HAMLET (human alpha-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death

HAMLET, a complex of partially unfolded alpha-lactalbumin and oleic acid, kills a wide range of tumor cells. Here we propose that HAMLET causes macroautophagy in tumor cells and that this contributes to their death. Cell death was accompanied by mitochondrial damage and a reduction in the level of active mTOR and HAMLET triggered extensive cytoplasmic vacuolization and the formation of double-membrane-enclosed vesicles typical of macroautophagy. In addition, HAMLET caused a change from uniform (LC3-I) to granular (LC3-II) staining in LC3-GFP-transfected cells reflecting LC3 translocation during macroautophagy, and this was blocked by the macroautophagy inhibitor 3-methyladenine. HAMLET also caused accumulation of LC3-II detected by Western blot when lysosomal degradation was inhibited suggesting that HAMLET caused an increase in autophagic flux. To determine if macroautophagy contributed to cell death, we used RNA interference against Beclin-1 and Atg5. Suppression of Beclin-1 and Atg5 improved the survival of HAMLET-treated tumor cells and inhibited the increase in granular LC3-GFP staining. The results show that HAMLET triggers macroautophagy in tumor cells and suggest that macroautophagy contributes to HAMLET-induced tumor cell death.

On producing and sharing knowledge across boundaries: experiences from the interfaces of an international development research network

The number of large research networks and programmes engaging in knowledge production for development has grown over the past years. One of these programmes devoted to generating knowledge about and for development is National Centre of Competence in Research (NCCR) North–South, a cross-disciplinary, international development research network funded by the Swiss Agency for Development and Cooperation and the Swiss National Science Foundation. Producing relevant knowledge for development is a core goal of the programme and an important motivation for many of the participating researchers. Over the years, the researchers have made use of various spaces for exchange and instruments for co-production of knowledge by academic and non-academic development actors. In this article we explore the characteristics of co-producing and sharing knowledge in interfaces between development research, policy and NCCR North–South practice. We draw on empirical material of the NCCR North–South programme and its specific programme element of the Partnership Actions. Our goal is to make use of the concept of the interface to reflect critically about the pursued strategies and instruments applied in producing and sharing knowledge for development across boundaries.

Flavor-phenomenology of two-Higgs-doublet models with generic Yukawa structure

In this article, we perform an extensive study of flavor observables in a two-Higgs-doublet model with generic Yukawa structure (of type III). This model is interesting not only because it is the decoupling limit of the minimal supersymmetric standard model but also because of its rich flavor phenomenology which also allows for sizable effects not only in flavor-changing neutral-current (FCNC) processes but also in tauonic B decays. We examine the possible effects in flavor physics and constrain the model both from tree-level processes and from loop observables. The free parameters of the model are the heavy Higgs mass, tanβ (the ratio of vacuum expectation values) and the “nonholomorphic” Yukawa couplings ϵfij(f=u,d,ℓ). In our analysis we constrain the elements ϵfij in various ways: In a first step we give order of magnitude constraints on ϵfij from ’t Hooft’s naturalness criterion, finding that all ϵfij must be rather small unless the third generation is involved. In a second step, we constrain the Yukawa structure of the type-III two-Higgs-doublet model from tree-level FCNC processes (Bs,d→μ+μ−, KL→μ+μ−, D¯¯¯0→μ+μ−, ΔF=2 processes, τ−→μ−μ+μ−, τ−→e−μ+μ− and μ−→e−e+e−) and observe that all flavor off-diagonal elements of these couplings, except ϵu32,31 and ϵu23,13, must be very small in order to satisfy the current experimental bounds. In a third step, we consider Higgs mediated loop contributions to FCNC processes [b→s(d)γ, Bs,d mixing, K−K¯¯¯ mixing and μ→eγ] finding that also ϵu13 and ϵu23 must be very small, while the bounds on ϵu31 and ϵu32 are especially weak. Furthermore, considering the constraints from electric dipole moments we obtain constrains on some parameters ϵu,ℓij. Taking into account the constraints from FCNC processes we study the size of possible effects in the tauonic B decays (B→τν, B→Dτν and B→D∗τν) as well as in D(s)→τν, D(s)→μν, K(π)→eν, K(π)→μν and τ→K(π)ν which are all sensitive to tree-level charged Higgs exchange. Interestingly, the unconstrained ϵu32,31 are just the elements which directly enter the branching ratios for B→τν, B→Dτν and B→D∗τν. We show that they can explain the deviations from the SM predictions in these processes without fine-tuning. Furthermore, B→τν, B→Dτν and B→D∗τν can even be explained simultaneously. Finally, we give upper limits on the branching ratios of the lepton flavor-violating neutral B meson decays (Bs,d→μe, Bs,d→τe and Bs,d→τμ) and correlate the radiative lepton decays (τ→μγ, τ→eγ and μ→eγ) to the corresponding neutral current lepton decays (τ−→μ−μ+μ−, τ−→e−μ+μ− and μ−→e−e+e−). A detailed Appendix contains all relevant information for the considered processes for general scalar-fermion-fermion couplings.

