gebhart/patrepeval huggingface dataset:
The first-in-class anti-CD47 antibody Hu5F9-G4 is active and well tolerated alone or with azacitidine in AML and MDS patients: Initial phase 1b results. (2019)

7009 Background: Hu5F9-G4 (5F9) is an antibody targeting CD47, a macrophage immune checkpoint and “don’t eat me” signal on cancers. CD47 blockade induces tumor phagocytosis and eliminates leukemia stem cells (LSC) in AML models. Azacitidine (AZA) synergizes with 5F9 by inducing “eat me” signals on AML, enhancing phagocytosis. This trial explored the safety/efficacy of 5F9 alone or with AZA in AML/MDS patients (pts). Methods: This Phase 1b treated: r/r AML/MDS pts with 5F9; and untreated AML (induction chemo ineligible) and higher risk MDS pts with 5F9+AZA. A 5F9 priming/intrapatient dose escalation regimen (1-30 mg/kg weekly) was used to mitigate on target anemia. Results: 10 (6 AML, 4 MDS) r/r pts received 5F9 (median 2 prior therapies (range 1-6). 24 untreated pts (15 AML, 9 MDS) received 5F9+AZA. In total, median age was 73, 62% of AML pts were intermediate or poor cytogenetic risk (38% unknown), all MDS pts were intermediate or high risk by IPSS-R. 5F9 alone or with AZA was well-tolerated with no MTD reached. 5F9 did not potentiate AZA toxicities. Treatment-related AEs ( &gt; 10% of pts) for 5F9+AZA were anemia (25%), thrombocytopenia (20%), and infusion reactions (15%). In 25 efficacy evaluable pts, 8/15 (53%) untreated AML/MDS pts had a CR/CRi to 5F9+AZA (5/10 (50%) in AML, 3/5 (60%) in MDS). 1/10 (10%) r/r AML/MDS pts had a response (MLFS) to 5F9 alone. LSC frequency was reduced/eliminated in most 5F9+aza responders; 50% of responders were MRD negative by flow cytometry. 4/10 (40%) AML pts became RBC transfusion independent and 4/5 (80%) MDS pts had hematologic improvement. Time to response was more rapid (median 1.9 mos) than expected for AZA alone. As of Jan 2019, no responder has relapsed (median follow-up of 3.4 mos (range 1.1 – 6.8 mos). 2 pts had successful allogeneic transplant. Conclusions: 5F9+AZA is a novel immunotherapy blocking a key macrophage checkpoint. It has been well tolerated with robust activity in AML/MDS pts with rapid CRs and MRD negativity. Adding 5F9 to cytotoxic agents may be a promising treatment strategy. An expansion cohort is ongoing. Funded by Forty Seven and the California Institute for Regenerative Medicine. Clinical trial information: NCT03248479.
Intralenticular metallic foreign body (2002)

We report the case of a 58-year-old man who despite having an intralenticular metallic foreign body maintained good vision for at least 40 years. We describe the natural course of intraocular foreign body and the healing capacity of the anterior lens capsule as well as management issues to consider when dealing with intraocular foreign bodies.
Modest loss of peripheral axons, muscle atrophy and formation of brain inclusions in mice with targeted deletion of gigaxonin exon 1 (2008)

Mutations in the gigaxonin gene are responsible for giant axonal neuropathy (GAN), a progressive neurodegenerative disorder associated with abnormal accumulations of Intermediate Filaments (IFs). Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B. Here, we report the generation of a mouse model with targeted deletion of Gan exon 1 (Gan(Deltaexon1;Deltaexon1)). Analyses of the Gan(Deltaexon1;Deltaexon1) mice revealed increased levels of various IFs proteins in the nervous system and the presence of IFs inclusion bodies in the brain. Despite deficiency of full length gigaxonin, the Gan(Deltaexon1;Deltaexon1) mice do not develop overt neurological phenotypes and giant axons reminiscent of the human GAN disease. Nonetheless, at 6 months of age the Gan(Deltaexon1;Deltaexon1) mice exhibit a modest hind limb muscle atrophy, a 10% decrease of muscle innervation and a 27% axonal loss in the L5 ventral roots. This new mouse model should provide a useful tool to test potential therapeutic approaches for GAN disease.
Chromanol 293B Inhibits Slowly Activating Delayed Rectifier and Transient Outward Currents in Canine Left Ventricular Myocytes (2001)

