gebhart/patrepeval huggingface dataset:
First-in-human phase I study evaluating the safety, pharmacokinetics (PK), and intratumor pharmacodynamics (PD) of the novel, oral, ATP-competitive Akt inhibitor GDC-0068. (2011)

3022 Background: GDC-0068 is a highly selective ATP-competitive small molecule that inhibits all three isoforms of Akt with IC50 values of 5 to 30 nM. GDC-0068 selectively inhibits cancer cells with activated Akt signaling (e.g. via PTEN loss or PIK3CA mutations), allowing for a rational strategy to identify patients likely to benefit. Methods: Patients (pts) with advanced solid tumors were treated with GDC-0068 using a 3+3 escalation design. Treatment included a single dose with 1wk washout to study PK and PD markers, followed by dosing PO QD on a 21-day on, 7-day off schedule. Objectives were to determine MTD, safety, PK, and evaluate PD endpoints in surrogate (platelet rich plasma [PRP]) and tumor tissue (using reverse phase protein array [RPPA] and IHC in paired tumor biopsies). At least three patients per cohort had pre- and on-treatment tumor biopsies at doses ≥100mg QD. Results: Twenty-one pts were enrolled across 6 cohorts (25, 50, 100, 200, and 400 mg QD, and on-going at 800mg QD). Within the first 5 cohorts, most frequently reported GDC-0068-related AEs were Grade 1 to 2 hyperglycemia, asthenia, nausea, and decreased appetite; no DLTs were observed. Preliminary PK data indicated that GDC-0068 shows dose proportional increase in exposure, rapid absorption and a half-life of ~24 hours, supporting once daily dosing. GDC-0068 treatment was associated with up to 1000-fold increase in serum insulin level, and only modest, transient increase (up to 2-3 fold, lasting ~2 hours) in serum glucose. Preliminary PD data showed dose-dependent Akt pathway inhibition in the PRP assay, with >60% inhibition of pGSK3b in all pts at ≥200 mg QD dose, defining minimum effective dose (MED). Pre- and on-treatment tumor biopsies showed >60% Akt pathway suppression for all pts in the 400 mg QD cohort. Three patients had stable disease, with one patient on therapy for ≥6 cycles. Conclusions: GDC-0068 is well tolerated with a favorable safety profile. MED was reached; PD and efficacy data show GDC-0068 is active in pts, with >60% pathway inhibition in tumors and surrogate tissue. Dose-escalation continues and updated safety, PK and PD data will be presented.
Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep (2009)

Impaired sleep and enhanced stress hormone secretion are the hallmarks of stress-related disorders, including major depression. The central neuropeptide, corticotropin-releasing hormone (CRH), is a key hormone that regulates humoral and behavioral adaptation to stress. Its prolonged hypersecretion is believed to play a key role in the development and course of depressive symptoms, and is associated with sleep impairment. To investigate the specific effects of central CRH overexpression on sleep, we used conditional mouse mutants that overexpress CRH in the entire central nervous system (CRH-COE-Nes) or only in the forebrain, including limbic structures (CRH-COE-Cam). Compared with wild-type or control mice during baseline, both homozygous CRH-COE-Nes and -Cam mice showed constantly increased rapid eye movement (REM) sleep, whereas slightly suppressed non-REM sleep was detected only in CRH-COE-Nes mice during the light period. In response to 6-h sleep deprivation, elevated levels of REM sleep also became evident in heterozygous CRH-COE-Nes and -Cam mice during recovery, which was reversed by treatment with a CRH receptor type 1 (CRHR1) antagonist in heterozygous and homozygous CRH-COE-Nes mice. The peripheral stress hormone levels were not elevated at baseline, and even after sleep deprivation they were indistinguishable across genotypes. As the stress axis was not altered, sleep changes, in particular enhanced REM sleep, occurring in these models are most likely induced by the forebrain CRH through the activation of CRHR1. CRH hypersecretion in the forebrain seems to drive REM sleep, supporting the notion that enhanced REM sleep may serve as biomarker for clinical conditions associated with enhanced CRH secretion.
CRISPRseek: A Bioconductor Package to Identify Target-Specific Guide RNAs for CRISPR-Cas9 Genome-Editing Systems (2014)

