Correlation of Atrial Natriuretic Peptide and Cyclic Guanosine Monophosphate Plasma Concentrations in Patients with Heart Disorders During Rest and Exercise

Peer Reviewe

Non-invasive monitoring of Streptococcus pyogenes vaccine efficacy using biophotonic imaging.

Streptococcus pyogenes infection of the nasopharynx represents a key step in the pathogenic cycle of this organism and a major focus for vaccine development, requiring robust models to facilitate the screening of potentially protective antigens. One antigen that may be an important target for vaccination is the chemokine protease, SpyCEP, which is cell surface-associated and plays a role in pathogenesis. Biophotonic imaging (BPI) can non-invasively characterize the spatial location and abundance of bioluminescent bacteria in vivo. We have developed a bioluminescent derivative of a pharyngeal S. pyogenes strain by transformation of an emm75 clinical isolate with the luxABCDE operon. Evaluation of isogenic recombinant strains in vitro and in vivo confirmed that bioluminescence conferred a growth deficit that manifests as a fitness cost during infection. Notwithstanding this, bioluminescence expression permitted non-invasive longitudinal quantitation of S. pyogenes within the murine nasopharynx albeit with a detection limit corresponding to approximately 10(5) bacterial colony forming units (CFU) in this region. Vaccination of mice with heat killed streptococci, or with SpyCEP led to a specific IgG response in the serum. BPI demonstrated that both vaccine candidates reduced S. pyogenes bioluminescence emission over the course of nasopharyngeal infection. The work suggests the potential for BPI to be used in the non-invasive longitudinal evaluation of potential S. pyogenes vaccines

FDG uptake is a surrogate marker for defining the optimal biological dose of the mTOR inhibitor everolimus in vivo

This study aimed to test whether [18F]fluoro-D-glucose (FDG) uptake of tumours measured by positron emission tomography (PET) can be used as surrogate marker to define the optimal biological dose (OBD) of mTOR inhibitors in vivo. Everolimus at 0.05, 0.5, 5 and 15 mg kg−1 per day was administered to gastric cancer xenograft-bearing mice for 23 days and FDG uptake of tumours was measured using PET from day 1 to day 8. To provide standard comparators for FDG uptake, tumour volume, S6 protein phosphorylation, Ki-67 staining and everolimus blood levels were evaluated. Everolimus blood levels increased in a dose-dependent manner but antitumour activity of everolimus reached a plateau at doses ⩾5 mg kg−1 per day (tumour volume treated vs control (T/C): 51% for 5 mg kg−1 per day and 57% for 15 mg kg−1 per day). Correspondingly, doses ⩾5 mg kg−1 per day led to a significant reduction in FDG uptake of tumours. Dose escalation above 5 mg kg−1 per day did not reduce FDG uptake any further (FDG uptake T/C: 49% for 5 mg kg−1 per day and 52% for 15 mg kg−1 per day). Differences in S6 protein phosphorylation and Ki-67 index reflected tumour volume and changes in FDG uptake but did not reach statistical significance. In conclusion, FDG uptake might serve as a surrogate marker for dose finding studies for mTOR inhibitors in (pre)clinical trials

Electromagnetic Treatment to Old Alzheimer's Mice Reverses β-Amyloid Deposition, Modifies Cerebral Blood Flow, and Provides Selected Cognitive Benefit

Few studies have investigated physiologic and cognitive effects of “long-term" electromagnetic field (EMF) exposure in humans or animals. Our recent studies have provided initial insight into the long-term impact of adulthood EMF exposure (GSM, pulsed/modulated, 918 MHz, 0.25–1.05 W/kg) by showing 6+ months of daily EMF treatment protects against or reverses cognitive impairment in Alzheimer's transgenic (Tg) mice, while even having cognitive benefit to normal mice. Mechanistically, EMF-induced cognitive benefits involve suppression of brain β-amyloid (Aβ) aggregation/deposition in Tg mice and brain mitochondrial enhancement in both Tg and normal mice. The present study extends this work by showing that daily EMF treatment given to very old (21–27 month) Tg mice over a 2-month period reverses their very advanced brain Aβ aggregation/deposition. These very old Tg mice and their normal littermates together showed an increase in general memory function in the Y-maze task, although not in more complex tasks. Measurement of both body and brain temperature at intervals during the 2-month EMF treatment, as well as in a separate group of Tg mice during a 12-day treatment period, revealed no appreciable increases in brain temperature (and no/slight increases in body temperature) during EMF “ON" periods. Thus, the neuropathologic/cognitive benefits of EMF treatment occur without brain hyperthermia. Finally, regional cerebral blood flow in cerebral cortex was determined to be reduced in both Tg and normal mice after 2 months of EMF treatment, most probably through cerebrovascular constriction induced by freed/disaggregated Aβ (Tg mice) and slight body hyperthermia during “ON" periods. These results demonstrate that long-term EMF treatment can provide general cognitive benefit to very old Alzheimer's Tg mice and normal mice, as well as reversal of advanced Aβ neuropathology in Tg mice without brain heating. Results further underscore the potential for EMF treatment against AD

Multifactorial anticancer effects of digalloyl-resveratrol encompass apoptosis, cell-cycle arrest, and inhibition of lymphendothelial gap formation in vitro