Our results indicate that chromanol 293B is a relatively selective blocker of I(Ks) in canine left ventricular myocytes.
Secondary Ionization of Chemical Warfare Agent Simulants:  Atmospheric Pressure Ion Mobility Time-of-Flight Mass Spectrometry (2003)

For the first time, the use of a traditional ionization source for ion mobility spectrometry (radioactive nickel ((63)Ni) beta emission ionization) and three alternative ionization sources (electrospray ionization (ESI), secondary electrospray ionization (SESI), and electrical discharge (corona) ionization (CI)) were employed with an atmospheric pressure ion mobility orthogonal reflector time-of-flight mass spectrometer (IM(tof)MS) to detect chemical warfare agent (CWA) simulants from both aqueous- and gas-phase samples. For liquid-phase samples, ESI was used as the sample introduction and ionization method. For the secondary ionization (SESI, CI, and traditional (63)Ni ionization) of vapor-phase samples, two modes of sample volatilization (heated capillary and thermal desorption chamber) were investigated. Simulant reference materials, which closely mimic the characteristic chemical structures of CWA as defined and described by Schedule 1, 2, or 3 of the Chemical Warfare Convention treaty verification, were used in this study. A mixture of four G/V-type nerve simulants (dimethyl methylphosphonate, pinacolyl methylphosphonate, diethyl phosphoramidate, and 2-(butylamino)ethanethiol) and one S-type vesicant simulant (2-chloroethyl ethyl sulfide) were found in each case (sample ionization and introduction methods) to be clearly resolved using the IM(tof)MS method. In many cases, reduced mobility constants (K(o)) were determined for the first time. Ion mobility drift times, flight times, relative signal intensities, and fragmentation product signatures for each of the CWA simulants are reported for each of the methods investigated.
A method for localizing EEG sources in realistic head models (1995)

A computationally practical method for performing moving dipole calculations to localize EEG sources in realistic, boundary element (integral equation) type of head models is presented. This method makes use of a rapid method of solving the forward problem of calculating the EEG's produced by a dipole in a realistic head model. This rapid forward calculation method allows the use of standard Simplex search techniques to solve the inverse problem of localizing electrical sources in the brain from EEG's measured on the scalp.
Genetic Disorders in the Growth Hormone – Insulin-Like Growth Factor-I Axis (2006)

In the last few years, our knowledge of genetically determined causes of short stature has greatly increased by reports of challenging patients, who offered the opportunity to study genes that play a role in growth. Since the first paper that showed the etiology of Laron syndrome [Godowski PJ, et al: Proc Natl Acad Sci USA 1989;86:8083-8087], many mutations in the growth hormone (GH) receptor have been identified. Recently, new mutations or deletions have been found in several components of the GH-insulin-like growth factor-I (IGF-I) axis: a homozygous mutation of the GH1 gene, resulting in a bio-inactive GH; mutations in the STAT5b gene, which plays a major role in the GH signal transduction; a homozygous missense mutation in the IGF-I gene; heterozygous mutations in the IGF-I receptor gene and a homozygous deletion of the acid-labile subunit gene. In this mini review, we describe the clinical and biochemical features of these genetic defects. Genetic analysis has become essential in the diagnostic workup of a patient with short stature. However, regarding the time consuming nature of molecular analysis, it is important to carefully select the patient for specific genetic evaluation. To help in this selection process, we developed flowcharts, based on the recently described patients, that can be used as guidelines in the diagnostic process of patients with severe short stature of unknown origin.
The counterflow pipeline processor architecture (1994)

The counterflow pipeline processor architecture (CFPP) is a proposal for a family of microarchitectures for RISC processors. The architecture derives its name from its fundamental feature, namely that instructions and results flow in opposite directions within a pipeline and interact as they pass. The architecture seeks geometric regularity in processor chip layout, purely local control to avoid performance limitations of complex global pipeline stall signals, and simplicity that might lead to provably correct processor designs. Moreover, CFPP designs allow asynchronous implementations, in contrast to conventional pipeline designs where the synchronization required for operand forwarding makes asynchronous designs unattractive. This paper presents the CFPP architecture and a proposal for an asynchronous implementation. Detailed performance simulations of a complete processor design are not yet available.
Epigenetic Control of Skeletal Development by the Histone Methyltransferase Ezh2 (2015)