CRISPR-Cas systems are a diverse family of RNA-protein complexes in bacteria that target foreign DNA sequences for cleavage. Derivatives of these complexes have been engineered to cleave specific target sequences depending on the sequence of a CRISPR-derived guide RNA (gRNA) and the source of the Cas9 protein. Important considerations for the design of gRNAs are to maximize aimed activity at the desired target site while minimizing off-target cleavage. Because of the rapid advances in the understanding of existing CRISPR-Cas9-derived RNA-guided nucleases and the development of novel RNA-guided nuclease systems, it is critical to have computational tools that can accommodate a wide range of different parameters for the design of target-specific RNA-guided nuclease systems. We have developed CRISPRseek, a highly flexible, open source software package to identify gRNAs that target a given input sequence while minimizing off-target cleavage at other sites within any selected genome. CRISPRseek will identify potential gRNAs that target a sequence of interest for CRISPR-Cas9 systems from different bacterial species and generate a cleavage score for potential off-target sequences utilizing published or user-supplied weight matrices with position-specific mismatch penalty scores. Identified gRNAs may be further filtered to only include those that occur in paired orientations for increased specificity and/or those that overlap restriction enzyme sites. For applications where gRNAs are desired to discriminate between two related sequences, CRISPRseek can rank gRNAs based on the difference between predicted cleavage scores in each input sequence. CRISPRseek is implemented as a Bioconductor package within the R statistical programming environment, allowing it to be incorporated into computational pipelines to automate the design of gRNAs for target sequences identified in a wide variety of genome-wide analyses. CRISPRseek is available under the GNU General Public Licence v3.0 at http://www.bioconductor.org.
Cytokine-Induced Apoptosis of Human Natural Killer Cells Identifies a Novel Mechanism to Regulate the Innate Immune Response (1997)

Interferon-gamma (IFN-gamma) is critical for an effective innate immune response against infection. A combination of interleukins (ILs) derived from activated T cells (IL-2) and monocytes (IL-12), or monocytes alone (IL-15 and IL-12), induces optimal production of IFN-gamma from natural killer (NK) cells. The mechanism by which human NK cells downregulate their production of IFN-gamma is unknown. Here we show that the same cytokines that induce human NK cell IFN-gamma production subsequently induce apoptosis of the NK cells. Fas, bcl-2, or bax do not appear to be involved in this process. The mechanism of cytokine-induced apoptosis of human NK cells appears to involve NK cell production of tumor necrosis factor-alpha (TNF-alpha). Neutralization of TNF-alpha or inhibition of TNF-alpha binding to the p80 TNF-alpha receptor partially inhibited apoptosis. Transforming growth factor-beta, which inhibits cytokine-induced NK cell production of IFN-gamma and TNF-alpha, also decreased cytokine-induced NK cell apoptosis. Costimulation of a CD3-CD56+ NK leukemia cell line with IL-2 and IL-12 or IL-15 and IL-12 induced apoptosis in vitro, which increased when combined with a chemotherapeutic agent. In summary, costimulation of human NK cells via the IL-2 receptor and the IL-12 receptor induces significant IFN-gamma production, followed by NK cell apoptosis and a decline in IFN-gamma production. Hence, cytokines that activate this innate immune response may also serve to limit it via apoptosis. This novel observation may have implications for the regulation of the innate immune response during infection, the toxicity of combination cytokine therapy, and the treatment of NK cell leukemia.
Neuropeptide signal transduction in lung cancer: clinical implications of bradykinin sensitivity and overall heterogeneity. (1992)

To define the role of neuropeptides in lung cancer biology, we evaluated the effect of seven peptide classes on signal transduction and growth in human lung and breast cancer cell lines. Flow cytometric methods were used to quantitate the calcium response in individual cells produced by these peptides alone or in combination. The effects on growth were assessed by [3H]thymidine, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, and soft agarose colony assays. All lung cancer cells demonstrated calcium responses to one or more peptides with classic small cell lines displaying the greatest responsiveness, followed by variant small cell lines and non-small cell lines. Breast cancer cell lines demonstrated little or no response. There was great variability in the magnitude of calcium response and pattern of response between lung cancer cell lines to individual neuropeptides. Bradykinin was the most potent peptide and produced responses in the highest fraction of lung cancer cell lines. Combinations of peptides produced greater intracellular calcium release than the single peptides, although in less than a quantitatively additive manner. Each peptide produced a refractory period which was peptide class specific. The growth stimulating effects of these neuropeptides were absent or small in magnitude and did not correlate with calcium signal transduction. These results imply that lung cancer cells display a wide sensitivity to neuropeptides but in a very heterogeneous manner. Knowledge of this heterogeneity should be incorporated into the design of antitumor strategies based on this autocrine pathway.
A Capacitance Type Chemical Sensor Based on AlPO4-5 Molecular Sieves (1997)

