gebhart/patrepeval huggingface dataset:
Everolimus in renal cell carcinoma (2010)

Everolimus (also known as RAD-001; Afinitor®) is an orally active inhibitor of the intracellular protein kinase mammalian target of rapamycin. The U.S. Food and Drug Administration and the European Medicines Agency recently approved everolimus for the treatment of advanced renal cell carcinoma (RCC) on the basis of the results of a randomized phase III clinical trial. In the trial, 10 mg daily everolimus was effective and well tolerated by patients with advanced RCC, whose disease had progressed while under the treatment with sunitinib and/or sorafenib. Everolimus treatment led to 36% of 6-month progression-free survival (PFS) rate and 31% of 3-month PFS rate. Most of the adverse events were mild to moderate (grade 1-2) in severity. The most frequent grade 3-4 adverse events were stomatitis, fatigue, pneumonitis and infections. Clinical trials on everolimus in combination with sunitinib, sorafenib, imatinib and vatalanib for the treatment of RCC are ongoing.
HDAC3 is crucial in shear- and VEGF-induced stem cell differentiation toward endothelial cells (2006)

Reendothelialization involves endothelial progenitor cell (EPC) homing, proliferation, and differentiation, which may be influenced by fluid shear stress and local flow pattern. This study aims to elucidate the role of laminar flow on embryonic stem (ES) cell differentiation and the underlying mechanism. We demonstrated that laminar flow enhanced ES cell-derived progenitor cell proliferation and differentiation into endothelial cells (ECs). Laminar flow stabilized and activated histone deacetylase 3 (HDAC3) through the Flk-1-PI3K-Akt pathway, which in turn deacetylated p53, leading to p21 activation. A similar signal pathway was detected in vascular endothelial growth factor-induced EC differentiation. HDAC3 and p21 were detected in blood vessels during embryogenesis. Local transfer of ES cell-derived EPC incorporated into injured femoral artery and reduced neointima formation in a mouse model. These data suggest that shear stress is a key regulator for stem cell differentiation into EC, especially in EPC differentiation, which can be used for vascular repair, and that the Flk-1-PI3K-Akt-HDAC3-p53-p21 pathway is crucial in such a process.
F0 generation mice fully derived from gene-targeted embryonic stem cells allowing immediate phenotypic analyses (2006)

A useful approach for exploring gene function involves generating mutant mice from genetically modified embryonic stem (ES) cells. Recent advances in genetic engineering of ES cells have shifted the bottleneck in this process to the generation of mice. Conventional injections of ES cells into blastocyst hosts produce F0 generation chimeras that are only partially derived from ES cells, requiring additional breeding to obtain mutant mice that can be phenotyped. The tetraploid complementation approach directly yields mice that are almost entirely derived from ES cells, but it is inefficient, works only with certain hybrid ES cell lines and suffers from nonspecific lethality and abnormalities, complicating phenotypic analyses. Here we show that laser-assisted injection of either inbred or hybrid ES cells into eight cell-stage embryos efficiently yields F0 generation mice that are fully ES cell-derived and healthy, exhibit 100% germline transmission and allow immediate phenotypic analysis, greatly accelerating gene function assignment.
Charge and lipophilicity govern the pharmacokinetics of glycopeptide antibiotics (1986)

The pharmacokinetics and urinary excretion of nine glycopeptide antibiotics with diverse pIs (3.8 to 8.5) and lipophilicities were studied. The disposition of the aridicin antibiotics and their hydrolysis products were examined in male CD-1 mice after subcutaneous and intravenous administration and compared with the disposition of teicoplanin, ristocetin, and vancomycin. The total systemic clearance, half-life, volume of distribution, and urinary excretion were highly correlated with pIs. In general, as the pI decreased, the clearance, urinary recovery, and volume of distribution decreased, whereas the half-life increased. With those glycopeptides that had similar pIs, clearance decreased and half-life increased with increasing lipophilicity. The urinary recovery of the glycopeptides decreased with decreasing pI and increasing lipophilicity. Because vancomycin (pI = 8.0) is cleared by glomerular filtration, increased binding to serum is the likely mechanism of reduced renal clearance for glycopeptides with low pIs. These results are consistent with previous findings concerning the correlation of physical-chemical properties and the drug disposition of small organic molecules. Results of these studies also indicate that desirable pharmacokinetic properties can be incorporated into glycopeptides through semisynthetic modifications.
Identification of the gene that codes for the σ2receptor (2017)

