Abraxis (United States)

In the paper “Hitting time distributions for efficient simulations of drift-diffusion processes”,1 we exhibited density functions and cumulative distributions for diffusion processes with and without drift. In particular, the previously well-known cumulative distribution for the hitting time T to a sphere of radius R of a particle released at the center of the sphere, and undergoing only diffusive transfer was shown in equation (4) loc. cit. It was there remarked that the distribution is convergent for T > 0 but not for T = 0 (as is immediately obvious from the series). Further, the series, as well as the series for the corresponding density of the distribution, were indicated in the paper as being derived from a previous equation (1) loc. cit., which gives the moment generating function. The derivation was said to follow when an inverse Laplace transform is computed by evaluation of the residues in a contour integral. However, during the peer-review process of a separate paper,2 we were alerted by an external reviewer, Dr. Enzhi Li, that the indicated derivation is also restricted to T > 0 only, a fact not explicitly mentioned in the paper. We would like to restate here that none of the results reported in Reference 1 are affected by this omission. Series like equation (4) of the paper, that are directly obtained from the moment generating functions are indeed not useful for nonzero times other than “large” times (ie, well away from time zero) where the probability of hitting the sphere is close to unity. Moreover, the point T = 0 is excluded in any algorithms or numerical methods for simulation, since the sphere is of radius unity (nonzero radius) and hence a zero hitting time has zero probability. In Reference 1, we emphasize the need for a Poisson resummation of such series for numerical evaluation for smaller, indeed for most times that occur in a simulation. These resummed series converge very fast near T = 0, and their T = 0 limit is also zero, though the series is not the expansion of any analytic function at time zero since all derivatives vanish. The fact that T = 0 is excluded arises from the following. The probability measure of time intervals close to zero is exponentially small in the inverse of the hitting times. When computing the hitting times near zero, we actually cut off the calculations at small enough times because the numerical programs have to evaluate large negative exponentials which result in underflow. The probabilities of hitting the sphere are set to zero at the smallest (nonzero) time for which the probabilities can be evaluated numerically. The hitting probabilities for the times at which we have to cut off the evaluations are less than e−1000, which is too small a probability to be distinguishable from zero for all practical purposes. We have introduced remarks similar to the above in the paper “Inverse functions for Monte-Carlo simulations with applications to hitting times distributions”2 following Dr. Li's comment. We thank Dr. Enzhi Li for pointing out the omission described above. Further, we would like to mention that Dr. Li has separately derived a density function that is free of this restriction.

BackgroundSpinal Muscular Atrophy type 1 (SMA1) is a rapidly progressing disease resulting in death/permanent ventilation by 2 years of age. In ENDEAR, ∼10% of patients died/required permanent ventilation within 2 months after therapy initiation; 39% died/required permanent ventilation by 6 months. This may reflect a non-immediate therapeutic impact related to loading dose schedule. This study explored the rapidity of therapeutic effect of onasemnogene abeparvovec (AVXS-101) gene-replacement therapy (phase 1 study) relative to nusinersen (phase 3 study, ENDEAR).MethodsSMA1 patients were treated with a one-time intravenous AVXS-101 injection (NCT02122952; cohort 2; N=12; 24 months follow-up). Outcomes were event-free survival (EFS, no death/permanent ventilation [AVXS-101: ≥16 hours ventilation/day for >2 weeks; ENDEAR: tracheostomy or ≥16 hours ventilation/day for >21 days]) and motor function improvements (CHOP-INTEND).ResultsAll patients treated with AVXS-101 survived event-free 24 months post-dose, while 49/80 nusinersen patients showed EFS. Rapid increases in CHOP-INTEND of 9.8 and 15.4 points were observed at 1- and 3-months post–AVXS-101 dose (nusinersen: ≤5-point increase at 2 months after initiation).ConclusionsAVXS-101 appears to improve survival and induce more rapid motor function improvements relative to nusinersen, consistent with rapid restoration of survival motor neuron expression in motor neurons with a single dose.

