gebhart/patrepeval huggingface dataset:
EXTH-77. ONC201 EXHIBITS PASSIVE DIFFUSION AND BROAD DISTRIBUTION IN THE CENTRAL NERVOUS SYSTEM (2020)

Abstract Imipridone ONC201 is an investigational agent in phase II clinical trials for H3 K27M-mutant diffuse midline glioma with evidence of durable objective responses and clinical symptom improvements as a single agent. The systemic pharmacokinetics of ONC201 and its ability to achieve target concentrations in supratentorial glioblastoma have been demonstrated in clinical trials; however, its clearance and distribution in midline structures and other areas of the central nervous system (CNS) haven’t been evaluated. A quantitative whole-body autoradiography study was conducted in Long-Evans rats with a single dose of [14C]-ONC201. [14C]-ONC201-related material was rapidly distributed throughout the body, with concentrations peaking at 1h for most tissues. The endocrine, metabolic/excretory, ocular and gastrointestinal tract tissues contained the highest distribution of [14C]-ONC201-derived radioactivity. Importantly, [14C]-ONC201 material was distributed evenly across brain substructures, including the meninges and midline structures of the brain; all tissues had a half-life of 1.4–7.9h, with the exception of the meninges (2397.3h). Given the uniform distribution throughout the CNS, we evaluated the permeability and efflux potential of ONC201 in bidirectional transport assays using human Caco-2 cell monolayers. ONC201 displayed high permeability in the apical to basolateral direction with apparent permeability values of 23–31×10–6 cm/s at 7–700μM. In the basolateral to apical direction, apparent permeability values were 11–24 × 10–6 cm/s. The efflux ratio values were 0.46–0.79 for ONC201, suggesting that ONC201 is not a substrate of efflux transporters. However, ONC201 exerted inhibitory potential on MDR1- (90.6%) and BCRP-mediated (81.6%) transport at 200mM. In summary, ONC201 exhibits passive diffusion without being effluxed, which may enable its rapid and wide distribution throughout the CNS. This distribution profile suggests that the compound may achieve therapeutic concentrations throughout the CNS with oral administration and that investigation of additional CNS tumors will not be hindered by drug delivery to specific anatomic structures.
Artifacts introduced by ion milling in Al‐Li‐Cu alloys (1988)

Ion milling is commonly used to prepare specimens for observation under transmission electron microscope (TEM). This technique sometimes introduces artifacts in specimens contributing to misleading interpretation of TEM results as observed in the present investigation of Al-Li-Cu alloys. This type of alloy, in general, contains several kinds of precipitates, namely delta', T1, and theta'. It is found that ion milling even for a short time produces drastic changes in the precipitate characteristics as compared to standard electropolishing methods of specimen preparation for TEM. Careful analysis of selected area diffraction patterns and micrographs shows that after ion milling delta' precipitates are very irregular, whereas other precipitates coarsen and they are surrounded by misfit dislocations. In situ hot-stage TEM experiments were performed to relate the microstructure to that observed in the ion-milled specimen. Results and causes of ion milling effects on the microstructure are discussed in relation to standard electropolishing techniques and in situ hot-stage experiment.
Current and future flexible wavelength routing cross-connects (2013)

Existing and evolving telecommunication services rely upon transport infrastructure for their carriage, including that provided by wavelength division multiplexing (WDM) based networking. In order to maximize reach in the photonic domain, thus limiting the total number of costly and power-greedy optoelectronic regenerators required for reliable transport, optimization of wavelength routing cross-connect (WRXC) properties is essential. There are several relevant WRXC properties. These include low physical impact on optical channels, enabling usage of advanced modulation formats with high spectral efficiency, support for flexible wavelength allocation as well as multi-directional, colorless, and contentionless insertion/ extraction of traffic, resilience against failures, and automatic lightpath setup. Other factors supporting WRXC deployment involve fair initial cost, compactness and modularity, and scalability to high connectivity and to significant add/drop capacity. Some of these features are a “must have” whereas others are a “nice to have.” This paper reviews the primary trends affecting current and future WRXC evolution considering these functionalities as well as the corresponding tradeoffs.
Supplementary Table 2 from Cleaved NOTCH1 Expression Pattern in Head and Neck Squamous Cell Carcinoma Is Associated with NOTCH1 Mutation, HPV Status, and High-Risk Features (2023)