Thin films of AlPO4-5 molecular sieves have been employed as the dielectric phase in a capacitance type chemical sensor. AlPO4-5 was deposited onto titanium nitride (bottom electrode) coated silicon wafers by laser ablation. A subsequent hydrothermal treatment of the ablated AlPO4-5 films was found to enhance the crystallinity. The capacitance sensor configuration was completed by the deposition of Pd/Au pads (upper electrode) through a mask. AlPO4-5 based sensors exhibited significant changes in capacitance upon exposure to small molecules such as CO2, CO, N2, and H2O.
Evaluation of Reverse Transcriptase Polymerase Chain Reaction for the Detection of Eastern Equine Encephalomyelitis Virus during Vector Surveillance (1996)

A reverse transcriptase polymerase chain reaction (RT-PCR) assay was evaluated for the detection of eastern equine encephalomyelitis virus (EEEV). EEEV was detected by amplification of a 416-bp PCR product from within the E2 gene. Internal restriction endonuclease digestion and hybridizations to EEEV RNA demonstrated that the PCR product was amplified from EEEV. PCR amplifications from serial dilutions of an EEEV isolate identified by a neutralization test and titered by an infectious assay in cell culture indicated that this RT-PCR assay detected viral RNA at concentrations below 1 plaque forming unit(PFU) per reaction. The performance of the PCR assay in detection of EEEV was compared with an infectious assay detection procedure (IA/IFA) as part of the New Jersey 1993 vector surveillance program. During 1993, 7,007 field-collected Culiseta melanura (Coquillett) were assayed in 522 pools by both RT-PCR and IA/IFA. EEEV was detected in 95 pools by RT-PCR and 17 pools by IA/IFA; all IA/IFA positive pools were also positive by RT-PCR. During the 1993 field season, RT-PCR consistently detected virus at enzootic foci earlier that IA/IFA and in greater numbers of mosquito pools. The data indicated that viral RNA may be present earlier and in more mosquitoes than indicated by IA/IFA.
Emergence of hepatitis B virus S gene mutant in a liver transplant recipient (1995)

Immunological and genomic analysis of the "a" determinant was carried out in seven patients with concurrent HBsAg and anti-HBs, four of whom were immunized against hepatitis B virus at liver transplant, two with histologically characterized chronic hepatitis B virus infection, and one HBsAg healthy carrier. The immune reactivity of the HBsAg "a" determinant was evaluated by binding to specific monoclonal antibodies, and the corresponding genomic sequence was studied by differential hybridization in microtiter plates and nucleotide sequence analysis. A double mutation generating an amino acid change (glycine to lysine) at residue 145, able to impair recognition by monoclonal antibodies, was observed in the post-transplant serum from one patient. No significant alteration of the "a" determinant sequence or reactivity was detected in the other patients. Amino acid residue 145 appears therefore to be critical for the recognition by anti-HBs antibodies. A previously undescribed glycine to lysine substitution at this level interferes with the immune reactivity of the "a" determinant.
Advances in neurostimulation for movement disorders (2000)

In just 12 years since its introduction, deep brain stimulation (DBS) has become well established as a safe and effective therapy in the treatment of medically refractory movement disorders. Ventralis intermedius (Vim) DBS has virtually replaced thalamotomy in the routine clinical treatment of essential tremor, affording relief to thousands of patients who previously would not have undergone surgery, and there is increasing usage of Vim DBS in other tremors of intention (e.g., multiple sclerosis). Subthalamic nucleus (STN) and globus pallidus internus (GPi) DBS have revolutionized the treatment of advanced stage Parkinson's disease, improving all cardinal disease features and increasing 'on' time without dyskinesias. Finally, DBS of various sub-cortical structures is being developed and tested in other less prevalent movement disorders such as dystonia. Future developments in this rapidly advancing area will no doubt include widening indications for this relatively safe surgical procedure, elucidation of the mechanisms of action of electrical stimulation, and technological advancements improving effectiveness and convenience.
Theory of hydrogen diffusion and reactions in crystalline silicon (1989)

