scholarly journals Plocabulin Displays Strong Cytotoxic Activity in a Personalized Colon Cancer Patient-Derived 3D Organoid Assay

Marine Drugs ◽  
2019 ◽  
Vol 17 (11) ◽  
pp. 648 ◽  
Author(s):  
Alba Costales-Carrera ◽  
Asunción Fernández-Barral ◽  
Pilar Bustamante-Madrid ◽  
Laura Guerra ◽  
Ramón Cantero ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cytotoxic Activity ◽  
Short Pulse ◽  
Three Dimensional ◽  
Antitumor Agent ◽  
Dose Dependence ◽  
Continuous Treatment ◽  
Cytotoxic Action ◽  
Order Of Magnitude ◽  
Tumor Organoids

Plocabulin is a novel microtubule-disrupting antitumor agent of marine origin that is currently undergoing phase II clinical trials. Plocabulin has potent antiproliferative and antiangiogenic actions in carcinoma cell lines and has antitumor activity in xenografted mice. Here, we used three-dimensional (3D) tumor organoids derived from three colorectal cancer (CRC) patients to study the effect of plocabulin in a personalized assay system that ensures dose dependence and high reproducibility. The cytotoxicity of plocabulin was an order of magnitude higher than that of the active irinotecan derivative SN38 (7-ethyl-10-hydroxy-camptothecin) in tumor organoids at different passages. Moreover, plocabulin maintained its strong cytotoxic activity in wash-out experiments, in which a short pulse treatment of tumor organoids was as efficient as continuous treatment. Our data show that plocabulin has a very potent cytotoxic action in CRC patient-derived tumor organoids, supporting ongoing clinical trials with plocabulin and the use of organoid assays to provide personalized validation of antitumor drugs.

Detection, Averaging, and 3D Reconstruction of Biological Specimens on Hypercubes (Transputer-based) Computers

1990 ◽  
Vol 48 (1) ◽  
pp. 454-455
Author(s):  
Jose-Maria Carazo ◽  
I. Benavides ◽  
S. Marco ◽  
J.L. Carrascosa ◽  
E.L. Zapata
Keyword(s):  
3D Reconstruction ◽  
3D Structure ◽  
Three Dimensional ◽  
Software Tools ◽  
Mapping Method ◽  
Computer Architectures ◽  
Parallel Computer ◽  
Reconstruction Process ◽  
Computing Power ◽  
Order Of Magnitude

Obtaining the three-dimensional (3D) structure of negatively stained biological specimens at a resolution of, typically, 2 - 4 nm is becoming a relatively common practice in an increasing number of laboratories. A combination of new conceptual approaches, new software tools, and faster computers have made this situation possible. However, all these 3D reconstruction processes are quite computer intensive, and the middle term future is full of suggestions entailing an even greater need of computing power. Up to now all published 3D reconstructions in this field have been performed on conventional (sequential) computers, but it is a fact that new parallel computer architectures represent the potential of order-of-magnitude increases in computing power and should, therefore, be considered for their possible application in the most computing intensive tasks.We have studied both shared-memory-based computer architectures, like the BBN Butterfly, and local-memory-based architectures, mainly hypercubes implemented on transputers, where we have used the algorithmic mapping method proposed by Zapata el at. In this work we have developed the basic software tools needed to obtain a 3D reconstruction from non-crystalline specimens (“single particles”) using the so-called Random Conical Tilt Series Method. We start from a pair of images presenting the same field, first tilted (by ≃55°) and then untilted. It is then assumed that we can supply the system with the image of the particle we are looking for (ideally, a 2D average from a previous study) and with a matrix describing the geometrical relationships between the tilted and untilted fields (this step is now accomplished by interactively marking a few pairs of corresponding features in the two fields). From here on the 3D reconstruction process may be run automatically.

Scanning-tunneling spectroscopy on conjugated polymer films

2003 ◽  
Vol 771 ◽  
Author(s):  
M. Kemerink ◽  
S.F. Alvarado ◽  
P.M. Koenraad ◽  
R.A.J. Janssen ◽  
H.W.M. Salemink ◽  
...  
Keyword(s):  
Polymer Films ◽  
Conjugated Polymer ◽  
Three Dimensional ◽  
Field Enhancement ◽  
Direct Consequence ◽  
Scanning Tunneling Spectroscopy ◽  
Tunneling Spectroscopy ◽  
Band Alignment ◽  
Scanning Tunneling ◽  
Order Of Magnitude

AbstractScanning-tunneling spectroscopy experiments have been performed on conjugated polymer films and have been compared to a three-dimensional numerical model for charge injection and transport. It is found that field enhancement near the tip apex leads to significant changes in the injected current, which can amount to more than an order of magnitude, and can even change the polarity of the dominant charge carrier. As a direct consequence, the single-particle band gap and band alignment of the organic material can be directly obtained from tip height-voltage (z-V) curves, provided that the tip has a sufficiently sharp apex.

