Search

Background: Orphans and other vulnerable children (OVC) who grow up in institutional care often show communication and language problems. The caregivers lack training, and there are few language didactics programmes aimed at supporting communication and language development in OVC in institutional care in Tanzania., Objectives: The purpose of the study was to adapt the German concept of relational communication therapy (RCT) as a support to language development in a Tanzanian early childhood education context in a culturally sensitive way. Following the adaptation of the concept, a training programme for Tanzanian caregiver students was developed to compare their competencies in language didactics before and after training., Methods: A convergent mixed methods design was used to examine changes following training in 12 participating caregiver students in a Tanzanian orphanage. The competencies in relational language didactics were assessed by a self-developed test and video recordings before and after intervention. Based on the results, we drew conclusions regarding necessary modifications to the training modules and to the concept of RCT., Results: The relational didactics competencies of the caregiver students improved significantly following their training. A detailed analysis of the four training modules showed that the improvement in relational didactics competencies varied depending on the topic and the teacher., Conclusion: The results provide essential hints for the professionalisation of caregivers and for using the concept of RCT for OVC in institutional care in Tanzania. Training programmes and concepts should not just be transferred across different cultures, disciplines and settings; they must be adapted to the specific cultural setting.

Although human malignant melanoma is a highly immunogenic cancer, both the endogenous antitumor immune response and melanoma immunotherapy often fail to control neoplastic progression. Accordingly, characterizing melanoma cell subsets capable of evading antitumor immunity could unravel optimized treatment strategies that might reduce morbidity and mortality from melanoma. By virtue of their preferential capacity to modulate antitumor immune responses and drive inexorable tumor growth and progression, malignant melanoma-initiating cells (MMICs) warrant closer investigation to further elucidate the cellular and molecular mechanisms underlying melanoma immune evasion and immunotherapy resistance. Here we describe methodologies that enable the characterization of immunoregulatory effects of purified MMICs versus melanoma bulk populations in coculture with syngeneic or allogeneic lymphocytes, using [ 3 H]thymidine incorporation, enzyme-linked immunosorbent spot (ELISPOT), or ELISA assays. These assays were traditionally developed to analyze alloimmune processes and we successfully adapted them for the study of tumor-mediated immunomodulatory functions.

Despite considerable progress in recent years, the overall prognosis of metastatic malignant melanoma remains poor, and curative therapeutic options are lacking. Therefore, better understanding of molecular mechanisms underlying melanoma progression and metastasis, as well as identification of novel therapeutic targets that allow inhibition of metastatic spread, are urgently required. The current study provides evidence for aberrant cyclin-dependent kinase 5 (CDK5) activation in primary and metastatic melanoma lesions by overexpression of its activator protein CDK5R1/p35. Moreover, using melanoma in vitro model systems, shRNA-mediated inducible knockdown of CDK5 was found to cause marked inhibition of cell motility, invasiveness, and anchorage-independent growth, while at the same time net cell growth was not affected. In vivo, CDK5 knockdown inhibited growth of orthotopic xenografts as well as formation of lung and liver colonies in xenogenic injection models mimicking systemic metastases. Inhibition of lung metastasis was further validated in a syngenic murine melanoma model. CDK5 knockdown was accompanied by dephosphorylation and overexpression of caldesmon, and concomitant caldesmon knockdown rescued cell motility and proinvasive phenotype. Finally, it was found that pharmacological inhibition of CDK5 activity by means of roscovitine as well as by a novel small molecule CDK5-inhibitor, N-(5-isopropylthiazol-2-yl)-3-phenylpropanamide, similarly caused marked inhibition of invasion/migration, colony formation, and anchorage-independent growth of melanoma cells. Thus, experimental data presented here provide strong evidence for a crucial role of aberrantly activated CDK5 in melanoma progression and metastasis and establish CDK5 as promising target for therapeutic intervention., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Recent work has identified dysfunctional Hippo signaling to be involved in maintenance and progression of various human cancers, although data on clear cell renal cell carcinoma (ccRCC) have been limited. Here, we provide evidence implicating aberrant Hippo signaling in ccRCC proliferation, invasiveness, and metastatic potential. Nuclear overexpression of the Hippo target Yes-associated protein (YAP) was found in a subset of patients with ccRCC. Immunostaining was particularly prominent at the tumor margins and highlighted neoplastic cells invading the tumor-adjacent stroma. Short hairpin RNA-mediated knockdown of YAP significantly inhibited proliferation, migration, and anchorage-independent growth of ccRCC cells in soft agar and led to significantly reduced murine xenograft growth. Microarray analysis of YAP knockdown versus mock-transduced ccRCC cells revealed down-regulation of endothelin 1, endothelin 2, cysteine-rich, angiogenic inducer, 61 (CYR61), and c-Myc in ccRCC cells as well as up-regulation of the cell adhesion molecule cadherin 6. Signaling pathway impact analysis revealed activation of the p53 signaling and cell cycle pathways as well as inhibition of mitogen-activated protein kinase signaling on YAP down-regulation. Our data suggest CYR61 and c-Myc as well as signaling through the endothelin axis as bona fide downstream effectors of YAP and establish aberrant Hippo signaling as a potential therapeutic target in ccRCC., (Copyright © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. All rights reserved.)

