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Tubulin-binding agents such as taxol, vincristine or vinblastine are well-established drugs in clinical treatment of metastatic cancer. However, because of their highly complex chemical structures, the synthesis and hence the supply issues are still quite challenging. Here we set on stage pretubulysin, a chemically accessible precursor of tubulysin that was identified as a potent microtubule-binding agent produced by myxobacteria. Although much simpler in chemical structure, pretubulysin abrogates proliferation and long-term survival as well as anchorage-independent growth, and also induces anoikis and apoptosis in invasive tumor cells equally potent to tubulysin. Moreover, pretubulysin posseses in vivo efficacy shown in a chicken chorioallantoic membrane (CAM) model with T24 bladder tumor cells, in a mouse xenograft model using MDA-MB-231 mammary cancer cells and finally in a model of lung metastasis induced by 4T1 mouse breast cancer cells. Pretubulysin induces cell death via the intrinsic apoptosis pathway by abrogating the expression of pivotal antiapoptotic proteins, namely Mcl-1 and Bcl-xL, and shows distinct chemosensitizing properties in combination with TRAIL in two- and three-dimensional cell culture models. Unraveling the underlying signaling pathways provides novel information: pretubulysin induces proteasomal degradation of Mcl-1 by activation of mitogen-activated protein kinase (especially JNK (c-Jun N-terminal kinase)) and phosphorylation of Mcl-1, which is then targeted by the SCF(Fbw7) E3 ubiquitin ligase complex for ubiquitination and degradation. In sum, we designate the microtubule-destabilizing compound pretubulysin as a highly promising novel agent for mono treatment and combinatory treatment of invasive cancer.
Background: The current taxonomy of the African giraffe (Giraffa camelopardalis) is primarily based on pelage pattern and geographic distribution, and nine subspecies are currently recognized. Although genetic studies have been conducted, their resolution is low, mainly due to limited sampling. Detailed knowledge about the genetic variation and phylogeography of the South African giraffe (G. c. giraffa) and the Angolan giraffe (G. c. angolensis) is lacking. We investigate genetic variation among giraffe matrilines by increased sampling, with a focus on giraffe key areas in southern Africa.
Results: The 1,562 nucleotides long mitochondrial DNA dataset (cytochrome b and partial control region) comprises 138 parsimony informative sites among 161 giraffe individuals from eight populations. We additionally included two okapis as an outgroup. The analyses of the maternally inherited sequences reveal a deep divergence between northern and southern giraffe populations in Africa, and a general pattern of distinct matrilineal clades corresponding to their geographic distribution. Divergence time estimates among giraffe populations place the deepest splits at several hundred thousand years ago.
Conclusions: Our increased sampling in southern Africa suggests that the distribution ranges of the Angolan and South African giraffe need to be redefined. Knowledge about the phylogeography and genetic variation of these two maternal lineages is crucial for the development of appropriate management strategies.
Hereditary angioedema (HAE) is a disease which is associated with random and often unpredictable attacks of painful swelling typically affecting the extremities, bowel mucosa, genitals, face and upper airway. Attacks are associated with significant functional impairment, decreased Health Related Quality of Life, and mortality in the case of laryngeal attacks. Caring for patients with HAE can be challenging due to the complexity of this disease. The care of patients with HAE in Canada is neither optimal nor uniform across the country. It lags behind other countries where there are more organized models for HAE management, and where additional therapeutic options are licensed and available for use. The objective of this guideline is to provide graded recommendations for the management of patients in Canada with HAE. This includes the treatment of attacks, short-term prophylaxis, long-term prophylaxis, and recommendations for self-administration, individualized therapy, quality of life, and comprehensive care. It is anticipated that by providing this guideline to caregivers, policy makers, patients and their advocates, that there will be an improved understanding of the current recommendations regarding management of HAE and the factors that need to be considered when choosing therapies and treatment plans for individual patients. The primary target users of this guideline are healthcare providers who are managing patients with HAE. Other healthcare providers who may use this guideline are emergency physicians, gastroenterologists, dentists and otolaryngologists, who will encounter patients with HAE and need to be aware of this condition. Hospital administrators, insurers and policy makers may also find this guideline helpful.
Jetzt, nach Beendigung vieler Jahre der Lehre und Forschung an der Goethe-Universität, kann ich diese Zeit mit einem Abstand überdenken. Der Freiraum für solch nicht zweckgerichtetes Verhalten ist während der praktischen Tätigkeit an der Universität äußerst gering und muss hart erkämpft werden, wie jedes Stück Freiheit. Rückblickend sehe ich, dass der Wunsch, über das Detailwissen hinaus ganzheitliche Zusammenhänge zu betrachten und über die eigene Fachgrenze hinauszugehen, meinen Weg geprägt hat.
Symbiotic nitrogen fixation (SNF) in root nodules of grain legumes such as chickpea is a highly complex process that drastically affects the gene expression patterns of both the prokaryotic as well as eukaryotic interacting cells. A successfully established symbiotic relationship requires mutual signaling mechanisms and a continuous adaptation of the metabolism of the involved cells to varying environmental conditions. Although some of these processes are well understood today many of the molecular mechanisms underlying SNF, especially in chickpea, remain unclear. Here, we reannotated our previously published transcriptome data generated by deepSuperSAGE (Serial Analysis of Gene Expression) to the recently published draft genome of chickpea to assess the root- and nodule-specific transcriptomes of the eukaryotic host cells. The identified gene expression patterns comprise up to 71 significantly differentially expressed genes and the expression of twenty of these was validated by quantitative real-time PCR with the tissues from five independent biological replicates. Many of the differentially expressed transcripts were found to encode proteins implicated in sugar metabolism, antioxidant defense as well as biotic and abiotic stress responses of the host cells, and some of them were already known to contribute to SNF in other legumes. The differentially expressed genes identified in this study represent candidates that can be used for further characterization of the complex molecular mechanisms underlying SNF in chickpea.