The σ<sub>2</sub> receptor is an enigmatic protein that has attracted significant attention because of its involvement in diseases as diverse as cancer and neurological disorders. Unlike virtually all other receptors of medical interest, it has eluded molecular cloning since its discovery, and the gene that codes for the receptor remains unknown, precluding the use of modern biological methods to study its function. Using a chemical biology approach, we purified the σ<sub>2</sub> receptor from tissue, revealing its identity as TMEM97, an endoplasmic reticulum-resident transmembrane protein that regulates the sterol transporter NPC1. We show that TMEM97 possesses the full suite of molecular properties that define the σ<sub>2</sub> receptor, and we identify Asp29 and Asp56 as essential for ligand recognition. Cloning the σ<sub>2</sub> receptor resolves a longstanding mystery and will enable therapeutic targeting of this potential drug target.
Metabolic engineering of Saccharomyces cerevisiae for polyhydroxybutyrate production (2013)

Establishing industrial biotechnology for the production of chemical compounds from the biosynthetic pathway has received a significant boost with the implementation of metabolic engineering. At present, metabolic engineering in Saccharomyces cerevisiae gains significant advantages of integration of knowledge acquired through a long history of use and data acquisition from novel –omics technologies hence enabling the development of a tailor-made S. cerevisiae with desired features for various industrial applications.With regard to environmentally friendly (eco-friendly) materials, engineering of biodegradable polyhydroxybutyrate (PHB) producing microbes has been studied as a potential alternative to petroleum-based thermoplastics. Heterologous expression of the bacterial PHB biosynthesis pathway in S. cerevisiae involves the utilization of acetyl-CoA, an intermediate of the central carbon metabolism, as precursor and NADPH, a redox cofactor used during anabolic metabolism, as a required cofactor for the catalyzing enzymes in the PHB biosynthesis pathway. Provision of acetyl-CoA and NADPH by alteration of the endogenous pathways and/or implementation of a heterologous gene/pathway was investigated with the aim to improve PHB production in S. cerevisiae. Since the specific growth rate and the type of carbon source (fermentable/non-fermentable) influence cell physiology and affect the growth of S. cerevisiae, PHB production was examined at different specific growth rates on different carbon sources. Overexpression of genes in the native ethanol degradation pathway and heterologous expression of a phosphoketolase pathway from Aspergillus nidulans aiming to increase the production of cytosolic acetyl-coA and chromosomal integration of gapN from Streptococcus mutans to enhance the availability of NADPH were evaluated for their possibility to promote PHB production in S. cerevisiae. The enhancement of acetyl-CoA and NADPH either by the combined strategies of the ethanol degradation pathway and gapN or utilization of the phosphoketolase pathway resulted in the improved PHB content from 4 mg/gDW in the reference strain to approximately 28 mg/gDW. It is difficult for S. cerevisiae to compete with other natural PHB producers like Ralstonia eutropha which benefit from native enzymes for the biosynthesis or with the engineered E. coli since the metabolism in S. cerevisiae is more complex and involves compartmentalization and shuttle systems for precursor and redox balancing. However, the strategies employed in this study involve both engineering of the central carbon and redox metabolism and it demonstrated that it is possible to substantially improve PHB production. Furthermore, the applied strategies may well be suitable also for improving the production of other chemicals, derived from acetyl-CoA and requires NADPH for its biosynthesis.
Serological Analysis of a Subgroup of Human T-Lymphotropic Retroviruses (HTLV-III) Associated with AIDS (1984)

