Les mucormycoses sont des infections opportunistes rares dues à des champignons filamenteux saprophytes à tropisme vasculaire. Les formes rhino-cérébrales et pulmonaires sont les plus fréquentes. Une atteinte cutanée primitive peut survenir en cas d’altération de la barrière cutanée. Nous rapportons deux cas survenant chez des patients avec décollements cutanés. Cas 1 : un homme de 52 ans, ayant une goutte et un psoriasis, était en réanimation pour érythrodermie érosive diffuse, pancytopénie, insuffisance rénale aiguë et cytolyse hépatique après mésusage de méthotrexate (MTX, 10 mg/j, 3 jours consécutifs) et prise de colchicine. Le diagnostic de toxicité au MTX était retenu. Après supplémentation folinique, le patient sortait d’aplasie mais un retard de cicatrisation des érosions était observé. À j30, apparaissaient 2 lésions nécrotiques sur des érosions de cuisse gauche. L’examen histologique était non spécifique. L’examen direct (grattage + biopsie cutanée) révélait des filaments non septés, rubanés, à bords non parallèles, évocateurs de mucormycose. La culture mycologique isolait une mucorale du genre Mucor et la PCR panmucorale était positive pour les genres Mucor/rhizopus dans la peau et négative dans le sérum. Le patient était traité par amphotéricine B et parage chirurgical. L’évolution initiale était favorable mais le patient décédait de choc septique 2,5 mois plus tard. Cas 2 : une patiente de 19 ans aux antécédents d’épisode dépressif majeur et d’épilepsie était hospitalisée en réanimation pour syndrome de Lyell à la lamotrigine (décollement 30 % avec atteinte du visage). Dès j2, on observait des lésions nécrotiques de la région périnasale. Les cartographies cutanées trouvaient des filaments et la culture était positive pour une mucorale de genre Lichtheimia. Les PCR mucorales dans la peau, le sérum et l’aspiration naso-pharyngée étaient positives. L’évolution était favorable sous amphotéricine B et la patiente a également guéri du syndrome de Lyell. Les mucorales sont souvent transmises par inhalation mais des contaminations par traumatismes cutanés sont décrites chez des polytraumatisés ou des brûlés. Elles n’ont pas été rapportées au cours de dermatoses décollées. Dans nos deux cas, c’est l’aspect ulcéro- ou fibrino-nécrotique inhabituel des lésions qui a attiré l’attention, conduisant au prélèvement mycologique. En effet, le diagnostic est confirmé par l’examen mycologique de prélèvements cutanés et la PCR panmucorale. Le pronostic vital dépend de la précocité du traitement associant amphotéricine B ou posaconazole à un parage chirurgical quand il est possible. Il faut évoquer une mucormycose devant l’apparition de lésions nécrotiques sur peau décollée.

According to Lang equation, the diameter of droplet generated by an ultrasonic atomizer is inversely proportional to the ultrasonic drive frequency to the two-thirds power. In an ultrasonic aeroponic cultivation system, nutrient solution droplet sizes influence plant growth speed directly. If nutrient solution droplet sizes can be changed to meet a plant growth need during its different growth stages, the plant growth will accelerate. So, obtaining various sizes of droplets more efficiently and cheaply is expected in an ultrasonic aeroponic system. A new ultrasonic atomizer with an acoustic levitation mechanism was developed to study the feasibility of using only one ultrasonic atomizer to obtain various sizes of droplets. The atomizer's atomization surface was designed as a hemispheric shape, and a ball called "Levitated ball" was against this atomization surface. The atomization surface was mounting vertically upward when the atomizer was working. An acoustic radiation force was generated due to ultrasonic vibration of the atomization surface. The levitated ball would be levitated if its gravity force was less than or equal to the acoustic radiation force acting on it. Sizes of droplets generated by this atomizer were measured when a ceramic, steel, and glass ball were levitated using a spray laser particle size analyzer. Measurement results showed that values of NMD and D50 of droplets generated by this atomizer with a ceramic, glass, and steel ball levitated were respectively 4.78% and 5.83%, 22.06% and 22.04%, 34.76% and 32.30% less than those of droplets generated by this atomizer with no ball levitated. It was verified that using only one ultrasonic atomizer to obtain various sizes of droplets were feasible by changing the levitated ball's weight. Vertical displacements of those levitated balls were measured using a laser displacement sensor. Vertical displacement measurement results showed that a levitated ball's kinematic parameters would be changed along with its' weight. Furthermore, changes of a levitated ball's kinematic parameters would influence processes of collision between droplets and the levitated ball. This might be the reason why an ultrasonic atomizer with a levitating mechanism could generate various sizes of droplets.

