A Single-Arm, Proof-Of-Concept Trial of Lopimune (Lopinavir/Ritonavir) as a Treatment for HPV-Related Pre-Invasive Cervical Disease

BACKGROUND: Cervical cancer is the most common female malignancy in the developing nations and the third most common cancer in women globally. An effective, inexpensive and self-applied topical treatment would be an ideal solution for treatment of screen-detected, pre-invasive cervical disease in low resource settings. METHODS: Between 01/03/2013 and 01/08/2013, women attending Kenyatta National Hospital's Family Planning and Gynaecology Outpatients clinics were tested for HIV, HPV (Cervista®) and liquid based cervical cytology (LBC -ThinPrep®). HIV negative women diagnosed as high-risk HPV positive with high grade squamous intraepithelial lesions (HSIL) were examined by colposcopy and given a 2 week course of 1 capsule of Lopimune (CIPLA) twice daily, to be self-applied as a vaginal pessary. Colposcopy, HPV testing and LBC were repeated at 4 and 12 weeks post-start of treatment with a final punch biopsy at 3 months for histology. Primary outcome measures were acceptability of treatment with efficacy as a secondary consideration. RESULTS: A total of 23 women with HSIL were treated with Lopimune during which time no adverse reactions were reported. A maximum concentration of 10 ng/ml of lopinavir was detected in patient plasma 1 week after starting treatment. HPV was no longer detected in 12/23 (52.2%, 95%CI: 30.6-73.2%). Post-treatment cytology at 12 weeks on women with HSIL, showed 14/22 (63.6%, 95%CI: 40.6-82.8%) had no dysplasia and 4/22 (18.2%, 95%CI: 9.9-65.1%) were now low grade demonstrating a combined positive response in 81.8% of women of which 77.8% was confirmed by histology. These data are supported by colposcopic images, which show regression of cervical lesions. CONCLUSIONS: These results demonstrate the potential of Lopimune as a self-applied therapy for HPV infection and related cervical lesions. Since there were no serious adverse events or detectable post-treatment morbidity, this study indicates that further trials are clearly justified to define optimal regimes and the overall benefit of this therapy. TRIAL REGISTRATION: ISRCTN Registry 48776874

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML

Occurrence of the BCR-ABL[superscript T315I] gatekeeper mutation is among the most pressing challenges in the therapy of chronic myeloid leukemia (CML). Several BCR-ABL inhibitors have multiple targets and pleiotropic effects that could be exploited for their synergistic potential. Testing combinations of such kinase inhibitors identified a strong synergy between danusertib and bosutinib that exclusively affected CML cells harboring BCR-ABL[superscript T315I]. To elucidate the underlying mechanisms, we applied a systems-level approach comprising phosphoproteomics, transcriptomics and chemical proteomics. Data integration revealed that both compounds targeted Mapk pathways downstream of BCR-ABL, resulting in impaired activity of c-Myc. Using pharmacological validation, we assessed that the relative contributions of danusertib and bosutinib could be mimicked individually by Mapk inhibitors and collectively by downregulation of c-Myc through Brd4 inhibition. Thus, integration of genome- and proteome-wide technologies enabled the elucidation of the mechanism by which a new drug synergy targets the dependency of BCR-ABL[superscript T315I] CML cells on c-Myc through nonobvious off targets

Pharmacological Investigations of the Dissociative ‘Legal Highs’ Diphenidine, Methoxphenidine and Analogues

1,2-Diarylethylamines including lanicemine, lefetamine, and remacemide have clinical relevance in a range of therapeutic areas including pain management, epilepsy, neurodegenerative disease and depression. More recently 1,2-diarylethylamines have been sold as ‘legal highs’ in a number of different forms including powders and tablets. These compounds are sold to circumvent governmental legislation regulating psychoactive drugs. Examples include the opioid MT-45 and the dissociative agents diphenidine (DPH) and 2-methoxy-diphenidine (2-MXP). A number of fatal and non-fatal overdoses have been linked to abuse of these compounds. As with many ‘legal highs’, little is known about their pharmacology. To obtain a better understanding, the effects of DPH, 2-MXP and its 3- and 4-MeO- isomers, and 2-Cl-diphenidine (2-Cl-DPH) were investigated using binding studies at 46 central nervous system receptors including the N-methyl-D-aspartate receptor (NMDAR), serotonin, dopamine, norepinephrine, histamine, and sigma receptors as well as the reuptake transporters for serotonin, dopamine and norepinephrine. Reuptake inhibition potencies were measured at serotonin, norepinephrine and dopamine transporters. NMDAR antagonism was established in vitro using NMDAR-induced field excitatory postsynaptic potential (fEPSP) experiments. Finally, DPH and 2-MXP were investigated using tests of pre-pulse inhibition of startle (PPI) in rats to determine whether they reduce sensorimotor gating, an effect observed with known dissociative drugs such as phencyclidine (PCP) and ketamine. The results suggest that these 1,2-diarylethylamines are relatively selective NMDAR antagonists with weak off-target inhibitory effects on dopamine and norepinephrine reuptake. DPH and 2-MXP significantly inhibited PPI. DPH showed greater potency than 2-MXP, acting with a median effective dose (ED50) of 9.5 mg/kg, which is less potent than values reported for other commonly abused dissociative drugs such as PCP and ketamine

