Not So Fast: Cultivating miRs as Kinks in the Chain of the Cell Cycle.

In this issue of Cancer Cell, Hydbring and colleagues define a novel class of microRNAs (miRNAs), deemed cell-cycle-targeting miRNAs, that target several cyclins/CDKs, reduce tumor cell growth, and induce apoptosis. These miRNAs effectively suppressed chemoresistant patient-derived xenograft growth in vivo, and efficacy could be prospectively predicted with an expression-based algorithm

Hormone whodunit: clues for solving the case of intratumor androgen production.

One of the key mechanisms by which prostate cancer cells evade hormone therapy is through intratumor testosterone production. New evidence points toward androstenedione as a potential precursor of intratumor androgen production and furthers nomination of AKR1C3 as a therapeutic target in advanced disease. Clin Cancer Res; 20(21); 5343-5. ©2014 AACR

Marine Interglacial Deposits in the Cuxhaven Area, NW Germany: A Comparison of Holsteinian, Eemian and Holocene Foraminiferal Faunas

Es werden interglaziale Foraminiferen-Faunen aus dem Holstein, dem Eem und dem Holozän für den Raum Cuxhaven beschrieben. Bei den bearbeiteten Proben handelt es sich um Material aus Kernbohrungen. Die Vergesellschaftungen werden mit vorliegenden Publikationen entsprechender Vorkommen aus Nordwestdeutschland und Dänemark verglichen. Jede der 3 untersuchten Faunen hat typische Züge. Von besonderem Interesse ist die Tatsache, daß die Anwesenheit und/oder Häufigkeit bestimmter Taxa für das Gebiet der südlichen Nordsee stratigraphische Korrelationen ermöglicht.researc

The cyclin D1b splice variant: an old oncogene learns new tricks

The function of cyclin D1 as a positive regulator of the cell cycle and proto-oncogene has been well established. Cyclin D1 elicits its pro-proliferative function early in G1 phase, through its ability to activate cyclin dependent kinase (CDK) 4 or 6. Active CDK4/6-cyclin D1 complexes phosphorylate substrates that are critical for modulating G1 to S phase progression, and in this manner promote cellular proliferation. Emerging data from a number of model systems revealed that cyclin D1 also holds multiple, kinase-independent cellular functions. First, cyclin D1 assists in sequestering CDK inhibitors (e.g. p27(kip1)), thus bolstering late G1 CDK activity. Second, cyclin D1 is known to bind and modulate the action of several transcription factors that hold significance in human cancers. Thus, cyclin D1 impinges on several distinct pathways that govern cancer cell proliferation. Although intragenic somatic mutation of cyclin D1 in human disease is rare, cyclin D1 gene translocation, amplification and/or overexpression are frequent events in selected tumor types. Additionally, a polymorphism in the cyclin D1 locus that may affect splicing has been implicated in increased cancer risk or poor outcome. Recent functional analyses of an established cyclin D1 splice variant, cyclin D1b, revealed that the cyclin D1b isoform harbors unique activities in cancer cells. Here, we review the literature implicating cyclin D1b as a mediator of aberrant cellular proliferation in cancer. The differential roles of cyclin D1 and the cyclin D1b splice variant in prostate cancer will be also be addressed, wherein divergent functions have been linked to altered proliferative control

Passive exercise of the hind limbs after complete thoracic transection of the spinal cord promotes cortical reorganization.

Physical exercise promotes neural plasticity in the brain of healthy subjects and modulates pathophysiological neural plasticity after sensorimotor loss, but the mechanisms of this action are not fully understood. After spinal cord injury, cortical reorganization can be maximized by exercising the non-affected body or the residual functions of the affected body. However, exercise per se also produces systemic changes - such as increased cardiovascular fitness, improved circulation and neuroendocrine changes - that have a great impact on brain function and plasticity. It is therefore possible that passive exercise therapies typically applied below the level of the lesion in patients with spinal cord injury could put the brain in a more plastic state and promote cortical reorganization. To directly test this hypothesis, we applied passive hindlimb bike exercise after complete thoracic transection of the spinal cord in adult rats. Using western blot analysis, we found that the level of proteins associated with plasticity - specifically ADCY1 and BDNF - increased in the somatosensory cortex of transected animals that received passive bike exercise compared to transected animals that received sham exercise. Using electrophysiological techniques, we then verified that neurons in the deafferented hindlimb cortex increased their responsiveness to tactile stimuli delivered to the forelimb in transected animals that received passive bike exercise compared to transected animals that received sham exercise. Passive exercise below the level of the lesion, therefore, promotes cortical reorganization after spinal cord injury, uncovering a brain-body interaction that does not rely on intact sensorimotor pathways connecting the exercised body parts and the brain

Beyond DNA repair: DNA-PK function in cancer.

