A randomised trial evaluating Bevacizumab as adjuvant therapy following resection of AJCC stage IIB, IIC and III cutaneous melanoma : an update

At present, there are no standard therapies for the adjuvant treatment of malignant melanoma. Patients with primary tumours with a high-Breslow thickness (stages IIB and IIC) or with resected loco-regional nodal disease (stage III) are at high risk of developing metastasis and subsequent disease-related death. Given this, it is important that novel therapies are investigated in the adjuvant melanoma setting. Since angiogenesis is essential for primary tumour growth and the development of metastasis, anti-angiogenic agents are attractive potential therapeutic candidates for clinical trials in the adjuvant setting. Therefore, we initiated a phase II trial in resected high-risk cutaneous melanoma, assessing the efficacy of bevacizumab versus observation. In the interim safety data analysis, we demonstrate that bevacizumab is a safe therapy in the adjuvant melanoma setting with no apparent increase in the surgical complication rate after either primary tumour resection and/or loco-regional lymphadenectomy

A role for TSPO in mitochondrial Ca2+ homeostasis and redox stress signaling

The 18 kDa translocator protein TSPO localizes on the outer mitochondrial membrane (OMM). Systematically overexpressed at sites of neuroinflammation it is adopted as a biomarker of brain conditions. TSPO inhibits the autophagic removal of mitochondria by limiting PARK2-mediated mitochondrial ubiquitination via a peri-organelle accumulation of reactive oxygen species (ROS). Here we describe that TSPO deregulates mitochondrial Ca2+ signaling leading to a parallel increase in the cytosolic Ca2+ pools that activate the Ca2+-dependent NADPH oxidase (NOX) thereby increasing ROS. The inhibition of mitochondrial Ca2+ uptake by TSPO is a consequence of the phosphorylation of the voltage-dependent anion channel (VDAC1) by the protein kinase A (PKA), which is recruited to the mitochondria, in complex with the Acyl-CoA binding domain containing 3 (ACBD3). Notably, the neurotransmitter glutamate, which contributes neuronal toxicity in age-dependent conditions, triggers this TSPO-dependent mechanism of cell signaling leading to cellular demise. TSPO is therefore proposed as a novel OMM-based pathway to control intracellular Ca2+ dynamics and redox transients in neuronal cytotoxicity

Eccentric black hole-neutron star mergers: effects of black hole spin and equation of state

There is a high level of interest in black hole-neutron star binaries, not only because their mergers may be detected by gravitational wave observatories in the coming years, but also because of the possibility that they could explain a class of short duration gamma-ray bursts. We study black hole-neutron star mergers that occur with high eccentricity as may arise from dynamical capture in dense stellar regions such as nuclear or globular clusters. We perform general relativistic simulations of binaries with a range of impact parameters, three different initial black hole spins (zero, aligned and anti-aligned with the orbital angular momentum), and neutron stars with three different equations of state. We find a rich diversity across these parameters in the resulting gravitational wave signals and matter dynamics, which should also be reflected in the consequent electromagnetic emission. Before tidal disruption, the gravitational wave emission is significantly larger than perturbative predictions suggest for periapsis distances close to effective innermost stable separations, exhibiting features reflecting the zoom-whirl dynamics of the orbit there. Guided by the simulations, we develop a simple model for the change in orbital parameters of the binary during close encounters. Depending upon the initial parameters of the system, we find that mass transfer during non-merging close encounters can range from essentially zero to a sizable fraction of the initial neutron star mass. The same holds for the amount of material outside the black hole post-merger, and in some cases roughly half of this material is estimated to be unbound. We also see that non-merging close encounters generically excite large oscillations in the neutron star that are qualitatively consistent with f-modes.Comment: 19 pages, 13 figures, revised according to referee comment

Measured g factors and the tidal-wave description of transitional nuclei near A = 100

The transient-field technique has been used in both conventional kinematics and inverse kinematics to measure the g factors of the 2+ states in the stable even isotopes of Ru, Pd and Cd. The statistical precision of the g(2+) values has been significantly improved, allowing a critical comparison with the tidal-wave version of the cranking model recently proposed for transitional nuclei in this region.Comment: Accepted for publication in Physical Review C, April 201

Circular Single-Stranded DNA Virus (Microviridae: Gokushovirinae: Jodiemicrovirus) Associated with the Pathobiome of the Flat-Back Mud Crab, Eurypanopeus depressus

A single-stranded DNA (ssDNA) virus is presented from a metagenomic data set derived from Alphaproteobacteria-infected hepatopancreatic tissues of the crab Eurypanopeus depressus. The circular virus genome (4,768 bp) encodes 14 hypothetical proteins, some similar to other bacteriophages (Microviridae). Based on its relatedness to other Microviridae, this virus represents a member of a novel genus.Joyner Open Access Publishing Support Fun