The two main subgroups of the family of human T-lymphotropic retroviruses (HTLV) that have previously been characterized are known as HTLV-I and HTLV-II. Both are associated with certain human leukemias and lymphomas. Cell surface antigens (p61 and p65) encoded by HTLV-I are frequently recognized, at low titers, by antibodies in the serum of patients with acquired immunodeficiency syndrome (AIDS) or with signs or symptoms that precede AIDS (pre-AIDS). This suggests an involvement of HTLV in these disorders. Another subgroup of HTLV, designated HTLV-III, has now been isolated from many patients with AIDS and pre-AIDS. In the studies described in this report, virus-associated antigens in T-cell clones permanently producing HTLV-III were subjected to biochemical and immunological analyses. Antigens of HTLV-III, specifically detected by antibodies in serum from AIDS or pre-AIDS patients and revealed by the Western blot technique, are similar in size to those found in other subgroups of HTLV. They include at least three serologically unrelated antigenic groups, one of which is associated with group-specific antigens (p55 and P24) and another with envelope-related (p65) proteins, while the antigens in the third group are of unknown affiliation. The data show that HTLV-III is clearly distinguishable from HTLV-I and HTLV-II but is also significantly related to both viruses. HTLV-III is thus a true member of the HTLV family.
Targeting the Janus kinases in rheumatoid arthritis: focus on tofacitinib (2013)

Tofacitinib is a new class of DMARDs orally available with a new mechanism of action and with strong clinical efficacy similar to biologic DMARDs. Multiple cytokines and signaling pathways are partially inhibited at clinical doses that are in contrast to biological DMARDs. Further investigation is necessary to come to a conclusion on risk-benefit ratio and selection of patients.
Interferon and Granulopoiesis Signatures in Systemic Lupus Erythematosus Blood (2003)

Systemic lupus erythematosus (SLE) is a prototype systemic autoimmune disease characterized by flares of high morbidity. Using oligonucleotide microarrays, we now show that active SLE can be distinguished by a remarkably homogeneous gene expression pattern with overexpression of granulopoiesis-related and interferon (IFN)-induced genes. Using the most stringent statistical analysis (Bonferroni correction), 15 genes were found highly up-regulated in SLE patients, 14 of which are targets of IFN and one, defensin DEFA-3, a major product of immature granulocytes. A more liberal correction (Benjamini and Hochberg correction) yielded 18 additional genes, 12 of which are IFN-regulated and 4 granulocyte-specific. Indeed immature neutrophils were identified in a large fraction of SLE patients white blood cells. High dose glucocorticoids, a standard treatment of disease flares, shuts down the interferon signature, further supporting the role of this cytokine in SLE. The expression of 10 genes correlated with disease activity according to the SLEDAI. The most striking correlation (P < 0.001, r = 0.55) was found with the formyl peptide receptor-like 1 protein that mediates chemotactic activities of defensins. Therefore, while the IFN signature confirms the central role of this cytokine in SLE, microarray analysis of blood cells reveals that immature granulocytes may be involved in SLE pathogenesis.
<title>Modeling and measurement of a micro-optic beam deflector</title> (1992)

We investigate the use of a unity-magnification micro-optic beam deflector. The deflector consists of two arrays of positively powered lenslets. The lenslets on each array are arranged in a square grid. Design criteria are based on usefulness in optical data storage devices. The deflector is designed to operate over a +/- 1.6 degree(s) range of deflection angles. We compare modeling results with interferometric analysis of the wavefront from a single lenslet pair. Our results indicate that the device is nearly diffraction limited, but there are substantial wavefront errors at the edges and corners of the lenslets.
Accurate and practical profile-driven compilation using the profile buffer (1996)

Profiling is a technique of gathering program statistics in order to aid program optimization. In particular, it is an essential component of compiler optimization for the extraction of instruction-level parallelism. Code instrumentation has been the most popular method of profiling. However, real-time, interactive, and transaction processing applications suffer from the high execution-time overhead imposed by software instrumentation. This paper suggests the use of hardware dedicated to the task of profiling. The hardware proposed consists of a set of counters, the profile buffer. A profile collection method that combines the use of hardware, the compiler and operating system support is described. Three methods for profile buffer indexing, address-mapping, selective indexing, and compiler indexing are presented that allow this approach to produce accurate profiling information with very little execution slowdown. The profile information obtained is applied to a prominent compiler optimization, namely superblock scheduling. The resulting instruction-level parallelism approaches that obtained through the use of perfect profile information.
High-frequency oscillations in human temporal lobe: simultaneous microwire and clinical macroelectrode recordings (2008)