The behavior of hydrogen in crystalline silicon is examined with state-of-the-art theoretical techniques, based on the pseudopotential-density-functional method in a supercell geometry. Stable sites, migration paths, and barriers for different charge states are explored and displayed in total-energy surfaces that provide immediate insight into these properties. The bond-center site is the global minimum for the neutral and positive charge states; in the negative charge state, the tetrahedral interstitial site is preferred. The positive charge state is energetically favorable in p-type material, providing a mechanism for passivation of shallow acceptors: electrons from the H atoms annihilate the free holes, and formation of H-acceptor pairs follows compensation. Also addressed are the issues of molecule formation and hydrogen-induced damage. A number of different mechanisms for defect formation are examined; hydrogen-assisted vacancy formation is found to be an exothermic process.
Human adipose tissue-derived cells delay re-epithelialization in comparison with skin fibroblasts in organotypic skin culture (2004)

The possibility of generating HSEs with different cell types represents an attractive approach for in vitro studies focusing on the mechanism of wound healing.
Neurophysiological Vocal Source Modeling for Biomarkers of Disease (2016)

Speech is potentially a rich source of biomarkers for detecting and monitoring neuropsychological disorders.Current biomarkers typically comprise acoustic descriptors extracted from behavioral measures of source, filter, prosodic and linguistic cues.In contrast, in this paper, we extract vocal features based on a neurocomputational model of speech production, reflecting latent or internal motor control parameters that may be more sensitive to individual variation under neuropsychological disease.These features, which are constrained by neurophysiology, may be resilient to artifacts and provide an articulatory complement to acoustic features.Our features represent a mapping from a low-dimensional acoustics-based feature space to a high-dimensional space that captures the underlying neural process including articulatory commands and auditory and somatosensory feedback errors.In particular, we demonstrate a neurophysiological vocal source model that generates biomarkers of disease by modeling vocal source control.By using the fundamental frequency contour and a biophysical representation of the vocal source, we infer two neuromuscular time series whose coordination provides vocal features that are applied to depression and Parkinson's disease as examples.These vocal source coordination features alone, on a single held vowel, outperform or are comparable to other features sets and reflect a significant compression of the feature space.
Anthracycline immunoconjugates prepared by a site-specific linkage via an amino-dextran intermediate carrier. (1991)

Anthracycline, either daunomycin or doxorubicin, was site specifically attached to the carbohydrate moiety of a monoclonal anticarcinoembryonic antigen antibody by using amino-dextran as the intermediate carrier. The reaction resulted in an immunoconjugate that contains approximately 20 to 25 molecules of drug per molecule of immunoglobulin G. Flow-cytometric studies revealed the retention of the antibody-binding activity. The immunoconjugate was cytotoxic to the target cells, as examined by the 75selenomethionine incorporation studies, and remained efficient for targeting a human colonic tumor (GW-39) in the nude mouse model. The conjugate possessed a greater antitumor activity against the subcutaneous tumor than either the free drug or an irrelevant antibody conjugate, and it was well tolerated by the animals at a much higher dose level than was the unconjugated drug.
Comparison of Failure Strength Between Metallic and Absorbable Interference Screws (1996)

Because of the good initial fixation strength of interference screws used in anterior cruciate ligament reconstruction, metal interference screws have become the standard method for fixation of bone-patellar tendon-bone grafts. To avoid some of the complications with metal screws, a bioabsorbable interference screw was developed. Data on fixation strength in older human cadavers indicate a similar failure strength between bioabsorbable and metal screws. We studied the failure mechanisms, insertion torques, and fixation strengths of absorbable and metal interference screws in cadaveric knees from young and middle-aged donors. With identical gap and screw size, the mean insertion torque for the metal screws (mean, 1.5 N-m; SD, 0.8) was significantly higher than for the absorbable screws (mean, 0.3 N-m; SD, 0.19). The mean failure load for the metal screws (mean 640 N; SD, 201) was also significantly higher than for the absorbable screws (mean, 418 N; SD, 118).
2-Chlorodeoxyadenosine: an effective new agent for the treatment of chronic lymphocytic leukemia (1988)

