TGF-beta signaling in onset and progression of hepatocellular carcinoma

Transforming growth factor (TGF)-beta is a central regulator in chronic liver disease, contributing to all stages of disease progression from initial liver injury through inflammation and fibrosis to cirrhosis and hepatocellular carcinoma. Liver damage-induced levels of active TGF-beta enhance hepatocyte destruction and mediate hepatic stellate cell and fibroblast activation resulting in a wound-healing response, including myofibroblast generation and extracellular matrix deposition. Further evidence points to a decisive role of cytostatic and apoptotic functions mediated on hepatocytes, which is critical for the control of liver mass, with loss of TGF-beta activities resulting in hyperproliferative disorders and cancer. This concept is based on studies that describe a bipartite role of TGF-beta with tumor suppressor functions at early stages of liver damage and regeneration, whereas during cancer progression TGF-beta may turn from a tumor suppressor into a tumor promoter that exacerbates invasive and metastatic behavior. We have delineated this molecular switch of the pathway from cytostatic to tumor promoting in further detail and identify activation of survival signaling pathways in hepatocytes as a most critical requirement. Targeting the TGF-beta signaling pathway has been explored to inhibit liver disease progression. While interfering with TGF-beta signaling in various short-term animal models has demonstrated promising results, liver disease progression in humans is a process of decades with different phases in which TGF-beta or its targeting may have both beneficial and adverse outcomes. We emphasize that, in order to achieve therapeutic effects, targeting TGF-beta signaling in the right cell type at the right time is required. Copyright © 2012 S. Karger AG, Base

A Mixed-Method Analysis of Fatal Attacks on Police by Far-Right Extremists

Several recent high-profile homicides of police officers have brought increased attention to issues of far-right extremist violence in the United States. We still, however, know very little about why (and how) certain encounters between far-right extremists and police result in violence. To fill this research gap, we conduct a mixed-method analysis of far-right antipolice homicides based on quantitative and qualitative data from the U.S. Extremist Crime Database. We begin by categorizing cases based on key aspects of homicide storylines. We then comparatively analyze attributes of event precursor, transaction, and aftermath stages across four storyline categories. Finally, a case study is purposively selected to follow-up on each storyline category to better capture the nuances of fluid homicide processes. Our findings have important implications for identifying triggering events, escalation factors, and other situated sets of conditions and circumstances that contribute to deadly outcomes for police officers

Ariel - Volume 2 Number 6

Editors Richard J. Bonanno Robin A. Edwards Associate Editors Steven Ager Stephen Flynn Shep Dickman Tom Williams Lay-out Editor Eugenia Miller Contributing Editors Michael J. Blecker W. Cherry Light James J. Nocon Lynne Porter Editors Emeritus Delvyn C. Case, Jr. Paul M. Fernhof

Редкие металлы в космической технике

В данной статье рассматривается применение редких металлов в космической технологии. Такжев статье описана классификация редких металлов, уникальные свойства и место каждой группыэлементов в конструировании комических аппаратов.Im vorliegenden Artikel wird die Verwendung von seltenen Metallen in der Raumfahrttechnik betrachtet.Der Artikel beschreibt auch die Klassifizierung von seltenen Metallen, die unikalen Eigenschaften jeder Gruppe undderen Funktion bei der Konstruktion von kosmischen Geräten

CD133 expression in cancer cells predicts poor prognosis of non-mucin producing intrahepatic cholangiocarcinoma

Background; CD133 is a marker of stem cells as well cancer stem cells. This study investigated the association between CD133 expression in cancer cells and the clinical outcome of non-mucin producing intrahepatic cholangiocarcinoma (ICC). Methods: Fifty-seven non-mucin producing ICC patients were enrolled in this study. Immunohistochemistry (IHC) and immunofluorescence staining for CD133 as well as other cancer-associated proteins, including cytokeratin 19, TGF-β1, p-Smad2 and epithelial–mesenchymal transition (EMT) markers S100A4, E-Cadherin and Vimentin were analyzed. Results: IHC staining showed that tumor cells in 52.6% of patients expressed CD133. The CD133+ patients had significantly higher metastasis rate than those without CD133+ tumor cells (36.7% vs. 10.1%, p = 0.03). The CD133+ patients had shorter overall and disease-free survival time as compared to the CD133− patients. Furthermore, 90.9% of CD133+ patients developed cancer recurrence, as compared to 64.3% of CD133− patients (p = 0.02). As compared to CD133− patients, tumor cells in CD133+ patients demonstrated high levels of TGF-β/p-Smad2 as well as EMT-like alteration, characterized by loss of E-Cadherin and expression of Vimentin and S100A4. Conclusions: CD133 expression in ICC tumor cells indicates poor prognosis of the disease and might be associated with TGF-β related EMT alterations

