TLN-4601 suppresses growth and induces apoptosis of pancreatic carcinoma cells through inhibition of Ras-ERK MAPK signaling

Abstract Background TLN-4601 is a structurally novel farnesylated dibenzodiazepinone discovered using Thallion's proprietary DECIPHER® technology, a genomics and bioinformatics platform that predicts the chemical structures of secondary metabolites based on gene sequences obtained by scanning bacterial genomes. Our recent studies suggest that TLN-4601 inhibits the Ras-ERK MAPK pathway post Ras prenylation and prior to MEK activation. The Ras-ERK MAPK signaling pathway is a well-validated oncogenic cascade based on its central role in regulating the growth and survival of cells from a broad spectrum of human tumors. Furthermore, RAS isoforms are the most frequently mutated oncogenes, occurring in approximately 30% of all human cancers, and KRAS is the most commonly mutated RAS gene, with a greater than 90% incidence of mutation in pancreatic cancer. Results To evaluate whether TLN-4601 interferes with K-Ras signaling, we utilized human pancreatic epithelial cells and demonstrate that TLN-4601 treatment resulted in a dose- and time-dependent inhibition of Ras-ERK MAPK signaling. The compound also reduced Ras-GTP levels and induced apoptosis. Finally, treatment of MIA PaCa-2 tumor-bearing mice with TLN-4601 resulted in antitumor activity and decreased tumor Raf-1 protein levels. Conclusion These data, together with phase I/II clinical data showing tolerability of TLN-4601, support conducting a clinical trial in advanced pancreatic cancer patients

Seeds of good anthropocenes: developing sustainability scenarios for Northern Europe

Scenario development helps people think about a broad variety of possible futures; however, the global environmental change community has thus far developed few positive scenarios for the future of the planet and humanity. Those that have been developed tend to focus on the role of a few common, large-scale external drivers, such as technology or environmental policy, even though pathways of positive change are often driven by surprising or bottom-up initiatives that most scenarios assume are unchanging. We describe an approach, pioneered in Southern Africa and tested here in a new context in Northern Europe, to developing scenarios using existing bottom-up transformative initiatives to examine plausible transitions towards positive, sustainable futures. By starting from existing, but marginal initiatives, as well as current trends, we were able to identify system characteristics that may play a key role in sustainability transitions (e.g., gender issues, inequity, governance, behavioral change) that are currently under-explored in global environmental scenarios. We suggest that this approach could be applied in other places to experiment further with the methodology and its potential applications, and to explore what transitions to desirables futures might be like in different places

Anosmin-1 contributes to brain tumor malignancy through integrin signal pathways

Anosmin-1, encoded by the KAL1 gene, is an extracellular matrix (ECM)-associated protein which plays essential roles in the establishment of olfactory and GNRH neurons during early brain development. Loss-of-function mutations of KAL1 results in Kallmann syndrome with delayed puberty and anosmia. There is, however, little comprehension of its role in the developed brain. As reactivation of developmental signal pathways often takes part in tumorigenesis, we investigated if anosmin-1-mediated cellular mechanisms associated with brain tumors. Our meta-analysis of gene expression profiles of patients' samples and public microarray datasets indicated that KAL1 mRNA was significantly upregulated in high-grade primary brain tumors compared with the normal brain and low-grade tumors. The tumor-promoting capacity of anosmin-1 was demonstrated in the glioblastoma cell lines, where anosmin-1 enhanced cell motility and proliferation. Notably, anosmin-1 formed a part of active β1 integrin complex, inducing downstream signaling pathways. ShRNA-mediated knockdown of anosmin-1 attenuated motility and growth of tumor cells and induced apoptosis. Anosmin-1 may also enhance the invasion of tumor cells within the ECM by modulating cell adhesion and activating extracellular proteases. In a mouse xenograft model, anosmin-1-expressing tumors grew faster, indicating the role of anosmin-1 in tumor microenvironment in vivo. Combined, these data suggest that anosmin-1 can facilitate tumor cell proliferation, migration, invasion, and survival. Therefore, although the normal function of anosmin-1 is required in the proper development of GNRH neurons, overexpression of anosmin-1 in the developed brain may be an underlying mechanism for some brain tumors