Aims: Pancreatic ductal adenocarcinomas (PDACs) are chemoresistant, resulting in extremely poor survival of patients; therefore, novel molecular targets, even in small subsets of genetically characterized tumours, are urgently needed. Tyrosine kinase receptor inhibitors (TKIs) are already in clinical use. The aims of this study were to examine the gene copy number and expression of fibroblast growth factor receptor 1 (FGFR1) in 155 patients with PDAC, and investigate the effects of the FGFR-specific inhibitor BGJ398 on FGFR1-amplified pancreatic tumour cells in vitro., Methods and Results: Fluorescence in-situ hybridization (FISH) and immunohistochemical analysis of 155 PDACs were performed using tissue microarrays. Amplification of FGFR1 was found in 2.6% (4/155) of cases. Four per cent of tumours (5/125) were shown to express FGFR1 by immunohistochemistry. Sequence analysis demonstrated an activating KRAS mutation (exon 2) in all FGFR1-amplified cases. The FGFR1-amplified pancreatic carcinoma cell line PT45P1 showed high levels of FGFR1 mRNA and protein expression. Proliferation of this cell line can be inhibited using the FGFR1 inhibitor BGJ398., Conclusions: FGFR1 represents a potential new therapeutic target in a subset of patients harbouring FGFR1-amplified tumours. Identification of pancreatic cancers harbouring FGFR1 amplification may be important in preselecting patients and/or interpreting clinical studies using TKIs., (© 2013 John Wiley & Sons Ltd.)

Introduction: Pancreatic neuroendocrine tumors (PNET) represent the second most common primary malignancy of the pancreas. Until recently, therapeutic options for advanced PNET have been limited., Areas Covered: A recently published Phase III clinical trial demonstrated striking therapeutic activity of the mTOR inhibitor everolimus in advanced PNET and led to its approval for this indication by the FDA. This review discusses this landmark discovery in the context of currently available therapeutic options, pathophysiology and molecular genetics of PNET., Expert Opinion: The approval of everolimus for the treatment of PNET marks a major step forward in the clinical management of this disease and represents a notable example of the successful translation of a targeted therapy that was initially developed based on findings at the lab bench, into everyday clinical practice. These results encourage hopes that the overall therapeutic efficacy of such approaches can be further enhanced by the introduction of combinatorial regimens, simultaneously targeting more than one oncogenic signaling pathway, as well as by stratification of patients based on the individual genetic setup of their tumors.

Importance of the Field: Pancreatic cancer is a devastating disease associated with near uniform mortality. Usually diagnosed at advanced, metastatic stages when surgical resection with curative intention is not possible any more, most patients succumb to progressive disease after a few months. Despite recent advances in understanding pancreatic carcinogenesis and continuous efforts in translational research, so far these results failed to translate into clinically relevant improvements of patient survival., Areas Covered in This Review: Preclinical evaluation of drug candidates and novel therapeutic strategies rely on in vitro and in vivo model systems to predict response in patients. This article reviews mouse models of pancreatic cancer, their respective applications in translational research and discusses their potential to predict clinical responses in patients., What the Reader Will Gain: This article provides a profound overview of individual strength as well as of shortcomings of mouse models of pancreatic cancer currently available for translational research., Take Home Message: Considerable progress in designing mouse models of pancreatic cancer has been made over the last decade and several xenograft as well as genetically engineered mouse models faithfully recapitulating human disease development has been developed. Taken together, these newly developed in vivo model systems provide powerful tools likely to boost preclinical evaluation and bench-to-bedside transition of novel therapeutic approaches directed against this dire malady.

