Kinome-Wide Functional Genomics Screen Reveals a Novel Mechanism of TNFα-Induced Nuclear Accumulation of the HIF-1α Transcription Factor in Cancer Cells

Hypoxia-inducible factor-1 (HIF-1) and its most important subunit, HIF-1α, plays a central role in tumor progression by regulating genes involved in cancer cell survival, proliferation and metastasis. HIF-1α activity is associated with nuclear accumulation of the transcription factor and regulated by several mechanisms including modulation of protein stability and degradation. Among recent advances are the discoveries that inflammation-induced cytokines and growth factors affect protein accumulation of HIF-1α under normoxia conditions. TNFα, a major pro-inflammatory cytokine that promotes tumorigenesis is known as a stimulator of HIF-1α activity. To improve our understanding of TNFα-mediated regulation of HIF-1α nuclear accumulation we screened a kinase-specific siRNA library using a cell imaging–based HIF-1α-eGFP chimera reporter assay. Interestingly, this systematic analysis determined that depletion of kinases involved in conventional TNFα signaling (IKK/NFκB and JNK pathways) has no detrimental effect on HIF-1α accumulation. On the other hand, depletion of PRKAR2B, ADCK2, TRPM7, and TRIB2 significantly decreases the effect of TNFα on HIF-1α stability in osteosarcoma and prostate cancer cell lines. These newly discovered regulators conveyed their activity through a non-conventional RELB-depended NFκB signaling pathway and regulation of superoxide activity. Taken together our data allow us to conclude that TNFα uses a distinct and complex signaling mechanism to induce accumulation of HIF-1α in cancer cells. In summary, our results illuminate a novel mechanism through which cancer initiation and progression may be promoted by inflammatory cytokines, highlighting new potential avenues for fighting this disease

The Potential of microRNAs for Stem Cell-based Therapy for Degenerative Skeletal Diseases

Purpose of review: degenerative skeletal disorders including osteoarthritis (OA) and osteoporosis (OP) are the result of attenuation of tissue regeneration and lead to painful conditions with limited treatment options. Preventative measures to limit the onset of OA and OP remain a significant unmet clinical need. MicroRNAs (miRNAs) are known to be involved in the differentiation of stem cells, and in combination with stem cell therapy could induce skeletal regeneration and potentially prevent OA and OP onset.Recent findings: the combination of stem cells and miRNA has been successful at regenerating the bone and cartilage in vivo. MiRNAs, including miR-146b known to be involved in chondrogenic differentiation, could provide innovative targets for stem cell-based therapy, for the repair of articular cartilage defects forestalling the onset of OA or in the generation of a stem cell-based therapy for OP.Summary: this review discusses the combination of skeletal stem cells (SSCs) and candidate miRNAs for application in a cell-based therapy approach for skeletal regenerative medicine

Magmatism, serpentinization and life: Insights through drilling the Atlantis Massif (IODP Expedition 357)