Current RNA-based Therapeutics in Clinical Trials

2019 ◽  
Vol 19 (3) ◽  
pp. 172-196 ◽  
Author(s):  
Ling-Yan Zhou ◽  
Zhou Qin ◽  
Yang-Hui Zhu ◽  
Zhi-Yao He ◽  
Ting Xu
Keyword(s):  
Clinical Trials ◽  
Rapid Development ◽  
Genetic Diseases ◽  
Three Dimensional ◽  
Therapeutic Effects ◽  
Messenger Rnas ◽  
Small Interfering Rnas ◽  
Rna Modifications ◽  
Guide Rna ◽  
Endogenous Genes

Long-term research on various types of RNAs has led to further understanding of diverse mechanisms, which eventually resulted in the rapid development of RNA-based therapeutics as powerful tools in clinical disease treatment. Some of the developing RNA drugs obey the antisense mechanisms including antisense oligonucleotides, small interfering RNAs, microRNAs, small activating RNAs, and ribozymes. These types of RNAs could be utilized to inhibit/activate gene expression or change splicing to provide functional proteins. In the meantime, some others based on different mechanisms like modified messenger RNAs could replace the dysfunctional endogenous genes to manage some genetic diseases, and aptamers with special three-dimensional structures could bind to specific targets in a high-affinity manner. In addition, the recent most popular CRISPR-Cas technology, consisting of a crucial single guide RNA, could edit DNA directly to generate therapeutic effects. The desired results from recent clinical trials indicated the great potential of RNA-based drugs in the treatment of various diseases, but further studies on improving delivery materials and RNA modifications are required for the novel RNA-based drugs to translate to the clinic. This review focused on the advances and clinical studies of current RNA-based therapeutics, analyzed their challenges and prospects.

scholarly journals Origin and Application of the Twinned Calcite Strain Gauge

Geosciences ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 296
Author(s):  
Richard H. Groshong
Keyword(s):  
Stress Analysis ◽  
Strain Gauge ◽  
Strain Tensor ◽  
Three Dimensional ◽  
Constant Strain Rate ◽  
Axis Orientation ◽  
Order Of Magnitude ◽  
Rate Experiment ◽  
Strain Axis ◽  
Expected Values

This paper is a personal account of the origin and development of the twinned-calcite strain gauge, its experimental verification, and its relationship to stress analysis. The method allows the calculation of the three-dimensional deviatoric strain tensor based on five or more twin sets. A minimum of about 25 twin sets should provide a reasonably accurate result for the magnitude and orientation of the strain tensor. The opposite-signed strain axis orientation is the most accurately located. Where one strain axis is appreciably different from the other two, that axis is generally within about 10° of the correct value. Experiments confirm a magnitude accuracy of 1% strain over the range of 1–12% axial shortening and that samples with more than 40% negative expected values imply multiple or rotational deformations. If two deformations are at a high angle to one another, the strain calculated from the positive and negative expected values separately provides a good estimate of both deformations. Most stress analysis techniques do not provide useful magnitudes, although most provide a good estimate of the principal strain axis directions. Stress analysis based on the number of twin sets per grain provides a better than order-of-magnitude approximation to the differential stress magnitude in a constant strain rate experiment.

scholarly journals Small footprint optoelectrodes using ring resonators for passive light localization

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Vittorino Lanzio ◽  
Gregory Telian ◽  
Alexander Koshelev ◽  
Paolo Micheletti ◽  
Gianni Presti ◽  
...  
Keyword(s):  
State Of The Art ◽  
Three Dimensional ◽  
Network Activity ◽  
Ring Resonators ◽  
Spatiotemporal Resolution ◽  
Optical Ring Resonators ◽  
Light Localization ◽  
Order Of Magnitude ◽  
Small Footprint

