction of Inca1−/ − embryonic fibroblasts (MEFs) in S phase was significantly increased. Ectopic INCA1 expression reduced proliferation and colony formation of proliferating cells such as primary bone marrow cells, HeLa, HuTu80 and 32D cell lines. Serum starvation rapidly induced and mitogenic signals inhibited Inca1 expression providing a further link to cell cycle regulation. To identify the molecular mechanism of cell cycle regulation by Inca1, we investigated the influence of Inca1 on the direct inhibition of CDK2. In spleen lysates from Inca1-deficient mice, cellular CDK2 kinase activity towards Histone H1 was significantly induced compared to lysates of wildtype littermates. In in vitro kinase assays, recombinant INCA1 strongly inhibited CDK2 activity. In addition, we hypothesized that other cyclin kinase inhibitors (CKI) could partially compensate in vivo for the loss of Inca1 function. p21cip1/waf1 mRNA and protein expression were induced in Inca1−/ − MEFs compared to wildtype cells hinting at a partial compensation of the loss of Inca1 by induction of p21. Loss of Inca1 combined with p21 knockdown synergistically increased S-phase. These results indicate that Inca1 could be functionally related to p21 and that the rather mild phenotype observed in Inca1−/ − mice and the modest differences in Cdk activity observed in cell lysates lacking Inca1 could be due to compensatory induction of the CKI p21. In summary, loss of Inca1 increased cell proliferation, replating efficiency, S-phase progression, and Cdk2 activity whereas gain of Inca1 suppressed these cell functions. Inca1 expression was induced during cell cycle arrest. We conclude that Inca1 could be a novel cell cycle suppressor regulating the quiescence of HSCs through the inhibition of Cdk2.

Using an endoscopic ultrasound (EUS) miniprobe, even highly stenotic esophageal cancers precluding the passage of a conventional probe can be examined without prior dilatation.To assess: (1) staging accuracy of conventional EUS probe and miniprobe, (2) variables influencing staging accuracy, (3) endoscopic features predicting tumor stage.Ninety-seven consecutive patients with esophageal cancer undergoing complete surgical resection were included. Preoperative EUS was performed using a conventional probe in nonstenotic tumors and a miniprobe in stenotic tumors. Accuracy of EUS for T and N stages was compared to pathohistological staging.Overall EUS staging accuracy was 73.2% for T stage and 74.2% for N stage. It was similar for the miniprobe used in stenotic tumors vs the conventional probe used in nonstenotic tumors. Based on EUS, 84.5% of the patients would have been assigned to the appropriate therapy protocol (primary surgery vs neoadjuvant therapy). Endoscopic tumor features had no influence on staging accuracy. Tumor length5 cm predicted advanced T and nodal positive stages.The miniprobe allows adequate EUS staging of stenotic esophageal tumors precluding the passage of a conventional probe. Therefore, dilatation therapy of stenotic cancers to conduct conventional EUS should be avoided.

8548 Background: High-dose chemotherapy (HDT) followed by autologous stem-cell transplantation (ASCT) is considered standard in the treatment of patients with relapsed or refractory aggressive peripheral T-cell lymphoma (PTCL). However, the optimal salvage regimen before ASCT has not yet been established. Methods: We retrospectively analyzed 31 patients with relapsed or refractory aggressive PTCL after anthracycline based first-line chemotherapy who received either DexaBEAM (n=16) or ICE (n=15) regimen as first salvage chemotherapy followed by HDT and ASCT between 1996 and 2009. The median patient age was 46 years (range, 18-66) in the DexaBEAM group and 40 years (range, 17-59) in the ICE group. Patients were included independent of WHO stage and IPI score. Results: The overall response rate (OR) was significantly higher for patients treated with DexaBEAM (69%) as compared to the ICE group (20%; P=0.01), with higher complete response (CR; 38% vs. 7%) as well as partial response (PR; 31% vs. 13%) rate. Changing regimen due to failure of the first salvage therapy, 12 patients initially receiving ICE still achieved an OR of 58% (33% CR, 25% PR) with DexaBEAM as second salvage therapy, whereas in 3 patients receiving ICE after DexaBEAM failure only 1 patient achieved an OR (1 PR). Median progression-free survival (PFS) was significantly higher in the DexaBEAM group (6.4 vs. 2 months; P=0.01). Median overall survival (OS) was not different between the two groups (22.8 vs. 29.8 months; P=0.72), most likely due to the good response rate of patients to DexaBEAM as 2nd salvage regimen after failure of ICE chemotherapy. Major adverse event in both groups was myelosuppression with higher but tolerable treatment-related toxicity for patients in the DexaBEAM group. Conclusions: In this retrospective comparison DexaBEAM salvage chemotherapy was superior to ICE for patients with relapsed or refractory aggressive PTCL for remission induction prior to autologous transplantation, with higher but manageable treatment-related toxicity.

The 2030 Agenda and the Sustainable Development Goals (SDGs) respond to humanity’s challenge to live humanely, justly, sustainably and in peace on our interconnected globe. Pursuit of the Agenda is inevitably subject to forces that ‘shake and stir’ it. Correspondingly, our analytical frameworks need to be shaken and stirred too, to be more perceptive and responsive to emergent objective threats, subjective fears, and their impacts. A human security perspective offers an essential complement to the thinking and action underway for the SDGs, because insecurities arise in diverse and fluctuating forms in the daily lives of most people, produced by local, national, international and global forces. The worldwide ‘shake and stir’ triggered by COVID-19 is a reminder of how serious and all-encompassing such disruption can be. A human security perspective should be added in and/or to SDGs planning and implementation, at country level and in multilateral arenas. The perspective can draw together many available tools and stimulate their use focused on recognising and managing threats in people’s daily lives, not least by increasing human resilience. This paper presents the approach’s rationale, certain components, and its relevance to the SDGs Agenda, then gives two extended case studies: first, from almost 20 years of experience with human security-related thinking and practice in Latvia, and, second, from the COVID-19 pandemic and the resulting crises. It concludes with suggestions for UN organizations, governments, and policy researchers.