Epigenetic control of gene expression is critical for normal fetal development. However, chromatin-related mechanisms that activate bone-specific programs during osteogenesis have remained underexplored. Therefore, we investigated the expression profiles of a large cohort of epigenetic regulators (>300) during osteogenic differentiation of human mesenchymal cells derived from the stromal vascular fraction of adipose tissue (AMSCs). Molecular analyses establish that the polycomb group protein EZH2 (enhancer of zeste homolog 2) is down-regulated during osteoblastic differentiation of AMSCs. Chemical inhibitor and siRNA knockdown studies show that EZH2, a histone methyltransferase that catalyzes trimethylation of histone 3 lysine 27 (H3K27me3), suppresses osteogenic differentiation. Blocking EZH2 activity promotes osteoblast differentiation and suppresses adipogenic differentiation of AMSCs. High throughput RNA sequence (mRNASeq) analysis reveals that EZH2 inhibition stimulates cell cycle inhibitory proteins and enhances the production of extracellular matrix proteins. Conditional genetic loss of Ezh2 in uncommitted mesenchymal cells (Prrx1-Cre) results in multiple defects in skeletal patterning and bone formation, including shortened forelimbs, craniosynostosis, and clinodactyly. Histological analysis and mRNASeq profiling suggest that these effects are attributable to growth plate abnormalities and premature cranial suture closure because of precocious maturation of osteoblasts. We conclude that the epigenetic activity of EZH2 is required for skeletal patterning and development, but EZH2 expression declines during terminal osteoblast differentiation and matrix production.
Neuronal antinuclear antibody in sensory neuronopathy from lung cancer (1985)

We found an antinuclear antibody highly restricted to nuclei of neurons in two patients with subacute sensory neuronopathy complicating oat cell carcinoma of the lung. Serum was tested by indirect immunofluorescence and immunoperoxidase staining. At low concentrations of antibody, only the nuclei of the neurons were stained. At high concentrations, there was also staining of the nuclei of glial cells and fetal nonneural tissues. The cytoplasm of most neurons was stained with the immunoperoxidase method.
Curcumin delays endometriosis development by inhibiting MMP-2 activity. (2012)

Endometriosis is a common reproductive disorder believed to be associated with matrix metalloproteinases (MMPs) activities for invasion and remodeling of endometrial tissues. Ectopic endometrium has higher capacity to produce proMMP-2 than eutopic tissues; however, the role of MMP-2 during early phase of endometriosis development is still unclear. In the present study, we investigated the role of MMP-2 in establishment and development of endometriosis in mouse model. The effect of curcumin on regression of endometriosis through protease/antiprotease balance between MMP-2 and TIMP-2 was also examined. After endometrial inoculation into peritoneum, we observed a significant elevation of proMMP-2 activity from day 2 onwards. This increased MMP-2 activity was associated with decreased expression of tissue inhibitor of MMP (TIMP)-2, while a significant up-regulation of active MMP-2 activity was observed from day 3 onwards. The activation of proMMP-2 to active MMP-2 was associated with increased expression of membrane type 1 matrix metalloproteinase (MT1MMP). Curcumin at a dose of 48 mg/kg b.w. repressed the MMP-2 activity via up-regulation of bound TIMP-2 expression, thus delayed endometriosis development. In addition, curcumin inhibited production of active MMP-2 by down-regulating MT1MMP expression. Moreover, endometriotic progression was directly linked with increased MMP-2/TIMP-2 ratio which was delayed by curcumin pretreatment. In summary, our study documents the regulation of MMP-2 activity by TIMP-2 during the early phase of endometriosis development and inhibitory action of curcumin thereon.
Phase II Study of Gemcitabine (2',2'-Difluorodeoxycytidine) in Previously Treated Ovarian Cancer Patients (1994)

Confirmatory trials are needed, and the activity of gemcitabine in previously untreated patients should be assessed.
Matrix metalloproteinase-7–dependent release of tumor necrosis factor-α in a model of herniated disc resorption (2000)