Background Thissingle-armphase1 studywasconductedtodefinethePK ofREG and its metabolites, M-2 and M-5, in Chinese patients with advanced solid tumors. Methods Patients from China mainland with locally advanced/metastatic, refractory solidtumorswereenrollediftheywerenotcandidatesforstandardtherapyorifthey had metastatic CRC or advanced GIST and REG was a treatment option. The primary objective was PK; secondary objectives were safety, tolerability, and efficacy. Single-dose PKwascollectedonCycle0Day1 upto96hoursafteradministrationofREG160mg followedby6daysofftreatment.FromCycle1Day1,REG160mgwasadministered dailyona3weekson/1 weekoffscheduleina28-daycycleuntiltumorprogression, toxicity,orwithdrawalofconsent.Optionalmultiple-doseREGPKwascollectedon Cycle 1 Day 21 up to 96 hours post dose where applicable. Results All 18 patients who received study treatment were valid for single-dose PK, safety, and efficacy analyses; 9 were valid for multiple-dose PK analysis. After singledose REG, the geometric mean AUC(o -t] ast) (mg-h/L) was 43.1 (REG), 17.1 (M-2), and 3.99(M-5),withmoderatetohighinter-individualvariability:Geo-CV63%(REG), 56% (M-2), 74% (M-5). After multiple-dosing, increases in AUC(o_24) and Cmax were observedforthe 3 analytes (accumulation ratios: REG, 1.83 AUC(o_24) and 1.61 Cm ax; M-2, 3.44 AUC(o_24) and3.51 CIliax M-5, 35.8 AUC(o_24) and 21.2 Cmax ). Themost common drug-related grade >3 treatment-emergent adverse events were hypophosphatemia (39%), lipase increase (22%), and hand-foot skin reaction (22%). The best overall response was stable disease in 10/18 (56%) patients with median overall treatment duration of9.4 weeks. Conclusions:Theinter-individualvariabilityofREG,M-2,andM-5wasmoderateto high after single- and multiple-dose REG, with observed accumulation after multiple dosing.Overall,thePKofREG,M-2,andM-5inpatientsfromChinamainlandwas consistent with that previously reported. The safety profile was consistent with the known safety profile of REG. No safety signals were detected to indicate a potential influence ofChinese ethnicity on the safety profile ofREG. Clinical trial indentification NCT02398513 Legal entity responsible for the study Bayer Funding Bayer Disclosure Q. Wang, Y. Liu, D. Lu, F. Huang: Employee ofBayer. I. Sturm: Employee of Bayer and owns stock in Bayer. A. Cleton: Employee ofBayer and has stockin Bayer, Astrazeneca, Pfizer. All other authors have declared no conflicts ofinterest.

The effects of electric field polarizations on pair production from a vacuum are investigated numerically by employing the real-time Dirac-Heisenberg-Wigner formalism. For few-cycle fields, it is found that the interference pattern in momentum spectra is absent and the circular distortion of momentum distribution becomes more apparent with the increase of polarization. For multi-cycle fields, it is found that the interference effects in momentum spectra are obvious. And as the polarization increases, the momentum distribution is split into two parts in the momentum $q_y$ direction first and then two separated parts are connected into a ring. The effects of polarizations on the number density of created particles exhibits two different characteristics. For a small laser frequency, the particle number density deceases with the polarization, while for a large laser frequency, the relation between them is sensitive to the field frequency nonlinearly. Some interpretations for the obtained results in this study, which is expected to be valuable to deepen the understanding of pair production in complex fields and also helpful for the study associated to strong-field ionization.