&lt;p&gt;Supplementary Table 2. Clinicopathological characteristics associated with NICD1 IHC staining pattern for NOTCH1-wild type only.&lt;/p&gt;
Summary Abstract: Rotational state population of NO scattered from clean and absorbate-covered Pt surfaces (1983)

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An Antiparasitic Compound from the Medicines for Malaria Venture Pathogen Box Promotes Leishmania Tubulin Polymerization (2020)

The few frontline antileishmanial drugs are poorly effective and toxic. To search for new drugs for this neglected tropical disease, we tested the activity of compounds in the Medicines for Malaria Venture (MMV) "Pathogen Box" against <i>Leishmania amazonensis</i> axenic amastigotes. Screening yielded six discovery antileishmanial compounds with EC<sub>50</sub> values from 50 to 480 nM. Concentration-response assays demonstrated that the best hit, MMV676477, had mid-nanomolar cytocidal potency against intracellular <i>Leishmania</i> amastigotes, <i>Trypanosoma brucei</i>, and <i>Plasmodium falciparum</i>, suggesting broad antiparasitic activity. We explored structure-activity relationships (SAR) within a small group of MMV676477 analogs and observed a wide potency range (20-5000 nM) against axenic <i>Leishmania</i> amastigotes. Compared to MMV676477, our most potent analog, SW41, had ∼5-fold improved antileishmanial potency. Multiple lines of evidence suggest that MMV676477 selectively disrupts <i>Leishmania</i> tubulin dynamics. Morphological studies indicated that MMV676477 and analogs affected <i>L. amazonensis</i> during cell division. Differential centrifugation showed that MMV676477 promoted partitioning of cellular tubulin toward the polymeric form in parasites. Turbidity assays with purified <i>Leishmania</i> and porcine tubulin demonstrated that MMV676477 promoted leishmanial tubulin polymerization in a concentration-dependent manner. Analogs' antiparasitic activity correlated with their ability to facilitate purified <i>Leishmania</i> tubulin polymerization. Chemical cross-linking demonstrated binding of the MMV676477 scaffold to purified <i>Leishmania</i> tubulin, and competition studies established a correlation between binding and antileishmanial activity. Our studies demonstrate that MMV676477 is a potent antiparasitic compound that preferentially promotes <i>Leishmania</i> microtubule polymerization. Due to its selectivity for and broad-spectrum activity against multiple parasites, this scaffold shows promise for antiparasitic drug development.
NKT Cell–Driven Enhancement of Antitumor Immunity Induced by Clec9a-Targeted Tailorable Nanoemulsion (2019)