IODP Expedition 357 used two seabed drills to core 17 shallow holes at 9 sites across Atlantis Massif ocean core complex (Mid-Atlantic Ridge 30°N). The goals of this expedition were to investigate serpentinization processes and microbial activity in the shallow subsurface of highly altered ultramafic and mafic sequences that have been uplifted to the seafloor along a major detachment fault zone. More than 57 m of core were recovered, with borehole penetration ranging from 1.3 to 16.4 meters below seafloor, and core recovery as high as 75% of total penetration in one borehole. The cores show highly heterogeneous rock types and alteration associated with changes in bulk rock chemistry that reflect multiple phases of magmatism, fluid-rock interaction and mass transfer within the detachment fault zone. Recovered ultramafic rocks are dominated by pervasively serpentinized harzburgite with intervals of serpentinized dunite and minor pyroxenite veins; gabbroic rocks occur as melt impregnations and veins. Dolerite intrusions and basaltic rocks represent the latest magmatic activity. The proportion of mafic rocks is volumetrically less than the amount of mafic rocks recovered previously by drilling the central dome of Atlantis Massif at IODP Site U1309. This suggests a different mode of melt accumulation in the mantle peridotites at the ridge-transform intersection and/or a tectonic transposition of rock types within a complex detachment fault zone. The cores revealed a high degree of serpentinization and metasomatic alteration dominated by talc-amphibole-chlorite overprinting. Metasomatism is most prevalent at contacts between ultramafic and mafic domains (gabbroic and/or doleritic intrusions) and points to channeled fluid flow and silica mobility during exhumation along the detachment fault. The presence of the mafic lenses within the serpentinites and their alteration to mechanically weak talc, serpentine and chlorite may also be critical in the development of the detachment fault zone and may aid in continued unroofing of the upper mantle peridotite/gabbro sequences. New technologies were also developed for the seabed drills to enable biogeochemical and microbiological characterization of the environment. An in situ sensor package and water sampling system recorded real-time variations in dissolved methane, oxygen, pH, oxidation reduction potential (Eh), and temperature and during drilling and sampled bottom water after drilling. Systematic excursions in these parameters together with elevated hydrogen and methane concentrations in post-drilling fluids provide evidence for active serpentinization at all sites. In addition, chemical tracers were delivered into the drilling fluids for contamination testing, and a borehole plug system was successfully deployed at some sites for future fluid sampling. A major achievement of IODP Expedition 357 was to obtain microbiological samples along a west–east profile, which will provide a better understanding of how microbial communities evolve as ultramafic and mafic rocks are altered and emplaced on the seafloor. Strict sampling handling protocols allowed for very low limits of microbial cell detection, and our results show that the Atlantis Massif subsurface contains a relatively low density of microbial life

Forward Modeling of Ground Penetrating Radar Data for a Horizontally Layered Earth

Introduction Ground Penetrating Radar (GPR) is often used in shallow subsurface investigation because of its ability to provide high resolution images from which detailed information may be extracted about the geology inhomogeneities. Apart from economic reasons, selection of survey parameters mainly depend on the electromagnetic properties of the area under investigation. Given the transmitting frequency, these material properties strongly influence the resolving power and depth of penetration of the emitted signals. A good indication of the diagnostic value of GPR for a variety of material properties can be obtained by performing a synthesis analysis by means of a forward electromagnetic modeling technique. For our study we select horizontally layered geological models as input for the modeling. Consequently, the highest resolving power for mapping of the interfaces is obtained by a dipole-dipole antenna configuration. Since we concentrate on the influence of material prope

There is a role for allografts in reconstructive surgery of the elbow and forearm

Purpose: Allografts play an important role in tendon, ligament, and bone reconstruction surgery, particularly when suitable available autologous tissue is limited. Enthusiasm for the use of allografts in reconstructive orthopedic surgery has increased over the past decade, with an increase in allograft use in a variety of procedures. The purpose of this review is to provide an overview of the various applications and indications for the use of allografts in reconstructive surgical procedures of the elbow and forearm. Methods: MEDLINE/PubMed was searched from 1990 through October 2018 for studies on tendon and bony allografts in elbow and forearm reconstructive surgery. Results: The Achilles tendon allograft is the most frequently used tendinous allograft, predominantly used in distal biceps and triceps reconstruction. Although reconstruction of the ulnar collateral ligament of the elbow is generally performed using autografts, it has been shown that semitendinosus and gracilis allografts may be equally effective. Extensor hallucis longus allografts are recommended for reconstruction of the lateral collateral ligaments in patients with posterolateral rotatory instability, and there may be a role for osteochondral allograft transplantation in capitellar osteochondral defects. In addition, the use of allografts in reconstruction of the interosseous membrane and various bone pathologies (fractures, bone tumors, forearm nonunions) has been described in current literature. Conclusion: There is a large variety of pathology and procedures involving the use of various types of allografts in orthopedic reconstructive surgery of the elbow and forearm