Le pemphigus paranéoplasique (PPN) est une dermatose cutanéomuqueuse auto-immune, souvent associée à une hémopathie. Nous rapportons un cas associé à une myasthénie dans un contexte de sarcome pseudo-folliculaire à cellules dendritiques d’évolution fatale vers un tableau faisant discuter un Lyell et/ou une poussée de PPN. Mme B., 49 ans, présentait depuis 3 semaines une dyspnée associée à une éruption érythématopapuleuse et érosive extensive, avec chéilite et érosions gingivales. L’imagerie thoracique révélait une masse médiastinale compressive. La confrontation anatomoclinique et les résultats immunologiques confirmaient le diagnostic de PPN. L’exérèse de la tumeur concluait à une maladie de Castelman hyalino-vasculaire monocentrique. La patiente était traitée par corticothérapie orale (1,3 mg/kg), immunoglobulines polyvalentes (2 g/kg) puis rituximab (375 mg/m2/semaine, 4 semaines). L’évolution initialement favorable permettait la décroissance progressive de la corticothérapie. Au cours du suivi, la patiente présentait une fatigabilité musculaire avec ptosis conduisant au diagnostic de myasthénie associée. L’évolution était marquée par une rechute du PPN, témoignant d’une récidive de la masse médiastinale. La reprise chirurgicale et la relecture de l’anatomopathologie faisaient finalement retenir le diagnostic de sarcome pseudo-folliculaire. Elle était traitée par 6 cycles de R-CHOP avec une réponse initiale puis une nouvelle récidive tumorale. Un traitement par erlotinib était alors proposé. Suite à une folliculite, de la doxycycline était introduite. À j7 de doxycycline et j14 d’erlotinib apparaissait une éruption cutanéomuqueuse extensive avec fièvre, évoluant vers un tableau de syndrome de Lyell, avec à l’histologie cutanée une nécrose épidermique de type Lyell. L’immunofluorescence directe était positive. Les anticorps anti-épiderme, s’étant négativés lors de la phase de rémission, étaient de nouveau positifs en immunofluorescence indirecte, Elisa (desmogleine) et blot (periplakine et envoplakine). Malgré un traitement par ciclosporine, elle décédait rapidement d’un sepsis sévère. Cette observation d’évolution dramatique témoigne de la gravité des rares PPN compliqués d’une myasthénie, souvent associés à une tumeur médiastinale (thymome, lymphome, tumeur de Castelman, sarcome dendritique). Leur pronostic est plus sévère quelle que soit la tumeur. La patiente est décédée dans un tableau de Lyell associant des caractéristiques cliniques, histologiques et immunologiques de syndrome de Lyell et de PPN. Même si le diagnostic définitif ne peut être ici formellement affirmé, syndrome de Lyell avec démasquage des antigènes épidermiques et/ou poussée majeure du PPN avec aspect de « lyellisation » dans le contexte de progression tumorale, ce cas souligne la gravité de certains PPN notamment associés à des myasthénies et la difficulté d’interprétation des examens sérologiques chez ces patients.

FinFET has become the mainstream logic device architecture in recent technology nodes due to its superior electrostatic and leakage control [1,2,3,4]. However, parasitic capacitance has been a key performance detractor in 3D FinFETs. In this work, a novel low temperature ALD-based SiBCN material has been identified, with an optimized spacer RIE process developed to preserve the low-k value and provide compatibility with the down-stream processes. The material has been integrated into a manufacturable 14nm replacement-metal-gate (RMG) FinFET baseline with a demonstrated ~8% performance improvement in the RO delay with reliability meeting the technology requirement [4]. A guideline for spacer design consideration for 10nm node and beyond is also provided based on the comprehensive material properties and reliability evaluations.