Herniated disc (HD), one of the major causes of low back pain, is often resolved spontaneously without surgical intervention. Resorption is associated with a marked increase in infiltrating macrophages, and the matrix metalloproteinases (MMP) MMP-3 and MMP-7 have been implicated in this phenomenon. We developed a murine organ culture model in which intact intervertebral discs were cocultured with peritoneal macrophages to investigate the role of MMPs in HD resorption. Using macrophages isolated from MMP-null mice, we report that macrophage-produced MMP-7 was required for proteoglycan degradation, loss of wet weight, and macrophage infiltration of cocultured discs. The inability of MMP-7-deficient macrophages to infiltrate discs could not be attributed to a defect in macrophage migration. MMP-7 was required for the release of the cytokine TNF-alpha from peritoneal macrophages. The generation of soluble TNF-alpha was essential for the induction of MMP-3 in disc cocultures, which in turn is required for the generation of a macrophage chemoattractant and subsequent macrophage infiltration. TNF-alpha release from macrophages was necessary but insufficient for disc resorption, which required macrophage infiltration. We conclude that there is extensive communication between macrophages and chondrocytes in HD resorption and that an essential component of this communication is the requirement for MMPs to release soluble bioactive factors.
Sparse DOA estimation with polynomial rooting (2015)

Direction-of-arrival (DOA) estimation involves the localization of a few sources from a limited number of observations on an array of sensors. Thus, DOA estimation can be formulated as a sparse signal reconstruction problem and solved efficiently with compressive sensing (CS) to achieve high-resolution imaging. Utilizing the dual optimal variables of the CS optimization problem, it is shown with Monte Carlo simulations that the DOAs are accurately reconstructed through polynomial rooting (Root-CS). Polynomial rooting is known to improve the resolution in several other DOA estimation methods. However, traditional methods involve the estimation of the cross-spectral matrix hence they require many snapshots and stationary incoherent sources and are suitable only for uniform linear arrays (ULA). Root-CS does not have these limitations as demonstrated on experimental towed array data from ocean acoustic measurements.
EMerging BiomARKers in Inflammatory Bowel Disease (EMBARK) Study Identifies Fecal Calprotectin, Serum MMP9, and Serum IL-22 as a Novel Combination of Biomarkers for Crohn's Disease Activity: Role of Cross-Sectional Imaging (2013)

Incorporation of both ICO and CTE into a single measure increased biomarker performance in CD. Combinations of fecal calprotectin and serum MMP9 for UC, and combinations of fecal calprotectin, serum MMP9, and serum interleukin-22 in CD, demonstrated the strongest association with imaging/endoscopy-defined inflammation.
Imaging natural occlusal caries lesions with optical coherence tomography (2010)

Several studies have demonstrated that polarization-sensitive optical coherence tomography (PS-OCT) can be used to nondestructively measure the severity of demineralization in the important occlusal surfaces. The purpose of this study was to assess the potential of PS-OCT and OCT methods for the measurement of the depth of natural occlusal carious lesions. Teeth were screened for potential occlusal lesions using near infrared imaging (NIR). A PS-OCT system operating at 1310-nm was used to acquire polarization resolved images of the area of interest on the occlusal surface. The teeth were serial sectioned to 200 μm thickness and examined with polarized light microscopy (PLM) and Transverse Microradiography (TMR) for comparison. The lesion depth measured nondestructively with PS-OCT was compared to the lesion depth measured with PLM and TMR to assess the performance of these methods and determine if polarization sensitivity is required. The lesion depth measured using OCT correlated well with the lesion depths measured with TMR and PLM. Although polarization sensitivity provided better contrast it was not necessary to have polarization sensitivity to identify deep occlusal lesions.
Identification of a retinoic acid response element upstream of the murine Hox-4.2 gene. (1993)