A retroperitoneal bronchogenic cyst mimicking a pancreatic or adrenal mass

Retroperitoneal location of bronchogenic cysts is extremely rare. Most commonly they are encountered in the posterior mediastinum. Bronchogenic cysts arise from developmental aberrations of the tracheobronchial tree in the early embryologic period. We report a 42-year-old female patient with a retroperitoneal bronchogenic cyst in the left adrenal region. She was admitted to our hospital with epigastric pain and subsequently underwent CT of the abdomen. The examination revealed a mass related to the left adrenal gland. Endocrine tests for adrenal hypersecretion were negative. Because of the uncertain entity, laparoscopic adrenalectomy was performed. Pathological examination revealed a bronchogenic cyst in proximity to an inconspicuous left adrenal gland. Although very rare, bronchogenic cysts should be considered in the differential diagnosis of retroperitoneal cystic lesions and surgical resection pursued for symptom resolution and to establish a definitive histology.

I shouldn't have to do this: Illegitimate tasks as a stressor in relation to organizational control and resource deficits

The performance of tasks that are perceived as unnecessary or unreasonable, illegitimate tasks, represents a new stressor concept that refers to assignments that violate the norms associated with the role requirements of professional work. Research has shown that illegitimate tasks are associated with stress and counterproductive work behaviour. The purpose of this study was to provide insight into the contribution of characteristics of the organization on the prevalence of illegitimate tasks in the work of frontline and middle managers. Using the Bern Illegitimate Task Scale (BITS) in a sample of 440 local government operations managers in 28 different organizations in Sweden, this study supports the theoretical assumptions that illegitimate tasks are positively related to stress and negatively related to satisfaction with work performance. Results further show that 10% of the variance in illegitimate tasks can be attributed to the organization where the managers work. Multilevel referential analysis showed that the more the organization was characterized by competition for resources between units, unfair and arbitrary resource allocation and obscure decisional structure, the more illegitimate tasks managers reported. These results should be valuable for strategic-level management since they indicate that illegitimate tasks can be counteracted by means of the organization of work.

New evidence for the symbiosis between Tuber aestivum and Picea abies

The Burgundy truffle (Tuber aestivum Vittad.), an ectomycorrhizal fungus living in association with host plants, is one of the most exclusive delicacies. The symbiosis with deciduous oak, beech, and hazel dominates our concept of truffle ecophysiology, whereas potential conifer hosts have rarely been reported. Here, we present morphological and molecular evidence of a wildlife T. aestivum symbiosis with Norway spruce (Picea abies Karst.) and an independent greenhouse inoculation experiment, to confirm our field observation in southwest Germany. A total of 27 out of 50 P. abies seedlings developed T. aestivum ectomycorrhizae with a mean mycorrhization rate of 19.6 %. These findings not only suggest P. abies to be a productive host species under suitable biogeographic conditions but also emphasize the broad ecological amplitude and great symbiotic range of T. aestivum. While challenging common knowledge, this study demonstrates a significant expansion of the species' cultivation potential to the central European regions, where P. abies forests occur on calcareous soils.

Beyond questionnaires – Exploring adult education teachers' mathematical beliefs with pictures and interviews

Because of the impact that mathematical beliefs have on an individual’s behaviour, they are generally well researched. However, little mathematical belief research has taken place in the field of adult education. This paper presents preliminary results from a study conducted in this field in Switzerland. It is based on Ernest’s (1989) description of mathematics as an instrumental, Platonist or problem solving construct. The analysis uses pictures drawn by the participants and interviews conducted with them as data. Using a categorising scheme developed by Rolka and Halverscheid (2011), the author argues that adults’ mathematical beliefs are complex and especially personal aspects are difficult to capture with said scheme. Particularly the analysis of visual data requires a more refined method of analysis.

Glucagon-like-peptide-1 receptor expression in normal and diseased human thyroid and pancreas.