Identification and Filtering of Uncharacteristic Noise in the CMS Hadron Calorimeter

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Constitutive Expression of TNF-Related Activation-Induced Cytokine (TRANCE)/Receptor Activating NF-κB Ligand (RANK)-L by Rat Plasmacytoid Dendritic Cells

Plasmacytoid dendritic cells (pDCs) are a subset of DCs whose major function relies on their capacity to produce large amount of type I IFN upon stimulation via TLR 7 and 9. This function is evolutionary conserved and place pDC in critical position in the innate immune response to virus. Here we show that rat pDC constitutively express TNF-related activation-induced cytokine (TRANCE) also known as Receptor-activating NF-κB ligand (RANKL). TRANCE/RANKL is a member of the TNF superfamily which plays a central role in osteoclastogenesis through its interaction with its receptor RANK. TRANCE/RANK interaction are also involved in lymphoid organogenesis as well as T cell/DC cross talk. Unlike conventional DC, rat CD4high pDC were shown to constitutively express TRANCE/RANKL both at the mRNA and the surface protein level. TRANCE/RANKL was also induced on the CD4low subsets of pDC following activation by CpG. The secreted form of TRANCE/RANKL was also produced by rat pDC. Of note, levels of mRNA, surface and secreted TRANCE/RANKL expression were similar to that observed for activated T cells. TRANCE/RANKL expression was found on pDC in all lymphoid organs as well blood and BM with a maximum expression in mesenteric lymph nodes. Despite this TRANCE/RANKL expression, we were unable to demonstrate in vitro osteoclastogenesis activity for rat pDC. Taken together, these data identifies pDC as novel source of TRANCE/RANKL in the immune system

Evaluation of a novel nanocrystalline hydroxyapatite paste Ostim® in comparison to Alpha-BSM® - more bone ingrowth inside the implanted material with Ostim® compared to Alpha BSM®

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to evaluate the performance a newly developed nanocrystalline hydroxyapatite, OSTIM^®following functional implantation in femoral sites in thirty-eight sheep for 1, 2 or 3 months. Ostim^®35 was compared to an established calcium phosphate, Alpha BSM^®.</p> <p>Methods</p> <p>Biomechanical testing, μ-CT analysis, histological and histomorphological analyses were conducted to compare the treatments including evaluation of bone regeneration level, material degradation, implant biomechanical characteristics.</p> <p>Results</p> <p>The micro-computed tomography (μCT) analysis and macroscopic observations showed that Ostim^®seemed to diffuse easily particularly when the defects were created in a cancellous bone area. Alpha BSM^®remained in the defect.</p> <p>The performance of Ostim was good in terms of mechanical properties that were similar to Alpha BSM^®and the histological analysis showed that the bone regeneration was better with Ostim^®than with Alpha BSM^®. The histomorphometric analysis confirmed the qualitative analysis and showed more bone ingrowth inside the implanted material with Ostim^®when compared to Alpha BSM ^®at all time points.</p> <p>Conclusions</p> <p>The successful bone healing with osseous consolidation verifies the importance of the nanocrystalline hydroxyapatite in the treatment of metaphyseal osseous volume defects in the metaphyseal spongiosa.</p

Study of mass and momentum transfer in diesel sprays base on X-ray mass distribution measurements and on a theoretical derivation