BACKGROUND: Digalloyl-resveratrol (di-GA) is a synthetic compound aimed to combine the biological effects of the plant polyhydroxy phenols gallic acid and resveratrol, which are both radical scavengers and cyclooxygenase inhibitors exhibiting anticancer activity. Their broad spectrum of activities may probably be due to adjacent free hydroxyl groups. METHODS: Protein activation and expression were analysed by western blotting, deoxyribonucleoside triphosphate levels by HPLC, ribonucleotide reductase activity by 14 C-cytidine incorporation into nascent DNA and cell-cycle distribution by FACS. Apoptosis was measured by Hoechst 33258/propidium iodide double staining of nuclear chromatin and the formation of gaps into the lymphendothelial barrier in a three-dimensional co-culture model consisting of MCF-7 tumour cell spheroids and human lymphendothelial monolayers. RESULTS: In HL-60 leukaemia cells, di-GA activated caspase 3 and dose-dependently induced apoptosis. It further inhibited cell-cycle progression in the G1 phase by four different mechanisms: rapid downregulation of cyclin D1, induction of Chk2 with simultaneous downregulation of Cdc25A, induction of the Cdk-inhibitor p21(Cip/Waf) and inhibition of ribonucleotide reductase activity resulting in reduced dCTP and dTTP levels. Furthermore, di-GA inhibited the generation of lymphendothelial gaps by cancer cell spheroid-secreted lipoxygenase metabolites. Lymphendothelial gaps, adjacent to tumour bulks, can be considered as gates facilitating metastatic spread. CONCLUSION: These data show that di-GA exhibits three distinct anticancer activities: induction of apoptosis, cell-cycle arrest and disruption of cancer cell-induced lymphendothelial disintegration. British Journal of Cancer (2010) 102, 1361-1370. doi:10.1038/sj.bjc.6605656 www.bjcancer.com (C) 2010 Cancer Research U

Intracellular Trafficking Considerations in the Development of Natural Ligand-Drug Molecular Conjugates for Cancer

Overexpressed receptors, characteristic of many cancers, have been targeted by various researchers to achieve a more specific treatment for cancer. A common approach is to use the natural ligand for the overexpressed receptor as a cancer-targeting agent which can deliver a chemically or genetically conjugated toxic molecule. However, it has been found that the therapeutic efficacy of such ligand-drug molecular conjugates can be limited, since they naturally follow the intracellular trafficking pathways of the endogenous ligands. Therefore, a thorough understanding of the intracellular trafficking properties of these ligands can lead to novel design criteria for engineering ligands to be more effective drug carriers. This review presents a few commonly used ligand/receptor systems where intracellular trafficking considerations can potentially improve the therapeutic efficacy of the ligand-drug molecular conjugates

Temperature Dependence of Luminescence Decay from the 4\text{}^{4}G 5/2\text{}_{5}\text{}_{/}\text{}_{2} State of Sm3+\text{}^{3+} in Cs2\text{}_{2}NaSmx\text{}_{x}Y1−x\text{}_{1-x}Cl6\text{}_{6} and Cs2\text{}_{2}NaSmx\text{}_{x}Euy\text{}_{y}Y1−x−y\text{}_{1-x-y}Cl6\text{}_{6}

Luminescence decay curves for the $\text{}^{4}$G $\text{}_{5}\text{}_{/}\text{}_{2}$ → $\text{}^{6}$H $\text{}_{7}\text{}_{/}\text{}_{2}$ emission of Sm$\text{}^{3+}$ in the cubic hexachloroelpasolite crystals Cs$\text{}_{2}$NaSm$\text{}_{x}$Y$\text{}_{1-x}$Cl$\text{}_{6}$ (x=0.005 to x=1) and Cs$\text{}_{2}$NaSm$\text{}_{x}$Eu$\text{}_{y}$Y$\text{}_{1-x-y}$Cl$\text{}_{6}$ (x=0.01 to x=0.95, y=0.05 to y =0.99) have been measured over the temperature range 10 K to 300 K using pulsed laser excitation into the $\text{}^{4}$G $\text{}_{5}\text{}_{/}\text{}_{2}$ state of Sm$\text{}^{3+}$. The luminescence from this state is strongly quenched by cross relaxation to Sm$\text{}^{3+}$ acceptors and energy transfer to the $\text{}^{5}$D$\text{}_{0}$ state of Eu$\text{}^{3+}$. The temperature dependence of cross relaxation and of energy transfer is discussed in terms of the involved mechanisms

Cross Relaxation and Energy Transfer in Cs2\text{}_{2}NaSmx\text{}_{x}Euy\text{}_{y}Y1−x−y\text{}_{1-x-y}Cl6\text{}_{6}

Luminescence decay curves have been measured for the Sm$\text{}^{3+}$ $\text{}^{4}$G $\text{}_{5}\text{}_{/}\text{}_{2}$ → $\text{}^{6}$H $\text{}_{7}\text{}_{/}\text{}_{2}$ emission in the cubic crystal Cs$\text{}_{2}$NaSm$\text{}_{x}$Eu$\text{}_{y}$Y$\text{}_{1-x-y}$Cl$\text{}_{6}$ (x = 0.005 to x = 1, y = 0 to y = 0.99) over the temperature range 10 K to 300 K using pulsed laser excitation into the $\text{}^{4}$G $\text{}_{5}\text{}_{/}\text{}_{2}$ state of Sm$\text{}^{3+}$. The luminescence from the $\text{}^{4}$G $\text{}_{5}\text{}_{/}\text{}_{2}$ state of Sm$\text{}^{3+}$ is strongly quenched by both, cross relaxation to nearest-neighbour Sm$\text{}^{3+}$ ions and energy transfer to the $\text{}^{5}$D$\text{}_{0}$ state of Eu$\text{}^{3+}$. We interpret these processes in terms of a recently developed discrete shell model. The dependence of energy transfer from the Sm$\text{}^{3+}$ donor ion to Eu$\text{}^{3+}$ acceptor ions on y is readily studied and modelled. The temperature dependence shows that the cross relaxation occurs mainly by electric dipole vibronic-electric dipole vibronic interaction while in the energy-transfer process magnetic dipole allowed electronic contributions are also involved