Glucagon-like-peptide-1 (GLP1) analogs may induce thyroid or pancreatic diseases in animals, raising questions about their use in diabetic patients. There is, however, controversy regarding expression of GLP1 receptors (GLP1R) in human normal and diseased thyroid and pancreas. Here, 221 human thyroid and pancreas samples were analyzed for GLP1R immunohistochemistry and compared with quantitative in vitro GLP1R autoradiography. Neither normal nor hyperplastic human thyroids containing parafollicular C cells express GLP1R with either method. Papillary thyroid cancer do not, and medullary thyroid carcinomas rarely express GLP1R. Insulin- and somatostatin-producing cells in the normal pancreas express a high density of GLP1R, whereas acinar cells express them in low amounts. Ductal epithelial cells do not express GLP1R. All benign insulinomas express high densities of GLP1R, whereas malignant insulinomas rarely express them. All ductal pancreatic carcinomas are GLP1R negative, whereas 6/20 PanIN 1/2 and 0/12 PanIN 3 express GLP1R. Therefore, normal thyroid, including normal and hyperplastic C cells, or papillary thyroid cancer are not targets for GLP1 analogs in humans. Conversely, all pancreatic insulin- and somatostatin-producing cells are physiological GLP1 targets, as well as most acini. As normal ductal epithelial cells or PanIN 3 or ductal pancreatic carcinomas do not express GLP1R, it seems unlikely that GLP1R is related to neoplastic transformation in pancreas. GLP1R-positive medullary thyroid carcinomas and all benign insulinomas are candidates for in vivo GLP1R targeting.Modern Pathology advance online publication, 12 September 2014; doi:10.1038/modpathol.2014.113.

Prognostic and predictive roles of MGMT protein expression and promoter methylation in sporadic pancreatic neuroendocrine neoplasms.

BACKGROUND/AIMS O(6)-methylguanine-methyltransferase (MGMT) is an important enzyme of DNA repair. MGMT promoter methylation is detectable in a subset of pancreatic neuroendocrine neoplasms (pNEN). A subset of pNEN responds to the alkylating agent temozolomide (TMZ). We wanted to correlate MGMT promoter methylation with MGMT protein loss in pNEN, correlate the findings with clinico-pathological data and determine the role of MGMT to predict response to TMZ chemotherapy. METHODS We analysed a well-characterized collective of 141 resected pNEN with median follow-up of 83 months for MGMT protein expression and promoter methylation using methylation-specific PCR (MSP). A second collective of 10 metastasized, pretreated and progressive patients receiving TMZ was used to examine the predictive role of MGMT by determining protein expression and promoter methylation using primer extension-based quantitative PCR. RESULTS In both collectives there was no correlation between MGMT protein expression and promoter methylation. Loss of MGMT protein was associated with an adverse outcome, this prognostic value, however, was not independent from grade and stage in multivariate analysis. Promoter hypermethylation was significantly associated with response to TMZ. CONCLUSION Loss of MGMT protein expression is associated with adverse outcome in a surgical series of pNET. MGMT promoter methylation could be a predictive marker for TMZ chemotherapy in pNEN, but further, favourably prospective studies will be needed to confirm this result and before this observation can influence clinical routine.

Immunologic response to the survivin-derived multi-epitope vaccine EMD640744 in patients with advanced solid tumors

PURPOSE Survivin is a member of the inhibitor-of-apoptosis family. Essential for tumor cell survival and overexpressed in most cancers, survivin is a promising target for anti-cancer immunotherapy. Immunogenicity has been demonstrated in multiple cancers. Nonetheless, few clinical trials have demonstrated survivin-vaccine-induced immune responses. EXPERIMENTAL DESIGN This phase I trial was conducted to test whether vaccine EMD640744, a cocktail of five HLA class I-binding survivin peptides in Montanide(®) ISA 51 VG, promotes anti-survivin T-cell responses in patients with solid cancers. The primary objective was to compare immunologic efficacy of EMD640744 at doses of 30, 100, and 300 μg. Secondary objectives included safety, tolerability, and clinical efficacy. RESULTS In total, 49 patients who received ≥2 EMD640744 injections with available baseline- and ≥1 post-vaccination samples [immunologic-diagnostic (ID)-intention-to-treat] were analyzed by ELISpot- and peptide/MHC-multimer staining, revealing vaccine-activated peptide-specific T-cell responses in 31 patients (63 %). This cohort included the per study protocol relevant ID population for the primary objective, i.e., T-cell responses by ELISpot in 17 weeks following first vaccination, as well as subjects who discontinued the study before week 17 but showed responses to the treatment. No dose-dependent effects were observed. In the majority of patients (61 %), anti-survivin responses were detected only after vaccination, providing evidence for de novo induction. Best overall tumor response was stable disease (28 %). EMD640744 was well tolerated; local injection-site reactions constituted the most frequent adverse event. CONCLUSIONS Vaccination with EMD640744 elicited T-cell responses against survivin peptides in the majority of patients, demonstrating the immunologic efficacy of EMD640744.