This article presents an overview of the recently published first two parts of the Memorandum III "Methods for Health Services Research" discussed and approved by the member societies of the German Network Health Services Research [Deutsches Netzwerk Versorgungsforschung e.V.]. Part one of this memorandum covers methodical principles and minimum standards for the subject areas of health services research "Epidemiological Methods for Health Services Research", "Methods for Organisational Health Services Research" and "Methods for Quality of Life Research", the second part the topics "Methods of Health Economic Evaluation" and "Registries for the Health Services Research". The Memorandum is addressed to health services researchers and to reviewers who are planning, conducting, publishing studies as well as evaluating research proposals and publications. Assurance of quality and increase of the health services research are the aims of the Memorandum III. According to the advanced knowledge in health services research the Memorandum needs regular updates. Therefore the Memorandum has to be understood as "work in progress".

To determine whether different racial groups shared common types of vaginal microbiota, we characterized the composition and structure of vaginal bacterial communities in asymptomatic and apparently healthy Japanese women in Tokyo, Japan, and compared them with those of White and Black women from North America. The composition of vaginal communities was compared based on community profiles of terminal restriction fragments of 16S rRNA genes and phylogenetic analysis of cloned 16S rRNA gene sequences of the numerically dominant bacterial populations. The types of vaginal communities found in Japanese women were similar to those of Black and White women. As with White and Black women, most vaginal communities were dominated by lactobacilli, and only four species of Lactobacillus (Lactobacillus iners, Lactobacillus crispatus, Lactobacillus jensenii, and Lactobacillus gasseri) were commonly found. Communities dominated by multiple species of lactobacilli were common in Japanese and White women, but rare in Black women. The incidence, in Japanese women, of vaginal communities with several non-Lactobacillus species at moderately high frequencies was intermediate between Black women and White women. The limited number of community types found among women in different ethnic groups suggests that host genetic factors, including the innate and adaptive immune systems, may be more important in determining the species composition of vaginal bacterial communities than are cultural and behavioral differences.

Highly immunogenic cancers such as malignant melanoma are capable of inexorable tumor growth despite the presence of antitumor immunity. Thus, only a restricted minority of tumorigenic malignant cells may possess the phenotypic and functional characteristics needed to modulate tumor-directed immune activation. Here we provide evidence supporting this hypothesis. Tumorigenic ABCB5(+) malignant melanoma initiating cells (MMICs) possessed the capacity to preferentially inhibit IL-2-dependent T-cell activation and to support, in a B7.2-dependent manner, induction of CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs). Compared with melanoma bulk cell populations, ABCB5(+) MMICs displayed lower levels of MHC class I, aberrant positivity for MHC class II, and lower expression levels of the melanoma-associated antigens MART-1, ML-IAP, NY-ESO-1, and MAGE-A. Additionally, these tumorigenic ABCB5(+) subpopulations preferentially expressed the costimulatory molecules B7.2 and PD-1, both in established melanoma xenografts and in clinical tumor specimens. In immune activation assays, MMICs inhibited mitogen-dependent human peripheral blood mononuclear cell (PBMC) proliferation and IL-2 production more efficiently than ABCB5(-) melanoma cell populations. Moreover, coculture with ABCB5(+) MMICs increased the abundance of Tregs, in a B7.2 signaling-dependent manner, along with IL-10 production by mitogen-activated PBMCs. Consistent with these findings, MMICs also preferentially inhibited IL-2 production and induced IL-10 secretion by cocultured patient-derived, syngeneic PBMCs. Our findings identify novel T-cell modulatory functions of ABCB5(+) melanoma subpopulations and suggest specific roles for these MMICs in the evasion of antitumor immunity and in cancer immunotherapeutic resistance.