Invariant natural killer T (iNKT) cells are a subset of lymphocytes with immune regulatory activity. Their ability to bridge the innate and adaptive immune systems has been studied using the glycolipid ligand α-galactosylceramide (αGC). To better harness the immune adjuvant properties of iNKT cells to enhance priming of antigen-specific CD8<sup>+</sup> T cells, we encapsulated both αGC and antigen in a Clec9a-targeted nanoemulsion (TNE) to deliver these molecules to cross-presenting CD8<sup>+</sup> dendritic cells (DC). We demonstrate that, even in the absence of exogenous glycolipid, iNKT cells supported the maturation of CD8α<sup>+</sup> DCs to drive efficient cross-priming of antigen-specific CD8<sup>+</sup> T cells upon delivery of Clec9a/OVA-TNE. The addition of αGC to the TNE (Clec9a/OVA/αGC) further enhanced activation of iNKT cells, NK cells, CD8α<sup>+</sup> DCs, and polyfunctional CD8<sup>+</sup> T cells. When tested therapeutically against HPVE7-expressing TC-1 tumors, long-term tumor suppression was achieved with a single administration of Clec9a/E7 peptide/αGC TNE. Antitumor activity was correlated with the recruitment of mature DCs, NK cells, and tumor-specific effector CD8<sup>+</sup> T cells to the tumor-draining lymph node and tumor tissue. Thus, Clec9a-TNE codelivery of CD8<sup>+</sup> T-cell epitopes with αGC induces alternative helper signals from activated iNKT cells, elicits innate (iNKT, NK) immunity, and enhances antitumor CD8<sup>+</sup> T-cell responses for control of solid tumors.
MRI: recent advances and new horizons (2013)

In the past 10 years, a variety of innovative MRI approaches have been proposed for the noninvasive assessment of molecular or cellular events. While MRI is intrinsically a molecular imaging technique, it has to cope with its inherent low sensitivity and consequently has to be performed on a large number of nuclei. The assessment of specific molecular processes occurring at the cellular level requires generating or modulating magnetic resonance signals with exogenous probes to overcome this intrinsic lack of sensitivity. A variety of highly promising approaches will be reviewed to achieve this goal through the increase of the detected signal, the development of specific probes generating field-dependent relaxation properties and of the associated imaging hardware to make use of such contrast mechanisms. Recent developments drawing future perspectives will then be reported and their respective outcomes will be discussed.
Endothelial dysfunction in the pathogenesis of acute Lassa Fever (2018)

Abstract Lassa fever (LF) is an acute disease characterized by enhanced vascular permeability resulting from infection with Lassa virus (LV), a non-lytic, Old World arenavirus. Animal models of arenavirus-induced vascular damage suggest that cytotoxic CD8+ T cells serve a critical role in the destruction of vascular endothelium by destroying LV infected endothelial cells as well as impairing platelet aggregation. Using plasma samples from acute LF patients, we sought to identify predictive biomarkers associated with endothelial integrity and platelet aggregation in fatal versus non-fatal LF cases by testing platelet function and measuring hemostasis markers with ELISA. We discovered a significant increase in plasminogen activation inhibitor-1 (PAI-1), endothelial protein C receptor (EPCR) and thrombomodulin in LF Ag+ cases compared to LF IgM+ and febrile non-LF controls. In addition, platelets from uninfected controls displayed decreased aggregation when mixed with plasma from 28 of 33 acute LF patients compared to plasma from uninfected controls. Our results demonstrate that severe LF (determined by Ag positivity) is associated with platelet dysfunction and abnormal regulation of coagulation, and suggest that similar to the LCMV Clone 13 model, immune-mediated endothelial activation leading to loss of barrier function, impaired hemostasis, and altered thrombogenicity may be an important mechanism in the pathogenesis of acute LF. Studies are underway to relate these biomarkers to the state of T cell activation in this cohort of patients.
Computer extracted nuclear features from tumor and benign regions of Feulgen and H&E images to help predict recurrence in prostate cancer patients following radical prostatectomy. (2017)