2-Chlorodeoxyadenosine, a new lymphocyte-selective, anti-neoplastic drug was administered to 18 patients with advanced chronic lymphocytic leukemia of B-cell origin. All patients were resistant to conventional treatment. A total of 44 courses of 2-chlorodeoxyadenosine were completed with minimal toxicity. An overall response rate of 55% was achieved with four of 18 patients demonstrating partial response and six of 18 patients experiencing clinical improvement. Only minor bone marrow suppression occurred during administration of the drug, indicating a high degree of lymphocyte selectivity. Reduction of lymphocyte infiltration in bone marrow occurred in treated patients including one patient who experienced normalization of the bone marrow. Three of four patients with concurrent autoimmune hemolytic anemia experienced resolution of hemolysis, as indicated by elimination of transfusion requirement, fall in reticulocyte count, elevation of hemoglobin, and ability to taper prednisone without recurrence of hemolysis. Duration of responses ranged from 2 to 15 months without maintenance therapy.
Connections between RNA splicing and DNA intron mobility in yeast mitochondria: RNA maturase and DNA endonuclease switching experiments. (1992)

The intron-encoded proteins bI4 RNA maturase and aI4 DNA endonuclease can be faithfully expressed in yeast cytoplasm from engineered forms of their mitochondrial coding sequences. In this work we studied the relationships between these two activities associated with two homologous intron-encoded proteins: the bI4 RNA maturase encoded in the fourth intron of the cytochrome b gene and the aI4 DNA endonuclease (I-SceII) encoded in the fourth intron of the gene coding for the subunit I of cytochrome oxidase. Taking advantage of both the high recombinogenic properties of yeast and the similarities between the two genes, we constructed in vivo a family of hybrid genes carrying parts of both RNA maturase and DNA endonuclease coding sequences. The presence of a sequence coding for a mitochondrial targeting peptide upstream from these hybrid genes allowed us to study the properties of their translation products within the mitochondria in vivo. We thus could analyze the ability of the recombinant proteins to complement RNA maturase deficiencies in different strains. Many combinations of the two parental intronic sequences were found in the recombinants. Their structural and functional analysis revealed the following features. (i) The N-terminal half of the bI4 RNA maturase could be replaced in total by its equivalent from the aI4 DNA endonuclease without affecting the RNA maturase activity. In contrast, replacing the C-terminal half of the bI4 RNA maturase with its equivalent from the aI4 DNA endonuclease led to a very weak RNA maturase activity, indicating that this region is more differentiated and linked to the maturase activity. (ii) None of the hybrid proteins carrying an RNA maturase activity kept the DNA endonuclease activity, suggesting that the latter requires the integrity of the aI4 protein. These observations are interesting because the aI4 DNA endonuclease is known to promote the propagation, at the DNA level, of the aI4 intron, whereas the bI4 RNA maturase, which is required for the splicing of its coding intron, also controls the splicing process of the aI4 intron. We propose a scenario for the evolution of these intronic proteins that relies on a switch from DNA endonuclease to RNA maturase activity.
<title>Storage server requirements for delivery of hypermedia documents</title> (1995)

Current approaches for continuous media (CM) file systems focus on scheduling requirements for sessions consisting of single video or audio streams. This paper examines the multimedia delivery problem from the perspective of hypermedia document servers. Such hypermedia documents can be characterized as a web of nodes, each node containing a set of time-dependent CM and discrete media objects. We first look at a hypothetical user's view of a hypermedia session. We then present two service models, the CM service model and the hypermedia service model, and compare them. We propose a new view of session, a hypermedia session, suitable for scheduling the delivery of hypermedia documents, and present sample scheduling algorithms. This notion of hypermedia session is examined from the standpoint of resource management at the orchestration layer of distributed MM system.
Determination of the Mode of Hydrolysis of Chitooligosaccharides by Chitosanase Derived from Aspergillus Orvzae by Thin Layer Chromatography (1992)

Abstract We found that the enzyme from rice-koji of Aspergillus oryzae removed single glucosamine residue from a sequence of β-(1-4)-linked glucosamine chain, such as chitosan and glucosamine oligosaccharides. It became clear that the N-acetyl-β-d-glucosaminidase of Aspergillus orvzae was characterized as an exo-β-d-glucosaminidase.