Hox genes play an important role in the process of vertebrate pattern formation, and their expression is intricately regulated both temporally and spatially. All-trans-retinoic acid (RA), a physiologically active metabolite of vitamin A, affects the expression of a large number of Hox genes in vitro and in vivo. However, the regulatory mechanisms underlying the RA response of these genes have not been extensively studied, and no response element for RA receptors (RARs) has been characterized in a Hox regulatory region. The expression of murine Hox-4.2 and its human homolog, HOX4B, is increased in embryonal carcinoma (EC) cell lines upon RA treatment (M. S. Featherstone, A. Baron, S. J. Gaunt, M.-G. Mattei, and D. Duboule, Proc. Natl. Acad. Sci. USA 85:4760-4764, 1988; A. Simeone, D. Acampora, V. Nigro, A. Faiella, M. D'Esposito, A. Stornaiuolo, F. Mavilio, and E. Boncinelli, Mech. Dev. 33:215-228, 1991). Using transient expression assays, we showed that luciferase reporter gene constructs carrying genomic sequences located upstream of Hox-4.2 responded to RA in murine P19 EC cells. A 402-bp NcoI fragment was necessary for the RA responsiveness of reporter constructs. This fragment contained a regulatory element, 5'-AGGTGA(N)5AGGTCA-3', that closely resembles the consensus sequence for an RA response element. The Hox-4.2 RA response element was critical for the RA induction and specifically bound RARs. In addition, the response to RA could be inhibited by expressing a dominant negative form of RAR alpha in transfected P19 EC cells. These results suggested that Hox-4.2 is a target for RAR-mediated regulation by RA.
Genetic and developmental analysis of polytene section 17 of the X chromosome of Drosophila melanogaster. (1992)

Polytene section 17 of the X chromosome of Drosophila melanogaster, previously known to contain six putative lethal complementation groups important in oogenesis and embryogenesis, has here been further characterized genetically and developmentally. We constructed fcl+Y, a duplication of this region, which allowed us to conduct mutagenesis screens specific for the region and to perform complementation analyses (previously not possible). We recovered 67 new lethal mutations which defined 15 complementation groups within Df(1)N19 which deletes most of polytene section 17. The zygotic lethal phenotypes of these and preexisting mutations within polytene section 17 were examined, and their maternal requirements were analysed in homozygous germline clones using the dominant female sterile technique. We present evidence that an additional gene, which produces two developmentally regulated transcripts, is located in this region and is involved in embryogenesis, although no mutations in this gene were identified. In this interval of 37 to 43 polytene chromosome bands we have defined 17 genes, 12 (71%) of which are of significance to oogenesis or embryogenesis.
HIV / SIV Escape from Immune Surveillance: Focus on Nef (2004)

During a progressive HIV-1 infection, the gradual decrease in functional CD4+ T(helper) cells leads to immunodeficiency and eventually death in the untreated patient. The virulence role of the lentiviral accessory gene nef was first reported from deletion studies in the macaque model, and research during the past decade has revealed a pluripotent protein capable of multiple points of interference with cellular mechanisms. Importantly, Nef has the capacity to modify the plasma membrane signalling by regulation of receptor/ligand endocytosis as well as to modulate cellular regulation such as apoptosis and lymphocyte activation. This effective defence against an apparent vigorous and specific immune response is crucial for the ability of HIV-1 to persist in the host. Here we review the multitude of functions exerted by Nef and discuss the functional domains of the protein in terms of cellular interaction partners and the effect of nef mutations in the course of AIDS disease progression.
Conditional lineage ablation to model human diseases (1998)

Cell loss contributes to the pathogenesis of many inherited and acquired human diseases. We have developed a system to conditionally ablate cells of any lineage and developmental stage in the mouse by regulated expression of the diphtheria toxin A (DTA) gene by using tetracycline-responsive promoters. As an example of this approach, we targeted expression of DTA to the hearts of adult mice to model structural abnormalities commonly observed in human cardiomyopathies. Induction of DTA expression resulted in cell loss, fibrosis, and chamber dilatation. As in many human cardiomyopathies, transgenic mice developed spontaneous arrhythmias in vivo, and programmed electrical stimulation of isolated-perfused transgenic hearts demonstrated a strikingly high incidence of spontaneous and inducible ventricular tachycardia. Affected mice showed marked perturbations of cardiac gap junction channel expression and localization, including a subset with disorganized epicardial activation patterns as revealed by optical action potential mapping. These studies provide important insights into mechanisms of arrhythmogenesis and suggest that conditional lineage ablation may have wide applicability for studies of disease pathogenesis.