Decay Data Evaluation Project (DDEP): evaluation of the main 243Cm and 245Cm decay characteristics

The results of new decay data evaluations are presented for (243)Cm (α) decay to nuclear levels in (239)Pu and (245)Cm (α) decay to nuclear levels in (241)Pu. These evaluated data have been obtained within the Decay Data Evaluation Project using information published up to 2011.     

T3+ and T4 Rectal Cancer Patients Seem to Benefit From the Addition of Oxaliplatin to the Neoadjuvant Chemoradiation Regimen

Background

To achieve T-downstaging and better resectability in locally advanced rectal cancer, neoadjuvant radiochemotherapy (RCT) has become the current standard of treatment. A variety of schemes have been used. This study investigates which scheme had the best effect on these parameters.

Methods

Our institution is a referral center for locally advanced rectal cancer. Different neoadjuvant radiochemotherapy regimens were administered: long course radiotherapy (RTH), 5-FU and leucovorin (5FUBolus), a combination of capecitabine and oxaliplatin (CORE), and capecitabine only (CAP). Selection of patients for 1 of the regimens was based on hospital policy rather than patient or tumor characteristics.

Results

The data of 504 consecutive patients (n?=?181 T3+, n?=?323 T4) without metastatic disease (cM0) who underwent surgery for advanced rectal carcinoma between 1994 and 2010 were reviewed. The RTH, 5FUBolus, CORE, and CAP scheme were administered to 106, 137, 155, and 106 patients, respectively. Odds ratios for downstaging were less effective for RTH, 5FUBolus, and CAP (0.31, 0.44, and 0.31; P?P?=?.003) or CRM+ resection (3.78, 2.73, 1.34; P?=?.001) were also in favor of the CORE. Hazard ratios for CSS were significantly better for the CORE scheme.

Conclusions

Downstaging with neoadjuvant treatment results in an increased number of radical resections. In our study, the combination of capecitabine and oxaliplatin appears to be the most effective regimen for locally advanced rectal cancer tumors. However, longer follow-up will be necessary to confirm this conclusion.     

Hypertonic sodium lactate improves fluid balance and hemodynamics in porcine endotoxic shock

Introduction

Based on the potential interest in sodium lactate as an energy substrate and resuscitative fluid, we investigated the effects of hypertonic sodium lactate in a porcine endotoxic shock.

Methods

Fifteen anesthetized, mechanically ventilated pigs were challenged with intravenous infusion of E. coli endotoxin. Three groups of five animals were randomly assigned to receive 5 mL/kg/h of different fluids: a treatment group received hypertonic sodium lactate 11.2% (HSL group); an isotonic control group receiving 0.9% NaCl (NC group); a hypertonic control group with the same amount of osmoles and sodium than HSL group receiving hypertonic sodium bicarbonate 8.4% (HSB group). Hemodynamic and oxygenation variables, urine output and fluid balance were measured at baseline and at 30, 60, 120, 210 and 300 min. Skin microvascular blood flow at rest and during reactive hyperemia was obtained using a laser Doppler flowmetry technique. Results were given as median with interquartile ranges.

Results

Endotoxin infusion resulted in hypodynamic shock. At 300 min, hemodynamics and oxygenation were significantly enhanced in HSL group: mean arterial pressure (103 [81–120] mmHg vs. 49 [41–62] in NC group vs. 71 [60–78] in HSB group), cardiac index (1.6 [1.2–1.8] L/min/m² vs. 0.9 [0.5–1.1] in NC group vs. 1.3 [0.9–1.6] in HSB group) and partial pressure of oxygen (366 [308–392] mmHg vs. 166 [130–206] in NC group vs. 277 [189–303] in HSB group). At the same time, microvascular reactivity was significantly better in HSL group with a lower venoarterial CO₂ tension difference (5.5 [4–10] mmHg vs. 17 [14–25] in NC group vs. 14 [12–15] in HSB group). The cumulative fluid balance was lower in HSL group (-325 [-655; -150] mL) compared to NC (+560 [+230; +900] mL, p = 0.008) and HSB (+185 [-110; +645] mL, p = 0.03) groups.

Conclusions

In our hypodynamic model of endotoxic shock, infusion of hypertonic sodium lactate improves hemodynamic and microvascular reactivity with a negative fluid balance and a better oxygenation.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-014-0467-3) contains supplementary material, which is available to authorized users.     

CD34+ leukemic subpopulation predominantly displays lower spontaneous apoptosis and has higher expression levels of Bcl-2 and MDR1 genes than CD34− cells in childhood AML

In view of obscure clinical and biological significance of leukemic cells heterogeneity, we studied the efficacy of apoptosis, proliferation, and expression levels of the Bcl-2, MDR1, LRP, and BCRP genes in sorted CD34+ and CD34− subpopulations of childhood AML leukemic samples. In five out of nine cases, CD34+ cells were less sensitive to spontaneous apoptosis and had from 1.2- to 5.0-fold higher expression levels of Bcl-2 (eight of ten) and from 1.5- to 28.7-fold higher expression levels of MDR1 (eight of ten). The expression levels of the LRP gene were from 1.1- to 1.8-fold higher in CD34+ subpopulations (five of ten cases), and the expression levels of the BCRP gene were from 1.1- to 22.4-fold higher in CD34+ leukemic cells (six of ten). In all M4 cases, the expression levels of LRP were higher in the CD34− subpopulation. Significant differences in the patterns of genes expression between patients do not allow us to conclude that the CD34+ fractions have more resistant phenotype than the CD34− subpopulations. Nevertheless, distinctions between CD34+ and CD34− cells may lead to different chemosensitivities between leukemic subpopulations in vivo and may determine the alteration of the leukemic immunophenotype during treatment and in relapse.     