Caveolin-1 in the regulation of cell metabolism: a cancer perspective

Caveolin-1 (CAV1) is an oncogenic membrane protein associated with endocytosis, extracellular matrix organisation, cholesterol distribution, cell migration and signaling. Recent studies reveal that CAV1 is involved in metabolic alterations – a critical strategy adopted by cancer cells to their survival advantage. Consequently, research findings suggest that CAV1, which is altered in several cancer types, influences tumour development or progression by controlling metabolism. Understanding the molecular interplay between CAV1 and metabolism could help uncover druggable metabolic targets or pathways of clinical relevance in cancer therapy. Here we review from a cancer perspective, the findings that CAV1 modulates cell metabolism with a focus on glycolysis, mitochondrial bioenergetics, glutaminolysis, fatty acid metabolism, and autophagy

TGF-β1 As Possible Link between Loss of Bone Mineral Density and Chronic Inflammation

and their possible role in bone homeostasis in primary human osteoblasts. application.

Non-Invasive Raman Tomographic Imaging of Canine Bone Tissue

Raman spectroscopic diffuse tomographic imaging has been demonstrated for the first time. It provides a noninvasive, label-free modality to image the chemical composition of human and animal tissue and other turbid media. This technique has been applied to image the composition of bone tissue within an intact section of a canine limb. Spatially distributed 785-nm laser excitation was employed to prevent thermal damage to the tissue. Diffuse emission tomography reconstruction was used, and the location that was recovered has been confirmed by micro-computed tomography (micro-CT) images. With recent advances, diffuse tomography shows promise for in vivo clinical imaging.1, 2 In principle, algorithms developed for fluorescence imaging in tissue can be applied to Raman signals. Although the Raman effect is weaker than fluorescence, the scattered signal is detectable, and thus tomography is achievable. Here we demonstrate the first diffuse tomography reconstructions based on Raman scatter. Raman mapping and imaging are well-established techniques for examining material surfaces.3 Subsurface mapping of simple planar objects was reported recently4, 5 using fiber optic probes with spatially separated injection and collection fibers.6 Noninvasive measurements of bone Raman spectra were demonstrated at depths of5mm role= presentation \u3e5mm below the skin.5 Bone is promising for Raman tomography because the spectra are rich in compositional information,7 which reflects bone maturity and health. Spectroscopically measured bone composition changes have been correlated with aging8 and susceptibility to osteoporotic fracture.9 The Raman spectrum of bone mineral is easily distinguished from the spectra of proteins and other organic tissue constituents, facilitating recovery of even weak signals by multivariate techniques. Assessments of bone quantity and quality are essential to detect and monitor fracture risk and fracture healing with disease or injury. Common sites for fracture with osteoporosis are the spine, proximal femur, and distal radius. Stress fractures are most frequently seen in the weight-bearing sites of the tibia and metatarsals. Fracture risk depends on bone geometry, architecture, and material properties, as well as the nature of applied load (magnitude, rate, and direction). As a result, noninvasive imaging and nondestructive analysis methods have been developed to assess many of these bone attributes that are increasingly important to clinical practice and basic research in orthopedics.10 Current clinical in vivo methods include dual-energy x-ray absorptiometry (DXA), quantitative computed tomography (QCT), magnetic resonance imaging (MRI), ultrasound, and most recently, high-resolution peripheral QCT. Ex vivo analyses of bone specimens from patients or animals have also utilized these and other techniques. In this study, we couple micro-computed tomography (micro-CT) and diffuse optical tomography with Raman spectroscopy to recover spatial and composition information from bone tissue ex vivo. We demonstrate the first reconstruction-based recovery of Raman signals through thick tissues to yield molecular information about subsurface bone tissue. Reconstructions from transcutaneous Raman measurements are challenging, because layers of skin, muscle, fat, and connective tissue lie over the bone sites of interest. These layers have different optical properties and thus variably scatter and polarize the injected light. We chose a canine model because of specimen availability and a bone size similar to human bone. We selected the tibia, a site that is clinically important and has relatively few overlying soft tissues. Measurements were made on the medial surface, where the only additional optical barrier is the crural extensor retinaculum ligament. The canine hind limb was harvested from an animal euthanized in an approved (UCUCA) University of Michigan study. The section of the limb distal to the knee was excised and scanned using in vivo micro-CT (eXplore Locus RS, GE Healthcare, Ontario, Canada). The tibia was scanned at80kV role= presentation \u3e80kV and 450μA role= presentation \u3e450μA with an exposure time of 100ms role= presentation \u3e100ms using a 360-deg scan technique. The image was reconstructed at a 93-μm role= presentation \u3e93-μm voxel resolution [Fig. 1a ]