AbstractThe combination of electrophysiology and optogenetics enables the exploration of how the brain operates down to a single neuron and its network activity. Neural probes are in vivo invasive devices that integrate sensors and stimulation sites to record and manipulate neuronal activity with high spatiotemporal resolution. State-of-the-art probes are limited by tradeoffs involving their lateral dimension, number of sensors, and ability to access independent stimulation sites. Here, we realize a highly scalable probe that features three-dimensional integration of small-footprint arrays of sensors and nanophotonic circuits to scale the density of sensors per cross-section by one order of magnitude with respect to state-of-the-art devices. For the first time, we overcome the spatial limit of the nanophotonic circuit by coupling only one waveguide to numerous optical ring resonators as passive nanophotonic switches. With this strategy, we achieve accurate on-demand light localization while avoiding spatially demanding bundles of waveguides and demonstrate the feasibility with a proof-of-concept device and its scalability towards high-resolution and low-damage neural optoelectrodes.

scholarly journals Toxicity of Combinations of Kinase Pathway Inhibitors to Normal Human Cells in a Three-Dimensional Culture

2021 ◽  
pp. 247263032110088
Author(s):  
Pouria Rafsanjani Nejad ◽  
Pradip Shahi Thakuri ◽  
Sunil Singh ◽  
Astha Lamichhane ◽  
Jacob Heiss ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Protein Kinase ◽  
Single Agent ◽  
Three Dimensional ◽  
Drug Combinations ◽  
Toxic Effects ◽  
Combination Drug ◽  
Normal Cells ◽  
Colon Cells

Resistance to single-agent chemotherapy and molecularly targeted drugs prevents sustained efficacy of treatments. To address this challenge, combination drug treatments have been used to improve outcomes for patients. Potential toxicity of combination treatments is a major concern, however, and has led to the failure of several clinical trials in different cancers. The use of cell-based models of normal tissues in preclinical studies enables testing and identifying toxic effects of drug combinations and facilitates an informed decision-making process for advancing the treatments to animal models and clinical trials. Recently, we established that combinations of molecular inhibitors of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase–protein kinase B (PI3K/Akt) pathways effectively and synergistically inhibit growth of BRAFmut and KRASmut colorectal tumor spheroids by blocking feedback signaling of downstream kinase pathways. These pathways are important for cell proliferation, however, and their simultaneous inhibition may cause toxicity to normal cells. We used a cellular spheroid model to study toxicities of drug combinations to human bone marrow and colon. Our results indicated that MAPK and PI3K/Akt inhibitors used simultaneously were only moderately toxic to bone marrow cells but significantly more toxic to colon cells. Our molecular analysis of proliferative cell activities and housekeeping proteins further corroborated these results. Overall, our approach to identify toxic effects of combinations of cancer drugs to normal cells in three-dimensional cultures will facilitate more informed treatment selections for subsequent animal studies.

scholarly journals Target alignment in the Shen-Guang II Upgrade laser facility

2018 ◽  
Vol 6 ◽  
Author(s):  
Lei Ren ◽  
Ping Shao ◽  
Dongfeng Zhao ◽  
Yang Zhou ◽  
Zhijian Cai ◽  
...  
Keyword(s):  
Inertial Confinement Fusion ◽  
Short Pulse ◽  
Three Dimensional ◽  
Nanosecond Laser ◽  
Alignment Error ◽  
Inertial Confinement ◽  
Pulse Beam ◽  
Rotation Sensor ◽  
Confinement Fusion ◽  
Laser Facility

The Shen-Guang II Upgrade (SG-II-U) laser facility consists of eight high-power nanosecond laser beams and one short-pulse picosecond petawatt laser. It is designed for the study of inertial confinement fusion (ICF), especially for conducting fast ignition (FI) research in China and other basic science experiments. To perform FI successfully with hohlraum targets containing a golden cone, the long-pulse beam and cylindrical hohlraum as well as the short-pulse beam and cone target alignment must satisfy tight specifications (30 and $20~\unicode[STIX]{x03BC}\text{m}$ rms for each case). To explore new ICF ignition targets with six laser entrance holes (LEHs), a rotation sensor was adapted to meet the requirements of a three-dimensional target and correct beam alignment. In this paper, the strategy for aligning the nanosecond beam based on target alignment sensor (TAS) is introduced and improved to meet requirements of the picosecond lasers and the new six LEHs hohlraum targets in the SG-II-U facility. The expected performance of the alignment system is presented, and the alignment error is also discussed.

