S-phase checkpoints regulate Apo2 ligand/TRAIL and CPT-11-induced apoptosis of prostate cancer cells

As S-phase checkpoints play critical roles in maintaining genomic integrity and replicating the human genome correctly, understanding the molecular mechanism by which they regulate the therapeutic response is of great interest. Previously, we reported that the cytotoxic effect of a zinc-bound form of Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL), which is currently evaluated in clinical trials, in combination with low-dose CPT-11, induces apoptosis of C4-2 human prostate cancer cells and tissues. Here, we show that apoptosis, induced synergistically by this combination treatment, was associated with accumulation of cells in early S phase, indicated by cell cycle analyses, increased proliferating cell nuclear antigen, and Chk2-Thr(68) phosphorylation in tumors xenografted in mice. The combination treatment induced an S-phase checkpoint response through activation of Chk2 and Chk1 by the ataxia telangiectasia mutated and ataxia telangiectasia mutated and Rad3 related kinases, leading to phosphorylation and decreased Cdc25A levels. Cdc25A-dependent regulation of cyclin-dependent kinase 2 (Cdk2) and changes in association of p21(WAF1/CIP1) and hSpy1 with Cdk2 resulted in inhibition of Cdk2-associated kinase activity. Knockdown of ataxia telangiectasia mutated/Chk2 and ataxia telangiectasia mutated and Rad3 related/Chk1 by small inhibitory RNAs abrogated the S-phase checkpoint and accelerated apoptosis, resulting in caspase-3 activation and poly(ADP-ribose) polymerase 1 cleavage following combination treatment. Thus, Apo2L/TRAIL + CPT-11 treatment-induced apoptosis is regulated through an S-phase checkpoint controlled by the Chk2-Cdc25A and Chk1-Cdc25A pathways and inhibition of Cdk2-associated kinase activity. Low-dose CPT-11 and aphidicolin increased the proportion of S-phase cells and sensitized cells to Apo2L/TRAIL, by inducing phosphatidylserine externalization, caspase activation, and poly(ADP-ribose) polymerase 1 cleavage. Combinations with S-phase arrest-inducing chemotherapeutic drugs may represent promising avenues for clinical development of Apo2L/TRAIL.     

Intramedullary ependymoma associated with Lhermitte-Duclos disease and Cowden syndrome

The authors describe the case of a 45-year-old man with progressive gait ataxia and sensorimotor deficits of the upper and lower extremities. The patient had been diagnosed earlier with Lhermitte-Duclos disease (LDD) in the left cerebellar hemisphere and Cowden syndrome (CS). MR imaging studies revealed an intraspinal tumor at C6-C7. Microsurgical gross total resection of the tumor was achieved. Histolopathological examination revealed an intramedullary ependymoma. Postoperatively, neurological deficits gradually improved. This is the first reported case of ependymoma in a patient with LDD and CD. Coexistence of an intraspinal ependymoma with cerebellar LDD and CS appears to be rare, but can lead to treatment failure if missed.     

Ancient DNA, pig domestication, and the spread of the Neolithic into Europe

The Neolithic Revolution began 11,000 years ago in the Near East and preceded a westward migration into Europe of distinctive cultural groups and their agricultural economies, including domesticated animals and plants. Despite decades of research, no consensus has emerged about the extent of admixture between the indigenous and exotic populations or the degree to which the appearance of specific components of the "Neolithic cultural package" in Europe reflects truly independent development. Here, through the use of mitochondrial DNA from 323 modern and 221 ancient pig specimens sampled across western Eurasia, we demonstrate that domestic pigs of Near Eastern ancestry were definitely introduced into Europe during the Neolithic (potentially along two separate routes), reaching the Paris Basin by at least the early 4th millennium B.C. Local European wild boar were also domesticated by this time, possibly as a direct consequence of the introduction of Near Eastern domestic pigs. Once domesticated, European pigs rapidly replaced the introduced domestic pigs of Near Eastern origin throughout Europe. Domestic pigs formed a key component of the Neolithic Revolution, and this detailed genetic record of their origins reveals a complex set of interactions and processes during the spread of early farmers into Europe.     