e16556 Background: Following radical prostatectomy, around 30% of prostate cancer (PCa) patients experience biochemical recurrence (BCR). H&amp;E highlights nuclear morphology and Feulgen reflects nuclear DNA content, a feature linked to PCa presence and aggressiveness. In this work we sought to explore whether computer extracted measurements of tumor morphology and tumor adjacent benign regions on H&amp;E and Feulgen tissue images could predict BCR. Methods: We used 108 patients (59 BCR and 49 non-recurrence (NR)) and each patient had 242 QH features calculated from both the tumor and benign region of stained TMA core images. Feature selection was performed on a training set (30 BCR, 24 NR) to select the 10 most discriminating tumor and tumor adjacent benign features of each stain. A random forest classifier was trained with features so identified and validated on a test set (29 BCR, 25 NR) to predict BCR. Predictions were displayed using Kaplan-Meier analysis and area under the ROC curve (AUC). Results: The most discriminating feature from the tumor regions of the H&amp;E stain was Fourier descriptors of nuclear shape and from the Feulgen stain was texture intensity while from the benign regions it was invariant moments of nuclear shape and texture contrast energy. Combining the significant features from tumor and tumor adjacent benign regions from H&amp;E and Feulgen resulted in the highest accuracy and a statistically significant difference (p &lt; 0.05) via a log-rank test (Table 1). Gleason score did not show statistically significant differences and had the lowest AUC. Conclusions: Combining nuclear morphology and DNA related features of the tumor and tumor adjacent benign regions enabled accurate prediction of BCR. With additional multi-site validation, the combined H&amp;E + Feulgen classifier could allow better risk stratification and post-surgical patient management. [Table: see text]
Analytical formulation and electrical measurements of self-heating in silicon BJT's (2003)

A new analytical formulation of the temperature at thermal runaway in silicon BJT's is presented and supported by measurements on a thermally very sensitive silicon-on-glass process. The linear relationship between V/sub BE/ and V/sub CB/ for a given collector current is used to define a straightforward method for electrically determining the biasing conditions at thermal runaway.
Phase IA/II, multicentre, open‐label study of the CD40 antagonistic monoclonal antibody lucatumumab in adult patients with advanced non‐Hodgkin or Hodgkin lymphoma (2013)

Despite advancements in the treatment of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL), patients continue to relapse and thus a need for new targeted therapies remains. The CD40 receptor is highly expressed on neoplastic B cells and activation leads to enhanced proliferation and survival. Lucatumumab (HCD122) is a fully human antagonistic CD40 monoclonal antibody. A phase IA/II study was designed to determine the maximum tolerated dose (MTD) and activity of lucatumumab in patients with relapsed/refractory lymphoma. Determination of the MTD was the primary objective of the phase IA dose escalation portion and clinical response was the primary objective of the phase II dose expansion portion. Patients received escalating doses of lucatumumab administered intravenously once weekly for 4 weeks of an 8-week cycle. MTD was determined at 4 mg/kg of lucatumumab. A total of 111 patients with NHL (n = 74) and HL (n = 37) were enrolled. Responses were observed across various lymphoma subtypes. The overall response rate by computed tomography among patients with follicular lymphoma (FL) and marginal zone lymphoma of mucosa-associated lymphatic tissue (MZL/MALT) was 33·3% and 42·9%, respectively. Lucatumumab demonstrates modest activity in relapsed/refractory patients with advanced lymphoma, suggesting that targeting of CD40 warrants further investigation.
Peak rate enforcement in ATM networks (1992)

The authors address peak rate enforcement in asynchronous transfer mode (ATM) networks by pick-up policing mechanisms. Since the network cannot rely on user's compliance when declaring his traffic parameters, the policing function has been introduced to monitor the traffic characteristics of any connection. Policing mechanisms proposed in the literature are actually pick-up mechanisms since cells can pass transparently through unless a policing action was performed according to some counting process. The authors analyze the impact of the cell multiplexing jitter on policing mechanism dimensioning. Recognizing that dimensioning is a critical point for such mechanisms. It is shown that network buffer overflow cannot be avoided in certain conditions. Therefore, a new policing scheme, called cell spacing, is introduced, and two spacing algorithms are presented.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Energy-efficient dynamic load distribution for heterogeneous access networks (2013)