This paper develops theory for bulk acoustic streaming in soft porous materials, with applications to biological tissue. The principal results of this paper are: (i) streaming equations for such porous media, which show interestingly significant differences from those that describe streaming in pure fluids; (ii) the Green functions obtained for these equations in isotropic, infinite media; and (iii) approximate evaluation of the sources in the streaming equations from acoustic wave forms often used, and the streaming velocities and particle trajectories resulting therefrom. People are now investigating acoustic enhancement of delivery of therapeutics such as drug molecules or other particulates, introduced directly into cellular tissue. A comparison of the predictions of the theory in this paper to available data is made and shown to be surprisingly good. Some macroscale effects of the ultrastructure of the tissue that are not contained in the current paper are pointed out for future studies.

Albumin is a key plasmic carrier of hydrophobic molecules and is highly accumulated in tumors. Nanoparticle albumin bound (nab) technology is a nanoparticle drug delivery platform that utilizes the unique transport and binding properties of albumin to achieve enhanced tumor penetration and accumulation of albumin-bound hydrophobic drugs while eliminating the need for toxic solvents coadministered with poorly soluble drugs. The first product in the nab drug family and the first protein nanotechnology-based chemotherapeutic approved by the US Food and Drug Administration and the EMA is nab-paclitaxel (Abraxane®, ABI- 007; manufactured by Celgene Corporation, Summit, NJ). It is a Cremophor-free, albumin-bound nanoparticle formulation of paclitaxel with a mean particle size of approximately 130 nm. A proprietary process combines paclitaxel with albumin to create a colloidal suspension of nanoparticles. Paclitaxel and albumin are not covalently linked but rather associated through hydrophobic interactions. The particles of paclitaxel are in a noncrystalline, amorphous, readily bioavailable state, allowing for rapid drug release from the particles following intravenous administration. Nanoparticles of nab-paclitaxel are complex three dimensional constructs that require careful design and engineering, detailed orthogonal analysis methods, and a reproducible scale-up and manufacturing process to achieve a consistent product with the intended physicochemical characteristics, biological behavior, and pharmacological profiles. Due to its complexity, the safety and efficacy may be influenced by minor variations in the physicochemical properties or the manufacturing process and needs to be carefully examined in preclinical and clinical studies.

\n Neste trabalho foram preparados híbridos PtRu/Carbono e Ni/Carbono pelo método da carbonização hidrotérmica para aplicação na oxidação eletroquímica do metanol. Nesse processo, uma fonte de carbono e os sais metálicos, em meio aquoso, foram submetidos ao tratamento hidrotérmico a 200 ºC em uma autoclave. Na preparação dos híbridos PtRu/Carbono foram estudados o uso de diferentes agentes para ajuste do pH do meio reacional, a influência da adição de surfactante, a razão atômica Pt:Ru, a fonte de carbono, a carga metálica e o tempo de síntese. Para os híbridos Ni/Carbono estudaram-se parâmetros como a fonte de carbono e a adição de brometo de cetiltrimetilamônio. Os materiais obtidos foram caracterizados por espectroscopia de energia dispersiva de raios-X, difração de raios-X (DRX), microscopia eletrônica de transmissão, análise termogravimétrica, isotermas de B.E.T, espectroscopia no infravermelho com transformada de Fourier e voltametria cíclica. Os materiais foram testados para a oxidação eletroquímica do metanol voltametria cíclica, cronoamperometria e em células unitárias operando diretamente com metanol. Os híbridos PtRu/Carbono como-sintetisados não apresentaram atividade na oxidação do metanol. Após tratamento térmico a 900 oC, os materiais tornaram-se ativos e o melhor desempenho foi obtido para o material preparado utilizando celulose, hidróxido de tetrapropilamônio para ajuste do pH do meio reacional e carga metálica nominal de 5% em massa. Os resultados indicam que a atividade dos híbridos PtRu/Carbono, provavelmente, está relacionada à estrutura de poros, tamanho de partícula e presença de rutênio segregado. Os híbridos PtRu/Carbono foram tratados termicamente resultando em um material contendo carbono amorfo e grafítico. Os eletrocatalisadores PtRu/C preparados utilizando os híbridos Ni/Carbono como suporte mostraram-se mais ativos que os preparados utilizando o carbono comercial Vulcan XC72, considerado referência na área.\n