Effects of Secondhand Smoke Exposure on the Health and Development of African American Premature Infants

Objective. To explore the effects of secondhand smoke exposure on growth, health-related illness, and child development in rural African American premature infants through 24 months corrected age. Method. 171 premature infants (72 boys, 99 girls) of African American mothers with a mean birthweight of 1114 grams. Mothers reported on household smoking and infant health at 2, 6, 12, 18, and 24 months corrected age. Infant growth was measured at 6, 12, 18, and 24 months, and developmental assessments were conducted at 12 and 24 months. Results. Thirty percent of infants were exposed to secondhand smoke within their first 2 years of life. Secondhand smoke exposure was associated with poorer growth of head circumference and the development of otitis media at 2 months corrected age. Height, weight, wheezing, and child development were not related to secondhand smoke exposure. Conclusion. Exposure to secondhand smoke may negatively impact health of rural African American premature infants. Interventions targeted at reducing exposure could potentially improve infant outcomes

: A Model System for Anti-Cancer Drug Discovery and Therapeutic Target Identification

The nematode Caenorhabditis elegans (C. elegans) offers a unique opportunity for biological and basic medical researches due to its genetic tractability and well-defined developmental lineage. It also provides an exceptional model for genetic, molecular, and cellular analysis of human disease-related genes. Recently, C. elegans has been used as an ideal model for the identification and functional analysis of drugs (or small-molecules) in vivo. In this review, we describe conserved oncogenic signaling pathways (Wnt, Notch, and Ras) and their potential roles in the development of cancer stem cells. During C. elegans germline development, these signaling pathways regulate multiple cellular processes such as germline stem cell niche specification, germline stem cell maintenance, and germ cell fate specification. Therefore, the aberrant regulations of these signaling pathways can cause either loss of germline stem cells or overproliferation of a specific cell type, resulting in sterility. This sterility phenotype allows us to identify drugs that can modulate the oncogenic signaling pathways directly or indirectly through a high-throughput screening. Current in vivo or in vitro screening methods are largely focused on the specific core signaling components. However, this phenotype-based screening will identify drugs that possibly target upstream or downstream of core signaling pathways as well as exclude toxic effects. Although phenotype-based drug screening is ideal, the identification of drug targets is a major challenge. We here introduce a new technique, called Drug Affinity Responsive Target Stability (DARTS). This innovative method is able to identify the target of the identified drug. Importantly, signaling pathways and their regulators in C. elegans are highly conserved in most vertebrates, including humans. Therefore, C. elegans will provide a great opportunity to identify therapeutic drugs and their targets, as well as to understand mechanisms underlying the formation of cancer

Total error shift patterns for daily CT on rails image-guided radiotherapy to the prostate bed

<p>Abstract</p> <p>Background</p> <p>To evaluate the daily total error shift patterns on post-prostatectomy patients undergoing image guided radiotherapy (IGRT) with a diagnostic quality computer tomography (CT) on rails system.</p> <p>Methods</p> <p>A total of 17 consecutive post-prostatectomy patients receiving adjuvant or salvage IMRT using CT-on-rails IGRT were analyzed. The prostate bed's daily total error shifts were evaluated for a total of 661 CT scans.</p> <p>Results</p> <p>In the right-left, cranial-caudal, and posterior-anterior directions, 11.5%, 9.2%, and 6.5% of the 661 scans required no position adjustments; 75.3%, 66.1%, and 56.8% required a shift of 1 - 5 mm; 11.5%, 20.9%, and 31.2% required a shift of 6 - 10 mm; and 1.7%, 3.8%, and 5.5% required a shift of more than 10 mm, respectively. There was evidence of correlation between the x and y, x and z, and y and z axes in 3, 3, and 3 of 17 patients, respectively. Univariate (ANOVA) analysis showed that the total error pattern was random in the x, y, and z axis for 10, 5, and 2 of 17 patients, respectively, and systematic for the rest. Multivariate (MANOVA) analysis showed that the (x,y), (x,z), (y,z), and (x, y, z) total error pattern was random in 5, 1, 1, and 1 of 17 patients, respectively, and systematic for the rest.</p> <p>Conclusions</p> <p>The overall daily total error shift pattern for these 17 patients simulated with an empty bladder, and treated with CT on rails IGRT was predominantly systematic. Despite this, the temporal vector trends showed complex behaviors and unpredictable changes in magnitude and direction. These findings highlight the importance of using daily IGRT in post-prostatectomy patients.</p