[EN] In this paper, a research aimed at quantifying mass and momentum transfer in the near-nozzle field of diesel sprays injected into stagnant ambient air is reported. The study combines X-ray measurements for two different nozzles and axial positions, which provide mass distributions in the spray, with a theoretical model based on momentum flux conservation, which was previously validated. This investigation has allowed the validation of Gaussian profiles for local fuel concentration and velocity near the nozzle exit, as well as the determination of Schmidt number at realistic diesel spray conditions. This information could be very useful for those who are interested in spray modeling, especially at high-pressure injection conditions. © 2010 Springer-Verlag.This work was partly sponsored by "Vicerrectorado de Investigacion, Desarrollo e Innovacion'' of the "Universidad Politecnica de Valencia'' in the frame of the project "Estudio del flujo en el interior de toberas de inyeccion Diesel'', reference no. 3150 and by "Generalitat Valenciana'' in the frame of the project with the same title and reference GV/2009/031. This support is gratefully acknowledged by the authors.Desantes, J.; Salvador Rubio, FJ.; López, JJ.; De La Morena, J. (2011). Study of mass and momentum transfer in diesel sprays base on X-ray mass distribution measurements and on a theoretical derivation. Experiments in Fluids. 50(2):233-246. https://doi.org/10.1007/s00348-010-0919-8S233246502Abramovich GN (1963) The theory of turbulent jets. 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Fuel 85:910–917Desantes JM, Arrègle J, López JJ, Cronhjort A (2006b) Scaling laws for free turbulent gas jets and Diesel-like sprays. Atomization Spray 16:443–473Desantes JM, Payri R, García JM, Salvador FJ (2007) A contribution to the understanding of isothermal diesel spray dynamics. Fuel 86:1093–1101Dumouchel C (2008) On the experimental investigation on primary atomization of liquid streams. Exp Fluids 45:371–422Heimgärtner C, Leipertz A (2000) of the primary spray break-up close to the nozzle of a common-rail high pressure diesel injection system. SAE Paper 2000-01-1799Hinze JO (1975) Turbulence. McGraw Hill, New YorkHiroyasu H, Arai M (1990) Structures of fuel sprays in diesel engines. SAE Paper 900475Jawad B, Gulari E, Henein NA (1992) Characteristics of intermittent fuel sprays. Combust Flame 88:384–396Lefèbvre AH (1989) Atomization and sprays. 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J Fluid Mech 11:21–32Rife J, Heywood JB (1974) Photographic and performance studies of diesel combustion with a rapid compression machine. SAE Paper 740948Roisman IV, Tropea C (2001) Flux measurements in sprays using phase doppler techniques. Atomization Spray 11:667–699Roisman IV, Araneo L, Tropea C (2007) Effect of ambient pressure on penetration of a diesel spray. Int J Multiphase Flow 33(8):904–920Saliba R, Baz I, Champoussin JC, Lance M, Marié JL (2004) Cavitation effect on the near nozzle spray development in high-pressure diesel injection. In: Proc 19th ILASS (Europe)Schlichting H (1978) Boundary layer theory. McGraw Hill, New YorkSinnamon JF, Lancaster DR, Stiener JC (1980) An experimental and analytical study of engine fuel spray trajectories. SAE Paper 800135Sou A, Hosokawa S, Tomiyama A (2007) Effects of cavitation in a nozzle on liquid jet atomization. Int J Heat Mass Tran 50(17–18):3575–3582Spalding DB (1979) Combustion and mass transfer. Pergamon Press, New YorkSubramaniam S (2001) Statistical modelling of a spray as using the droplet distribution function. Phys Fluids 13(3):624–642Tanner FX, Feigl A, Ciatti SA, Powell CF, Cheong S-K, Liu J, Wang J (2006) Structure of high-velocity dense sprays in the near-nozzle region. Atomization Spray 16:579–597Way RJB (1977) Investigation of interaction between swirl and jets in direct injection diesel engines using a water model. SAE Paper 770412Wu KJ, Santavicca DA, Bracco FV (1984) LDV measurements of drop velocity in diesel-type sprays. AAIA J 22(9):1263–1270Wu KJ, Reitz RD, Bracco FV (1986) Measurements of drop size at the spray edge near the nozzle in atomising liquid jets. Phys Fluids 29(4):941–951Yue Y, Powell CF, Poola R, Wang J, Schaller JK (2001) Quantitative measurements of diesel fuel spray characteristics in the near-nozzle region using X-ray absorption. Atomization Spray 11(4):471–49

Activin/Nodal Inhibition Alone Accelerates Highly Efficient Neural Conversion from Human Embryonic Stem Cells and Imposes a Caudal Positional Identity

Background Neural conversion from human embryonic stem cells (hESCs) has been demonstrated in a variety of systems including chemically defined suspension culture, not requiring extrinsic signals, as well as in an adherent culture method that involves dual SMAD inhibition using Noggin and SB431542 (an inhibitor of activin/nodal signaling). Previous studies have also determined a role for activin/nodal signaling in development of the neural plate and anterior fate specification. We therefore sought to investigate the independent influence of SB431542 both on neural commitment of hESCs and positional identity of derived neural progenitors in chemically defined substrate-free conditions. Methodology/Principal Findings We show that in non-adherent culture conditions, treatment with SB431542 alone for 8 days is sufficient for highly efficient and accelerated neural conversion from hESCs with negligible mesendodermal, epidermal or trophectodermal contamination. In addition the resulting neural progenitor population has a predominantly caudal identity compared to the more anterior positional fate of non-SB431542 treated cultures. Finally we demonstrate that resulting neurons are electro-physiologically competent. Conclusions This study provides a platform for the efficient generation of caudal neural progenitors under defined conditions for experimental study

Mechanical analysis of infant carrying in hominoids

In all higher nonhuman primates, species survival depends upon safe carrying of infants clinging to body hair of adults. In this work, measurements of mechanical properties of ape hair (gibbon, orangutan, and gorilla) are presented, focusing on constraints for safe infant carrying. Results of hair tensile properties are shown to be species-dependent. Analysis of the mechanics of the mounting position, typical of heavier infant carrying among African apes, shows that both clinging and friction are necessary to carry heavy infants. As a consequence, a required relationship between infant weight, hair–hair friction coefficient, and body angle exists. The hair–hair friction coefficient is measured using natural ape skin samples, and dependence on load and humidity is analyzed. Numerical evaluation of the equilibrium constraint is in agreement with the knuckle-walking quadruped position of African apes. Bipedality is clearly incompatible with the usual clinging and mounting pattern of infant carrying, requiring a revision of models of hominization in relation to the divergence between apes and hominins. These results suggest that safe carrying of heavy infants justify the emergence of biped form of locomotion. Ways to test this possibility are foreseen here