The momentum signatures in nonperturbative multiphoton pair production for general elliptic polarization electric fields are investigated by employing the real-time Dirac-Heisenberg-Wigner formalism. For a linearly polarized electric field we find that the positions of the nodes in momentum spectra of created pairs depend only on the electric-field frequency. The polarization of external fields could not only change the node structures or even make the nodes disappear but also change the thresholds of pair production. The momentum signatures associated to the node positions in which the even-number photon pair creation process is forbidden could be used to distinguish the orbital angular momentum of created pairs on the momentum spectra. These distinguishable momentum signatures could be relevant for providing the output information of created particles and also the input information of ultrashort laser pulses.

The mass shift effects in multiphoton pair production of a nonperturbative nature for arbitrary polarized electric fields are investigated numerically by employing the real-time Dirac-Heisenberg-Wigner formalism, and theoretically by proposing an effective energy concept. It is found that the theoretical results are agreement with the numerical ones very well. It is the first time to consider the roles of the momenta of created particles and the polarizations of external fields played in the mass shift effects. These results can deepen the understanding of pair production in the nonperturbative threshold regime. Moreover, the distinct mass shift effects are observable in the forthcoming experiments and can be used as a probe to distinguish the electron-positron pair production from other background events.

In the quantum kinetic framework, we investigate the momentum spectrum and the number density of created electron-positron pairs from vacuum in the combined electric fields composed of two sets of alternating-sign electric field pulse trains, a strong but slowly varying one and a weak but rapidly changing one. It is found that the pair production can be strongly enhanced by combining the multiple-slit interference effect with the dynamically assisted Schwinger mechanism. By considering the contribution of the transverse momentum, we find that the number density of created particles depends linearly on the electric field pulse number, i.e., a power law with index 1. Moreover, we study the effect of interpulse time delay on pair production and find that the number density is very sensitive to the interpulse time delay. The symmetry of the momentum spectrum for an $N$-pulse electric field and the difference of the multiple-slit interference effect between the nonperturbative Schwinger mechanism and the perturbative multiphoton electron-positron pair creation are also studied. Some possible explanations for observed results of momentum spectrum and number density are also given and discussed.

Localized surface plasmon (LSP) and surface plasmon polaritons (SPP) are identified in silver grating structure on back-electrode organic photovoltaic (OPV) devices. Their strong interaction indicated by anti-crossing behavior affects absorption enhancement of OPV devices.

Interferon (IFN)-β has efficient antitumor effect both in vitro and in vivo, but its clinical implication is limited by short half-life and systemic toxicities. Gene therapy could be the choice to avoid the defects. Adenovirus vector containing human IFN-β gene was transfected into esophageal squamous cell carcinoma KYSE150 cells. Expression of human (h)IFN-β was detected by reverse transcription polymerase chain reaction and immunocytochemistry in KYSE150 cells. Cell growth and clonogenic assays, and flow cytometry were used to observe the antiproliferation effect and apoptosis on tumor cells, respectively. Reverse transcription polymerase chain reaction and immunocytochemistry showed obvious hIFN-β expression in KYSE150 cells after transfection and the tumor cell proliferation was obviously inhibited through cell proliferation and clonogenic assays. Flow cytometry analysis showed 27.3% cell apoptosis in adenovirus vector containing human IFN-β gene transfection group compared with 1.12% in empty vector control group. These findings indicate that hIFN-β gene mediated by recombinant adenovirus may have antitumor activity against human esophageal carcinoma cell by inducing apoptosis in vitro.