UNLABELLED: The DNA-dependent protein kinase (DNA-PK) is a pivotal component of the DNA repair machinery that governs the response to DNA damage, serving to maintain genome integrity. However, the DNA-PK kinase component was initially isolated with transcriptional complexes, and recent findings have illuminated the impact of DNA-PK-mediated transcriptional regulation on tumor progression and therapeutic response. DNA-PK expression has also been correlated with poor outcome in selected tumor types, further underscoring the importance of understanding its role in disease. Herein, the molecular and cellular consequences of DNA-PK are considered, with an eye toward discerning the rationale for therapeutic targeting of DNA-PK. SIGNIFICANCE: Although DNA-PK is classically considered a component of damage response, recent findings illuminate damage-independent functions of DNA-PK that affect multiple tumor-associated pathways and provide a rationale for the development of novel therapeutic strategies

Marine High Resolution Records of the Last Interglacial in Northwest Europe: A Review

The last Interglacial in Northwest Europe (the Eemian) corresponds to stable oxygen isotope substage 5e (ca. 130-115 ka BP). Foraminiferal studies from northern Denmark suggest that déglaciation after the Saalian Glacial (stage 6) occurred gradually over a period of about 3000 years. Data from borings on the island of Anholt show that the déglaciation was interrupted by a climatic fluctuation equivalent to the Allerod-Younger Dryas-Preboreal cycle at the Weichselian-Holocene transition (stage 2/1). The environmental interpretation of the foraminiferal data when compared to that of the deep sea stable isotope stratigraphy indicates that this climatic oscillation may have been a global event. An initial sea level rise of about 50-60 m occurred at the Saalian-Eemian transition (stage 6/5e at about 130 ka BP) and the assemblages indicate that the sea level rose further in the middle part of the Eemian prior to a gradual drop in sea level in the Late Eemian. The Eemian/ Weichselian boundary (stage 5e/5d at about 115 ka BP) was characterized by a major sea level drop and a temperature decrease from lusitanian to boreal conditions. The final change to fully glacial conditions did not occur until the Early-Middle Weichselian transition (stage 5/4 at about 74 ka BP).Le dernier interglaciaire dans le nord-ouest de l'Europe (l'Éémien) correspond au stade isotopique 5e (d'environ 130-115 ka BP). Les études sur les foramini-fères effectuées dans le nord du Danemark indiquent que la déglaciation s'est réalisée graduellement sur environ 3000 ans après le Saalien (stade 6). Les données obtenues des forages dans l'île de Anholt démontrent que la déglaciation a été interrompue par une fluctuation climatique correspondant au cycle Allerod-Dryas inférieur-Préboréal à la transition Wechselien-Holocène. L'interprétation environnementale des données sur les foraminifères comparée à la stratigraphie isotopique marine démontre que cette oscillation climatique était à l'échelle mondiale. La hausse initiale du niveau marin de 50 à 60 m a eu lieu à la transition entre le Saalien et l'Éémien (stade 6/5e vers 130 ka BP) et les assemblages montrent que la hausse s'est poursuivie à l'Éémien moyen avant une baisse graduelle à l'Éémien supérieur. Aux confins de l'Éémien-Weichselien (stade 5e/5d vers 115 ka BP), il y eut une importante baisse du niveau marin accompagnée d'une diminution des températures, passant ainsi de conditions climatiques lusitaniennes à des conditions boréales. L'établissement des conditions glaciaires ne s'est fait qu'à la transition entre le Weichselien inférieur et le Weichselien moyen (stade 5/4 vers 74 ka BP).Die letzte Interglazialzeit in Europa (Eem) ent-spricht dem stabilen Sauerstoff-lsotopen-Unterstadium 5e (vor rund 130,000-115,000 Jahren). Foraminiferen-Untersuchungen von Nord-Danemark deuten darauf hin, dass das Abschmelzen nach der Saale-Eiszeit (Stadium 6) allmàhlich ùber eine Période von ungefâhr 3000 Jahren erfolgte. Bohrdaten von der Insel Anholt zeigen, dass das Abschmelzen durch Klimaschwankungen àhnlich denen des Allerôd-Jungere Dryas-Prâboreal Zykluses zur Zeit des Weichsel-Holozân Ùberganges (Stadium 2/1) unter-brochen wurde. Korreliert man Foramini-feren-Befunde von Bohrungen auf Anholt mit isotopenstratigraphischen Daten aus der Tiefsee, ergibt sich, dass dièse Klimaschwankungen vermutlich von globalem Ausmass waren. Wàhrend des Saale-Eem Ùberganges (Stadium 6/5e vor rund 130,000 J.) stieg der Meeresspiegel zunàchst um 50-60 m. In der mittleren Eem-Zeit hob er sich môglicherweise erneut, bevor er im spâ-ten Eem allmàhlich zurùckging. Der Ùber-gang vom Eem zur Weichsel (Unterstadium 5e/5d vor rund 115,000 J.) war gekenn-zeichnet durch eine starke Senkung des Meeresspiegels bei einem gleichzeitigen Rùckgang der Temperatur von lusitanischen zu borealen Verhâltnissen. Der endgùltige Wechsel zu vollstândig eiszeitlichen Bedingungen erfolgte erst am Ùbergang von der Frùhen zur Mittleren Weichselôiszeit (Stadium 5/4 vor rund 74,000 J.)