An Improved Assembling Algorithm in Boundary Elements With Galerkin Weighting Applied to Three-Dimensional Stokes Flows

2017 ◽  
Vol 140 (1) ◽  
Author(s):  
Sofia Sarraf ◽  
Ezequiel López ◽  
Laura Battaglia ◽  
Gustavo Ríos Rodríguez ◽  
Jorge D'Elía
Keyword(s):  
Boundary Element Method ◽  
Linear System ◽  
Boundary Element ◽  
Numerical Solutions ◽  
Three Dimensional ◽  
Boundary Integral ◽  
Computational Time ◽  
Creeping Flows ◽  
Order Of Magnitude ◽  
Element Method

In the boundary element method (BEM), the Galerkin weighting technique allows to obtain numerical solutions of a boundary integral equation (BIE), giving the Galerkin boundary element method (GBEM). In three-dimensional (3D) spatial domains, the nested double surface integration of GBEM leads to a significantly larger computational time for assembling the linear system than with the standard collocation method. In practice, the computational time is roughly an order of magnitude larger, thus limiting the use of GBEM in 3D engineering problems. The standard approach for reducing the computational time of the linear system assembling is to skip integrations whenever possible. In this work, a modified assembling algorithm for the element matrices in GBEM is proposed for solving integral kernels that depend on the exterior unit normal. This algorithm is based on kernels symmetries at the element level and not on the flow nor in the mesh. It is applied to a BIE that models external creeping flows around 3D closed bodies using second-order kernels, and it is implemented using OpenMP. For these BIEs, the modified algorithm is on average 32% faster than the original one.

scholarly journals Dynamics of Three-Dimensional Turbulent Wall Plumes and Implications for Estimates of Submarine Glacier Melting

2018 ◽  
Vol 48 (9) ◽  
pp. 1941-1950 ◽  
Author(s):  
Ekaterina Ezhova ◽  
Claudia Cenedese ◽  
Luca Brandt
Keyword(s):  
Three Dimensional ◽  
Characteristic Parameters ◽  
Buoyant Plumes ◽  
Tidewater Glaciers ◽  
Glacier Melting ◽  
Order Of Magnitude ◽  
Layer Flow ◽  
Using Data ◽  
Turbulent Wall ◽  
Wall Plume

AbstractSubglacial discharges have been observed to generate buoyant plumes along the ice face of Greenland tidewater glaciers. These plumes have been traditionally modeled using classical plume theory, and their characteristic parameters (e.g., velocity) are employed in the widely used three-equation melt parameterization. However, the applicability of plume theory for three-dimensional turbulent wall plumes is questionable because of the complex near-wall plume dynamics. In this study, corrections to the classical plume theory are introduced to account for the presence of a wall. In particular, the drag and entrainment coefficients are quantified for a three-dimensional turbulent wall plume using data from direct numerical simulations. The drag coefficient is found to be an order of magnitude larger than that for a boundary layer flow over a flat plate at a similar Reynolds number. This result suggests a significant increase in the melting estimates by the current parameterization. However, the volume flux in a wall plume is found to be one-half that of a conical plume that has 2 times the buoyancy flux. This finding suggests that the total entrainment (per unit area) of ambient water is the same and that the plume scalar characteristics (i.e., temperature and salinity) can be predicted reasonably well using classical plume theory.

scholarly journals Direct AFM-based nanoscale mapping and tomography of open-circuit voltages for photovoltaics

2018 ◽  
Vol 9 ◽  
pp. 1802-1808 ◽  
Author(s):  
Katherine Atamanuk ◽  
Justin Luria ◽  
Bryan D Huey
Keyword(s):  
Solar Cells ◽  
Open Circuit Voltage ◽  
Short Circuit ◽  
Photovoltaic Performance ◽  
Three Dimensional ◽  
Short Circuit Current ◽  
Open Circuit ◽  
Photovoltaic Properties ◽  
Order Of Magnitude ◽  
Individual Grains

The nanoscale optoelectronic properties of materials can be especially important for polycrystalline photovoltaics including many sensor and solar cell designs. For thin film solar cells such as CdTe, the open-circuit voltage and short-circuit current are especially critical performance indicators, often varying between and even within individual grains. A new method for directly mapping the open-circuit voltage leverages photo-conducting AFM, along with an additional proportional-integral-derivative feedback loop configured to maintain open-circuit conditions while scanning. Alternating with short-circuit current mapping efficiently provides complementary insight into the highly microstructurally sensitive local and ensemble photovoltaic performance. Furthermore, direct open-circuit voltage mapping is compatible with tomographic AFM, which additionally leverages gradual nanoscale milling by the AFM probe essentially for serial sectioning. The two-dimensional and three-dimensional results for CdTe solar cells during in situ illumination reveal local to mesoscale contributions to PV performance based on the order of magnitude variations in photovoltaic properties with distinct grains, at grain boundaries, and for sub-granular planar defects.

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