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is a key enzyme in prostaglandin (PG) metabolism. This study provides important evidence for inhibition of hepatocellular carcinoma (HCC) growth by 15-PGDH through the 15-keto-prostaglandin E2 (15-keto-PGE2)/peroxisome proliferator-activated receptor-γ (PPARγ)/p21(WAF1/Cip1) signaling pathway. Forced overexpression of 15-PGDH inhibited HCC cell growth in vitro, whereas knockdown of 15-PGDH enhanced tumor growth parameters. In a tumor xenograft model in severe combined immunodeficiency mice, inoculation of human HCC cells (Huh7) with overexpression of 15-PGDH led to significant inhibition of tumor growth, whereas knockdown of 15-PGDH enhanced tumor growth. In a separate tumor xenograft model in which mouse HCC cells (Hepa1-6) were inoculated into syngeneic C57BL/6 mice, intratumoral injection of adenovirus vector expressing 15-PGDH (pAd-15-PGDH) significantly inhibited xenograft tumor growth. The antitumor effect of 15-PGDH is mediated through its enzymatic product, 15-keto-PGE2, which serves as an endogenous PPARγ ligand. Activation of PPARγ by 15-PGDH-derived 15-keto-PGE2 enhanced the association of PPARγ with the p21(WAF1/Cip1) promoter and increased p21 expression and association with cyclin-dependent kinase 2 (CDK2), CDK4 and proliferating cell nuclear antigen. Depletion of p21 by short hairpin RNA reversed 15-PGDH-induced inhibition of HCC cell growth; overexpression of p21 prevented 15-PGDH knockdown-induced tumor cell growth. These results show a key 15-PGDH/15-keto-PGE2-mediated activation of PPARγ and p21(WAF1/Cip1) signaling cascade that regulates hepatocarcinogenesis and tumor progression.

Abstract Background: Trastuzumab emtansine (T-DM1) is a HER2-targeted antibody-drug conjugate composed of the humanized monoclonal antibody trastuzumab, the potent cytotoxic agent DM1 (a microtubule inhibitor), and a stable thioether linker. To estimate typical pharmacokinetic (PK) parameter values and interpatient variability, a population PK model for T-DM1 was previously developed from 1 phase 1 (0.3 to 4.8 mg/kg in qw or q3w regimens) and 2 phase 2 (3.6 mg/kg q3w) trials (Gupta, J Clin Pharmacol 2012). The model reported here has been updated with additional data from 2 randomized trials (phase 2 TDM4450g and phase 3 EMILIA, 3.6 mg/kg q3w). Another phase 2 trial (TDM4688g) was used for external validation of the model. The effect of demographic and pathophysiological covariates on the PK of T-DM1 was explored to better understand the clinical factors that might affect exposure and clinical outcome for individual patients. Methods: For the current analysis, 9934 T-DM1 serum concentration-time data points from 671 patients were simultaneously fitted using NONMEM® software. T-DM1 concentration-time data to date are best described using a 2-compartment linear model. All relevant and plausible covariates likely to have an effect on T-DM1 systemic exposure, or likely to have clinical relevance, were explored for possible correlation with the key T-DM1 PK parameters of clearance (CL) and central volume of distribution (Vc). These covariates include those related to demographics, renal and hepatic function, disease status, and treatment history. Results: The estimated CL for T-DM1 is 0.68 L/day, Vc is 3.13 L, and the terminal half-life is 3.94 days. Interindividual variability (IIV) of the base model is 25.6% and 17.5% for CL and Vc, respectively. Patients with greater body weight, sum of longest dimension of target lesions, serum concentration of shed HER2 extracellular domain, and aspartate aminotransferase concentrations, as well as patients with lower serum albumin and baseline trastuzumab concentrations, have statistically faster CL. Patients with greater body weight also have statistically larger Vc. Incorporation of these covariates (P<0.001 by likelihood ratio test) decreased IIV of CL and Vc to 19.1% and 11.7%, respectively. All covariates together explain 44.4% and 55.8% of IIV in CL and Vc, respectively. The model sensitivity analysis suggests that a patient with a statistically significant PK covariate value at the 5th or 95th percentile of the population will have a <20% difference in cumulative exposure (as represented by area under the T-DM1 concentration-time curve) compared with a typical patient with a median covariate value. Conclusions: A relatively small IIV for the estimated T-DM1 PK parameters of CL and Vc was observed. None of the evaluated covariates had a clinically meaningful magnitude of effect on T-DM1 exposure (<20% difference for patients with 5th and 95th percentiles vs patients with median value of covariates) that would justify a further dose adjustment. The body weight–based dose of 3.6 mg/kg q3w without further correction for other factors is considered appropriate in ongoing clinical trials. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-24.