Advanced glycation end products, oxidative stress and metalloproteinases are altered in the cerebral microvasculature during aging

Biological aging is associated with an increased incidence of cerebrovascular disease. Recent findings indicate that oxidative stress promoting age-related changes of cerebral circulation are involved in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease. The aim of this study was to evaluate the contribution of cerebral microvessels to the oxidative stress during brain aging, by: (i) assessment of precursors for advanced glycation end products (AGE) formation, (ii) activities of antioxidant enzymes, namely superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione disulfide reductase (GR), and (iii) the activities of metalloproteinases (MMPs), MMP-2 and MMP-9, involved in synaptogenesis and memory consolidation. The experiments were performed on two groups of male Wistar rats: 15 young (3-6 months old) and 15 aged (18-24 months old) animals. The cerebral microvessels were isolated by mechanical homogenization, the concentration of protein carbonyls and the activity of antioxidant enzymes were evaluated by spectrophotometry, and gelatin SDS-PAGE zymography was employed to evaluate MMP-2 and MMP-9 activities. The results showed that, by comparison with young rats, aged brain microvessels contain: (i) approximately 106 % increase of protein carbonyls production; (ii) approximately 68% higher GPx activity, unmodified activities of SOD and GR; (iii) approximately 30% diminishment in MMP-2 activity, and the specific occurrence of MMP-9 enzyme. The data suggest that the age-related changes of microvessels could increase the propensity for cerebral diseases and might represent, at least in part, a prerequisite for the deterioration of mental and physical status in the elderly.     

Respiratory biofeedback during CT-guided procedures

PURPOSE: Respiratory motion can be a complicating factor during image-guided interventions. The ability to reproduce breath-holds may facilitate safer needle-based procedures. The purpose of this study was to evaluate if respiratory biofeedback decreased variability among breath-holds and if the signals from the respiratory bellows belt can be used to measure target motion. MATERIALS AND METHODS: In phase 1 of the study, a respiratory bellows belt was applied to patients before image-guided interventional procedures. Belt stretch from respiratory motion was converted into voltage readings and displayed on a monitor as biofeedback. Patients were asked to perform inspiratory, expiratory, and midcycle breath-holds with and without the biofeedback. The variability in voltage readings between breath-holds with and without biofeedback was compared. In phase 2, the respiratory bellows belt was used during computed tomography (CT)-guided procedures with the patients blinded to the biofeedback. Voltage readings and CT series numbers were recorded as patients were asked to hold their breath during scans. The variability of CT z-axis targets was compared with the variability of voltage readings. RESULTS: A significant decrease in variability was found during expiratory breath-holds (P = .0083) with trends toward significance with midcycle and inspiratory breath-holds. A positive correlation (Kendall tau = 0.5; P = .024) was shown between CT z-axis and belt stretch variability in subjects who received smaller doses of moderate sedation compared with those who received larger doses or general anesthesia. CONCLUSIONS :Biofeedback may help the patient to have a more consistent breath-hold. The belt could decrease the error and unpredictability from craniocaudal motion of targets during image-guided interventions.     

Proof‐of‐concept evidence for trimodal simultaneous investigation of human brain function

The link between spatial (where) and temporal (when) aspects of the neural correlates of most psychological phenomena is not clear. Elucidation of this relation, which is crucial to fully understand human brain function, requires integration across multiple brain imaging modalities and cognitive tasks that reliably modulate the engagement of the brain systems of interest. By overcoming the methodological challenges posed by simultaneous recordings, the present report provides proof‐of‐concept evidence for a novel approach using three complementary imaging modalities: functional magnetic resonance imaging (fMRI), event‐related potentials (ERPs), and event‐related optical signals (EROS). Using the emotional oddball task, a paradigm that taps into both cognitive and affective aspects of processing, we show the feasibility of capturing converging and complementary measures of brain function that are not currently attainable using traditional unimodal or other multimodal approaches. This opens up unprecedented possibilities to clarify spatiotemporal integration of brain function.     

Interactions between proteins and platinum-containing anti-cancer drugs

Cisplatin and its congeners are well-known to exert their therapeutic effects on cancer via interaction with DNA in the cell nucleus. On the other hand, the undesirable side-effects of these drugs appear to also be linked, at least to some extent, to interaction of the platinum with proteins and peptides. For other classes of anticancer drugs, interaction with proteins is in fact the primary pathway whereby therapeutically-useful effects are achieved. Here, a review is given of the known instances of interaction of cisplatin and related compounds with proteins and biologically relevant peptides, with emphasis on structural and reactivity aspects.