Therapeutic Interleukin-6 Trans-signaling Inhibition by Olamkicept (sgp130Fc) in Patients With Active Inflammatory Bowel Disease

1. Download : Download high-res image (358KB)
2. Download : Download full-size image

     

Systematic, genome-wide identification of host genes affecting replication of a positive-strand RNA virus

Positive-strand RNA viruses are the largest virus class and include many pathogens such as hepatitis C virus and the severe acute respiratory syndrome coronavirus (SARS). Brome mosaic virus (BMV) is a representative positive-strand RNA virus whose RNA replication, gene expression, and encapsidation have been reproduced in the yeast Saccharomyces cerevisiae. By using traditional yeast genetics, host genes have been identified that function in controlling BMV translation, selecting BMV RNAs as replication templates, activating the replication complex, maintaining a lipid composition required for membrane-associated RNA replication, and other steps. To more globally and systematically identify such host factors, we used engineered BMV derivatives to assay viral RNA replication in each strain of an ordered, genome-wide set of yeast single-gene deletion mutants. Each deletion strain was transformed to express BMV replicase proteins and a BMV RNA replication template with the capsid gene replaced by a luciferase reporter. Luciferase expression, which is dependent on viral RNA replication and RNA-dependent mRNA synthesis, was measured in intact yeast cells. Approximately 4500 yeast deletion strains ( approximately 80% of yeast genes) were screened in duplicate and selected strains analyzed further. This functional genomics approach revealed nearly 100 genes whose absence inhibited or stimulated BMV RNA replication and/or gene expression by 3- to >25-fold. Several of these genes were shown previously to function in BMV replication, validating the approach. Newly identified genes include some in RNA, protein, or membrane modification pathways and genes of unknown function. The results further illuminate virus and cell pathways. Further refinement of virus screening likely will reveal contributions from additional host genes.     

Transferrin-Coated Gadolinium Nanoparticles as MRI Contrast Agent

Purpose

In this study, the contrasting properties of human serum albumin nanoparticles (HSA-NPs) loaded with gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) and coated with transferrin in MRI in mice are evaluated.

Procedures

HSA-NPs were conjugated with Gd-DTPA (Gd-HSA-NPs) and coupled with transferrin (Gd-HSA-NP-Tf). Mice underwent MRI before or after injection of Gd-DTPA, Gd-HSA-NP, or Gd-HSA-NP-Tf.

Results

All the studied contrast agents provided a contrast enhancement (CE) in the blood, heart muscle, and liver. Compared to Gd-DTPA, CE with HSA-NP was achieved at lower Gd doses. Gd-HSA-NP-Tf yielded significantly higher CE than Gd-HSA-NP in the skeletal muscle, blood, cardiac muscle, and liver (p?<?0.05). Gd-HSA-NP-Tf achieved a significantly higher CE than Gd-HSA-NP and Gd-DTPA in the blood, cardiac muscle, and liver (p?<?0.05). In the brain, only Gd-HSA-NP-Tf was found to cause a significant CE (p?<?0.05).

Conclusions

The Gd-HSA nanoparticles have potential as MRI contrast agents. In particular, Gd-HSA-NP-Tf has a potential as a specific contrast agent for the brain, while the blood–brain barrier is still intact, as well as in the heart, liver, and skeletal muscle.     

Amphetamine actions at the serotonin transporter rely on the availability of phosphatidylinositol-4,5-bisphosphate

Nerve functions require phosphatidylinositol-4,5-bisphosphate (PIP₂) that binds to ion channels, thereby controlling their gating. Channel properties are also attributed to serotonin transporters (SERTs); however, SERT regulation by PIP₂ has not been reported. SERTs control neurotransmission by removing serotonin from the extracellular space. An increase in extracellular serotonin results from transporter-mediated efflux triggered by amphetamine-like psychostimulants. Herein, we altered the abundance of PIP₂ by activating phospholipase-C (PLC), using a scavenging peptide, and inhibiting PIP₂-synthesis. We tested the effects of the verified scarcity of PIP₂ on amphetamine-triggered SERT functions in human cells. We observed an interaction between SERT and PIP₂ in pull-down assays. On decreased PIP₂ availability, amphetamine-evoked currents were markedly reduced compared with controls, as was amphetamine-induced efflux. Signaling downstream of PLC was excluded as a cause for these effects. A reduction of substrate efflux due to PLC activation was also found with recombinant noradrenaline transporters and in rat hippocampal slices. Transmitter uptake was not affected by PIP₂ reduction. Moreover, SERT was revealed to have a positively charged binding site for PIP₂. Mutation of the latter resulted in a loss of amphetamine-induced SERT-mediated efflux and currents, as well as a lack of PIP₂-dependent effects. Substrate uptake and surface expression were comparable between mutant and WT SERTs. These findings demonstrate that PIP₂ binding to monoamine transporters is a prerequisite for amphetamine actions without being a requirement for neurotransmitter uptake. These results open the way to target amphetamine-induced SERT-dependent actions independently of normal SERT function and thus to treat psychostimulant addiction.