In heterogeneous wireless access networks, it is important to achieve high variability of access resources. Bandwidth Aggregation (BAG) is considered to be a promising solution for this objective. However, power consumption has not been adequately addressed, although prolonging the battery life time of mobile devices with low power consumption has received attention lately. In this paper, we propose a novel dynamic energy-efficient load distribution algorithm for heterogeneous wireless networks. For the optimal load distribution, which is challenging combinatorial problem, we propose simple greedy load distribution algorithms that are inspired by the mathematical background of the Lagrangian algorithm. Furthermore, we propose another heuristic algorithm that extends the proposed algorithm when the retransmission scheme is hired for packet loss (e.g, TCP). Finally, an extensive Network Simulator 2 (NS2) simulation under various practical configurations demonstrates that the proposed algorithm could converge to the optimal distribution point with low complexity. Furthermore, it gives significantly increased the battery life time of mobile device with guarantee required Quality of Service (QoS) constraints.
Low Voltage Electron Microscopy (LVEM) as a Probe for Solubilized Membrane Protein Aggregation States (2004)

Extended abstract of a paper presented at Microscopy and Microanalysis 2004 in Savannah, Georgia, USA, August 1–5, 2004.
Direct gap photoluminescence of n-type tensile-strained Ge-on-Si (2009)

Room temperature direct gap photoluminescence (PL) was observed from n-type tensile-strained epitaxial Ge-on-Si. The PL intensity increases with n-type doping due to a higher electron population in the direct Γ valley as a result of increased Fermi level. The direct gap emission also increases with temperature due to thermal excitation of electrons into the direct Γ valley, exhibiting robustness to heating effects. These unique properties of direct gap emission in an indirect gap material agree with our theoretical model and make Ge a promising light emitting material in 1550 nm communication band.
Controlling Molecular Synthesis in the Solid State Using Linear Templates (2003)

Abstract For Abstract see ChemInform Abstract in Full Text.
Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial (2023)

Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2-20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1-69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7-13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05-0.87). A total of 56.2% (95% CI 41.1-70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).
Variable spreading factor-OFCDM with two dimensional spreading that prioritizes time domain spreading for forward link broadband wireless access (2004)

This paper proposes the optimum design for adaptively controlling the spreading factor in orthogonal frequency and code division multiplexing (OFCDM) with two-dimensional spreading according to the cell configuration, channel load, and propagation channel conditions, assuming the adaptive modulation and channel coding (AMC) scheme employing QPSK and 16QAM data modulation. Furthermore, we propose a two-dimensional channelization code assignment scheme to achieve skillfully orthogonal multiplexing of multiple physical channels. Computer simulation results elucidate that bit-interleaving in the frequency domain is superior to chip-interleaving especially for a full channel load because bit-interleaving exhibits a large randomization effect of burst errors, while still maintaining code orthogonality. In time domain spreading, the optimum spreading factor, except for an extremely high mobility case such as for the fading maximum Doppler frequency f/sub D/ = 1500 Hz, becomes SF/sub Time/ = 16, and it should be decreased to SF/sub Time/ = 8 for such a very fast fading environment using 16QAM modulation. When the channel load is light such as C/sub mux//SF = 0.25 (C/sub mux/ and SF denote the number of multiplexed codes and total spreading factor, respectively), the required average received signal energy per symbol-to-background noise power spectrum density ratio (E/sub s//N/sub 0/) is reduced as the spreading factor in the frequency domain is increased up to say SF/sub Freq/ = 32 for QPSK and 16QAM modulation, respectively (Note that, nevertheless, 16QAm modulation under such a lighter channel load condition is replaced by QPSK modulation together with two fold the channel load as 16QAM to achieve the same information bit rate). Meanwhile, when the channel load is close to full such as when C/sub mux//SF = 0.94, the optimum spreading factor in the frequency domain is SF/sub Freq/ = 1 for 16QAM modulation and SF/sub Freq/ = 1 to 8 for QPSK modulation according to the delay spread. Consequently, by setting several combinations of spreading factors in the time and frequency domains, the near maximum link capacity is achieved both in cellular and hot-spot cell configurations assuming various channel conditions.