Neuronal oscillations span a wide range of spatial and temporal scales that extend beyond traditional clinical EEG. Recent research suggests that high-frequency oscillations (HFO), in the ripple (80-250 Hz) and fast ripple (250-1000 Hz) frequency range, may be signatures of epileptogenic brain and involved in the generation of seizures. However, most research investigating HFO in humans comes from microwire recordings, whose relationship to standard clinical intracranial EEG (iEEG) has not been explored. In this study iEEG recordings (DC - 9000 Hz) were obtained from human medial temporal lobe using custom depth electrodes containing both microwires and clinical macroelectrodes. Ripple and fast-ripple HFO recorded from both microwires and clinical macroelectrodes were increased in seizure generating brain regions compared to control regions. The distribution of HFO frequencies recorded from the macroelectrodes was concentrated in the ripple frequency range, compared to a broad distribution of HFO frequencies recorded from microwires. The average frequency of ripple HFO recorded from macroelectrodes was lower than that recorded from microwires (143.3 +/- 49.3 Hz versus 116.3 +/- 38.4, Wilcoxon rank sum P<0.0001). Fast-ripple HFO were most often recorded on a single microwire, supporting the hypothesis that fast-ripple HFO are primarily generated by highly localized, sub-millimeter scale neuronal assemblies that are most effectively sampled by microwire electrodes. Future research will address the clinical utility of these recordings for localizing epileptogenic networks and understanding seizure generation.
High-efficiency RNA cloning enables accurate quantification of miRNA expression by deep sequencing (2013)

Small RNA cloning and sequencing is uniquely positioned as a genome-wide approach to quantify miRNAs with single-nucleotide resolution. However, significant biases introduced by RNA ligation in current protocols lead to inaccurate miRNA quantification by 1000-fold. Here we report an RNA cloning method that achieves over 95% efficiency for both 5′ and 3′ ligations. It achieves accurate quantification of synthetic miRNAs with less than two-fold deviation from the anticipated value and over a dynamic range of four orders of magnitude. Taken together, this high-efficiency RNA cloning method permits accurate genome-wide miRNA profiling from total RNAs.
A novel highly articulated robotic surgical system for epicardial ablation (2008)

We have developed a novel, highly articulated robotic surgical system to enable minimally invasive intrapericardial interventions through a subxiphoid approach and have performed preliminary tests of epicardial left atrial ablation in porcine (N=3) and human cadaver (N=2) preparations. In this study, the novel highly articulated robotic surgical system successfully provided safe epicardial ablations to the left atrium in porcine beating heart models via a subxiphoid approach. We have also performed complex guidance of the robot and subsequent ablation in a cadaveric preparation for successful pulmonary vein isolation.
Transforming Growth Factor Betal and Beta2 Induce Down-Modulation of Thrombomodulin in Human Umbilical Vein Endothelial Cells (1995)

To investigate the effects of transforming growth factor-betas (TGF-betas) on endothelial anticoagulant activity, we assayed thrombomodulin (TM) activity and antigen levels of human umbilical vein endothelial cells (HUVECs) incubated with TGF-betas in vitro. TGF-beta 1 suppressed surface TM activity and surface TM antigen levels maximally 12 h after incubation in dose-dependent manners. TGF-beta 2 was almost equipotent with TGF-beta 1 for the suppression of them. Both TGF-betas suppressed total TM antigen level in HUVECs, and the time course of the suppression was similar to that of the cell surface TM antigen level. The maximal reductions of TM mRNA levels by TGF-betas were observed at several hours ahead of those observed in both surface and total TM antigens levels, suggesting that the TGF-beta-mediated suppression of TM antigen of HUVECs is primarily regulated at the TM mRNA level. Our present work suggests that the down-modulation of TM level induced by TGF-betas in HUVECs contributes in vivo to promoting the thrombogenesis either at the sites of injury of vessel walls, such as atherosclerotic lesions where TGF-beta 1 is released from platelets, smooth muscle cells and monocytes, or at neovascular walls in tumors secreting TGF-beta 2.
A Balun-Free Helical Antenna for Minimally Invasive Microwave Ablation (2015)