Opinion article: Neurosurgical treatment for neuro-ophthalmologic conditions

A significant role of the neuro-ophthalmologist is to counsel patients on appropriate management and anticipated visual prognosis for conditions affecting the afferent and efferent visual systems, including those requiring neurosurgical treatment. However, the literature regarding anticipated neuro- ophthalmologic prognosis after neurosurgical intervention for cerebral aneurysms, sellar lesions, optic pathway tumors, and elevated intracranial pressure is limited with many key questions unanswered. For example, if a cerebral aneurysm is equally amenable to clipping or endovascular coiling, is there a preferred approach in terms of visual prognosis based on aneurysm location? Is dural venous sinus stenting (VSS) for idiopathic intracranial hypertension (IIH) superior, equivalent or inferior to shunting in terms of visual recovery and safety profile? Landmark studies on pituitary tumors using pre-operative optical coherence tomography (OCT) imaging of the optic nerve head to predict visual recovery after surgical decompression of the optic chiasm have changed neuro-ophthalmologic practice and enabled patients to be better informed regarding expected visual outcomes. 1,2 In order to optimize an interdisciplinary team approach to patient care, further studies of visual outcomes for neuro- ophthalmologic conditions requiring neurosurgical intervention are needed

Géographie humaine et sociologie

Falardeau J.-C. Géographie humaine et sociologie. In: Revue de géographie jointe au Bulletin de la Société de géographie de Lyon et de la région lyonnaise, vol. 25, n°4, 1950. pp. 342-346

Vitreo-Retinal Traction and Anastrozole Use

Purpose—This study tested a prediction stemming from the hypothesis that anastrozole users experience heightened vitreo-retinal traction. This hypothesis was based on the knowledge that menopause increases the risk of intraocular tractional events such as posterior vitreous detachments (PVDs). Methods—Retinal thickness was measured for 3 groups of amenorrheic women: (1) anastrozole users and (2) tamoxifen users undergoing adjuvant therapy for early-stage breast cancer, and (3) control subjects not using hormonal medication. Foveal shape indices were derived for subjects without PVDs. Results—For anastrozole users, the distance to the temporal side of the fovea became less than the distance to the nasal side at a sufficient height above the foveal base. This effect did not exist for control subjects; the between-group difference was appreciable. Results concerning tamoxifen users were inconclusive. Conclusions—The foveas of women using anastrozole appear to be subjected to more tractional force than are the foveas of women not using any hormonal medication

Ecological and Mechanistic Insights Into the Direct and Indirect Antimicrobial Properties of Bacillus subtilis Lipopeptides on Plant Pathogens

Members of the genus Bacillus produce a wide variety of antimicrobial compounds. Cyclic lipopeptides (CLP) produced by Bacillus subtilis strains have been shown to protect host plants from a numbers of pathogens. The representative families of these CLP (surfactins, fengycins, and iturins) share a polypeptide ring linked to a lipid tail of varying length. CLP provide plant protection through a variety of unique mechanisms. Members of the surfactin and fengycin families elicit induced systemic resistance in certain host plants, and they also function by directly affecting the biological membranes of bacterial and fungal pathogens, mainly resulting in membrane pore formation. Specific pore forming mechanisms differ between CLP families, causing differential activities. CLP also may aid in enhanced B. subtilis colonization of the plant environment in addition to potentially preventing the adhesion of competitive microorganisms. Several recent studies have highlighted the control of plant pathogens by CLP-producing B. subtilis strains. Strong ecological advantages through multifaceted activities of CLP provide these strains with immense promise in controlling pathogens in a variety of plant ecosystems