NIGELLA SATIVA L. has many effects including those on the gastrointestinal tract and trachea and is, therefore, used in the Mediteranean area and in India/Pakistan. Our aim was to investigate the effect of two main constituents, nigellone and thymoquinone, on trachea (antispasmodic effect) and their influence on respiratory clearance. The effects on Ba (2+)-, carbachol- and leukotriene-induced trachea contractions and the transport of the fluorescence dye rhodamin B concerning ciliary action in the tracheal area were investigated using a microdialysis technique. Nigellone and high concentrations of thymoquinone had a concentration-dependent inhibitory effect on the trachea when being contracted by the depolarizing effect of Ba (2+). The trachea contractions induced by leukotriene-d (4) were inhibited by nigellone and by thymoquinone. The cholinergic system (stimulation by carbachol) was hardly involved. The rate of ciliary clearance (mucociliary transport) was slightly modified by a high thymoquinone concentration (153.0 vs. 505.0 sec/12 mm distance, respectively), and was highly increased by nigellone (217.5 vs. 505.0 sec/12 mm distance). In conclusion, this study provides evidence for an antispasmodic effect and an increase in mucociliary clearance for nigellone but not for thymoquinone. Altogether the data indicate that nigellone but not thymoquinone may be useful in treatment of different respiratory diseases.

Background: Within the last years, health services research has gained increasing attention in Germany. This trend could also be observed in dentistry although this research field must be considered rather young. The methodical approach of health services research is complementary to the traditional clinical research paradigm. The latter focuses on the comprehension of causal mechanisms and the efficacy of interventions under ideal and standardized study conditions. In contrast to that, health services research focuses on the effectiveness under everyday conditions and the efficacy in the normal course of medical care., Research Projects: In the field of dentistry, various investigations exist that belong to that area of research in a broader sense. Articles in professional dental journals deal increasingly with topics related to health services research. Political discussions look in that subject more frequently. Concrete results, however, are rare and limited to selected aspects. At the beginning of 2005, the reimbursement policy of the German health insurance funds relative to prosthetic treatment changed completely. The resulting consequences are unknown and unexplored. Dramatic changes are to be expected. This clearly exemplifies the significance of scientific evaluations when changing key aspects of daily health care., Summary and Outlook: Hence it can be said that dental health services research in Germany is not sufficiently established yet. It can be assumed that the cumulating problems to be expected within the health care system will lead to an increasing demand for the respective research.

Since 2001, an interdisciplinary project on multimedia education in medicine has been sponsored by the Federal Ministry of Education and Research at the Charité. One part of the project is on dentistry. In the light of the results of a survey of dental students, an Internet-based education management system was created using open-source back-end systems. It supports four didactic levels for editing documentation of patient treatments. Each level corresponds to the learning abilities of the students. The patient documentation is organized to simulate the working methods of a physician or dentist. The system was tested for the first time by students in the summer semester of 2003 and has been used since the winter semester of 2003 as part of the curriculum.

When fresh blood is not available as a control in stain investigations extracted teeth, hair, preserved tissue samples, histological slides, cigarette butts or used stamps can also be used. This paper reports on a stain investigation performed 7 months after the death of the victim, where a bedside card from the medical records was successfully employed as a control blood sample. In a series of 10 bedside cards up to 9 years old, the investigation with the PCR method showed recognizable patterns in the STR systems SE 33 and TC 11. Matching patterns could be found from the 4 sections of each card (anti A, anti B, anti AB and anti D). A comparison of the oldest card with a fresh blood sample of the patient also showed matching patterns. AMPFLPs were successful with more recent cards. Using the PCR method typing of bedside cards from medical records up to 10 years old can be used in stain investigations.

A modification to the DNA extraction method "preferential lysis" (Gill et al. 1985) is proposed which can be applied to DNA mixtures of vaginal cells and spermatozoa. In mixtures with a low sperm content the further loss of sperm DNA caused by the extraction can be avoided by using "mild preferential lysis". Amplification by PCR (polymerase chain reaction) then yields sufficient DNA to be able to identify both components in the mixture.

The occurrence of unusual band patterns in the protein systems Gc, F XIII B and PLG is described. During the routine investigation of these systems in paternity, identity and criminal cases, several examples of alterations or additions to the normal band patterns have been observed. This was particularly noticeable in post mortem samples, stored liquid blood samples and blood stains. A connection between alterations in the form due to charge changes and changes to the isoelectric point from ageing of blood samples is demonstrated.