We present a balun-free coax-fed helical antenna for microwave ablation. The proposed antenna produces a localized specific absorption rate pattern at the desired frequency of operation without using a coaxial balun. This reduces the outer diameter of the antenna and, thus, its invasiveness. Balun-free operation of the proposed antenna is achieved by operating the helical antenna at the second resonant frequency of the helix where a current minimum occurs at the feed point, resulting in an intrinsically high feed-point impedance. This efficiently chokes the currents excited on the outer surface of the feeding cable. Using a compact quarter-wavelength impedance transformer or a coaxially implemented pi network of reactive elements at the antenna feed point, we achieve an excellent impedance match between the antenna and the main feeding line. We fabricated a prototype of the proposed helical antenna with an outer diameter of 2.2 mm using the pi matching network. We used this prototype to conduct ablation experiments in ex vivo bovine liver. The dimensions of the resulting ablation zones are similar to those produced by coaxially fed antennas that use coaxial baluns. Our balun-free antenna design offers a promising solution for reducing the invasiveness of interstitial antennas used in microwave ablation.
In vitro peptidoglycan synthesis by envelopes from Escherichia coli tolM mutants is inhibited by colicin M (1990)

An in vitro peptidoglycan synthesis reaction was employed to further characterize the role of the tolM product in colicin M-induced inhibition of peptidoglycan synthesis. It was found that the tolM product is not the colicin M target and that this gene product does not play a role in the interaction of the colicin with its target. Colicin M remained associated with envelopes prepared from colicin-treated tolM mutants. These findings suggested that the tolM product most likely is involved with the internalization of colicin M.
Small molecule and peptide-based CXCR4 modulators as therapeutic agents. A patent review for the period from 2010 to 2018 (2019)

<b>Introduction</b>: The chemokine receptor CXCR4 has been under intense study due to the central role it plays in immune system regulation and the pathology of many human diseases. The FDA approval of the first CXCR4 antagonist drug Plerixafor (i.e. AMD3100, Mozobil®) ushered in an increase in patent activity covering CXCR4 based therapeutic agents over the past decade.<b>Areas covered</b>: This article describes patent documents published during the period of 2010 through 2018 for both small molecules and peptide-based CXCR4 modulators as therapeutic agents. There is an expansion of intellectual property (IP) around existing and new small molecules of clinical interest, including new chemotypes featuring aromatic and aliphatic heterocycles. There is also significant IP covering peptide-based therapeutics, although about half as many in number as those covering small molecules.<b>Expert opinion</b>: In the last decade there has been significant interest in modulators of the CXCR4 receptor, as gauged by the number of patent filings and clinical investigations targeting this receptor for human disease intervention. Seven of the many CXCR4 modulators described herein, that are currently in human clinical trials, are likely to spur the creation of other FDA approved therapeutics in the near future, most likely as immune and oncology drugs.
Interbody Fusion and Instrumentation (1994)

Fusion indications in adult degenerative disk disease of the lumbosacral spine include isolated disk resorption, primary and secondary instability, recurrent disk herniation, and pseudarthrosis. Common to these indications are variable proportions of biomechanical insufficiency of the motion segment, instability, deformity, and spinal stenosis. Apart from favorable psychosocial and work related variables, satisfactory outcome is dependent on treatment by a combination of diskectomy, decompression, and deformity correction, in addition to fusion. Isolated intertransverse or interbody fusions show variable fusion rates that are increased by concurrent instrumentation. Persistent pseudarthrosis rates and instrumentation failures have prompted circumferential fusion techniques. Posterior lumbar interbody fusion (PLIF) and segmental pedicle-based plate fixation overcome earlier problems with PLIF by allowing for wide decompression and increased exposure for disk space preparation, minimizing neural injury. Pedicle fixation restores segmental stability and minimizes graft retropulsion. Restoration of anterior column support prolongs instrumentation life, and increases fusion rates irrespective of the number of levels fused. Disk space distraction, with the use of instrumentation as a working tool, permits safer decompression of the intraforaminal zone, a common area of stenosis, and single or multilevel deformity correction to restore coronal, axial, and sagittal alignment and spinal balance. Even though the surgical technique is demanding, fusion rates up to 96% and clinical success up to 86% are achieved.