gebhart/patrepeval huggingface dataset:
Monocyte Chemotactic Protein-1 Is a Potential Player in the Negative Cross-Talk between Adipose Tissue and Skeletal Muscle (2006)

Adipose tissue is a major secretory and endocrine active organ producing a variety of bioactive proteins that may regulate energy metabolism and insulin sensitivity. In several studies, we have already shown that adipocyte-secretory products induce skeletal muscle insulin resistance. However, the precise nature of these factors has remained elusive. Human adipocytes were found to secrete various cytokines including IL-6, IL-8, macrophage inflammatory protein-1alpha/beta, and monocyte chemotactic protein-1 (MCP-1). Among these candidates, MCP-1 alone impaired insulin signaling in skeletal muscle cells at doses similar to its physiological plasma concentrations (200 pg/ml), whereas IL-6, IL-8, and macrophage inflammatory protein-1beta were effective at very high concentrations only. In addition, MCP-1 significantly reduced insulin-stimulated glucose uptake in the myocytes. Expression analysis of chemokine receptors in skeletal muscle cells revealed the presence of chemokine CXC motif receptor 1/2 and chemokine CC motif receptor 1/2/4/5/10. The action of MCP-1 on insulin signaling in skeletal muscle cells occurs via ERK1/2 activation but does not involve activation of the nuclear factor kappaB pathway. In conclusion, our data show that adipocytes secrete various adipokines that may be involved in the negative cross-talk between adipose tissue and skeletal muscle. Human skeletal muscle cells are highly sensitive toward MCP-1, which impairs insulin signaling and glucose uptake at concentrations even below that found in the circulation. However, other cytokines that are released by adipocytes impair insulin action only at supraphysiological concentrations. Therefore, MCP-1 may represent a molecular link in the negative cross-talk between adipose tissue and skeletal muscle assigning a completely novel important role to MCP-1 besides inflammation.
PTEN Regulates Glutamine Flux to Pyrimidine Synthesis and Sensitivity to Dihydroorotate Dehydrogenase Inhibition (2017)

Metabolic changes induced by oncogenic drivers of cancer contribute to tumor growth and are attractive targets for cancer treatment. Here, we found that increased growth of <i>PTEN</i>-mutant cells was dependent on glutamine flux through the <i>de novo</i> pyrimidine synthesis pathway, which created sensitivity to the inhibition of dihydroorotate dehydrogenase, a rate-limiting enzyme for pyrimidine ring synthesis. S-phase <i>PTEN</i>-mutant cells showed increased numbers of replication forks, and inhibitors of dihydroorotate dehydrogenase led to chromosome breaks and cell death due to inadequate ATR activation and DNA damage at replication forks. Our findings indicate that enhanced glutamine flux generates vulnerability to dihydroorotate dehydrogenase inhibition, which then causes synthetic lethality in <i>PTEN</i>-deficient cells due to inherent defects in ATR activation. Inhibition of dihydroorotate dehydrogenase could thus be a promising therapy for patients with <i>PTEN</i>-mutant cancers.<b>Significance:</b> We have found a prospective targeted therapy for <i>PTEN</i>-deficient tumors, with efficacy <i>in vitro</i> and <i>in vivo</i> in tumors derived from different tissues. This is based upon the changes in glutamine metabolism, DNA replication, and DNA damage response which are consequences of inactivation of <i>PTEN</i><i>Cancer Discov; 7(4); 380-90. ©2017 AACR.</i><i>See related article by Brown et al., p. 391</i><i>This article is highlighted in the In This Issue feature, p. 339</i>.
Three-Dimensional Imaging of Metabolites in Tissues under Ambient Conditions by Laser Ablation Electrospray Ionization Mass Spectrometry (2009)

Three-dimensional (3D) imaging of molecular distributions offers insight into the correlation between biochemical processes and the spatial organization of a biological tissue. Simultaneous identification of diverse molecules is a virtue of mass spectrometry (MS) that in combination with ambient ion sources enables the atmospheric pressure investigation of biomolecular distributions and processes. Here, we report on the development of an MS-based technique that allows 3D chemical imaging of tissues under ambient conditions without sample preparation. The method utilizes laser ablation electrospray ionization (LAESI) for direct molecular imaging with lateral and depth resolutions of approximately 300 microm and 30-40 microm, respectively. We demonstrate the feasibility of LAESI 3D imaging MS of metabolites in the leaf tissues of Peace lily (Spathiphyllum lynise) and the variegated Zebra plant (Aphelandra squarrosa). Extensive tandem MS studies help with the structure identification of the metabolites. The 3D distributions are found to exhibit tissue-specific metabolite accumulation patterns that correlate with the biochemical roles of these chemical species in plant defense and photosynthesis. Spatial correlation coefficients between the intensity distributions of different ions help to identify colocalization of metabolites and potentially uncover connections between metabolic pathways.
Cloning and expression of a cDNA coding for the human platelet-derived growth factor receptor: evidence for more than one receptor class. (1988)

The complete nucleotide sequence of a cDNA encoding the human platelet-derived growth factor (PDGF) receptor is presented. The cDNA contains an open reading frame that codes for a protein of 1106 amino acids. Comparison to the mouse PDGF receptor reveals an overall amino acid sequence identity of 86%. This sequence identity rises to 98% in the cytoplasmic split tyrosine kinase domain. RNA blot hybridization analysis of poly(A)+ RNA from human dermal fibroblasts detects a major (approximately 5.7 kb) and a minor (approximately 4.8 kb) transcript using the cDNA as a probe. Baby hamster kidney cells, transfected with an expression vector containing the receptor cDNA, express an approximately equal to 190-kDa cell surface protein that is recognized by an anti-human PDGF receptor antibody. The recombinant PDGF receptor is functional in the transfected baby hamster kidney cells as demonstrated by ligand-induced phosphorylation of the receptor. Binding properties of the recombinant PDGF receptor were also assessed with pure preparations of BB and AB isoforms of PDGF (i.e., PDGF dimers composed of two B chains or an A and a B chain). Unlike human dermal fibroblasts, which bind both isoforms with high affinity, the transfected baby hamster kidney cells bind only the BB isoform of PDGF with high affinity. This observation is consistent with the existence of more than one PDGF receptor class.
Salutary effects of estrogen receptor-β agonist on lung injury after trauma-hemorrhage (2005)

Although 17beta-estradiol (E2) administration after trauma-hemorrhage attenuates lung injury in male rodents, it is not known whether the salutary effects are mediated via estrogen receptor (ER)-alpha or ER-beta. We hypothesized that the salutary effects of E2 lung are mediated via ER-beta. Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure 40 mmHg for 90 min, then resuscitation). E2 (50 microg/kg), ER-alpha agonist propyl pyrazole triol (PPT; 5 microg/kg), ER-beta agonist diarylpropiolnitrile (DPN; 5 microg/kg), or vehicle (10% DMSO) was injected subcutaneously during resuscitation. At 24 h after trauma-hemorrhage or sham operation, bronchoalveolar fluid (BALF) was collected for protein concentration, LDH activity, and nitrate/nitrite and IL-6 levels. Moreover, lung tissue was used for inducible nitric oxide synthase (iNOS) mRNA/protein expression, nitrate/nitrite and IL-6 levels, and wet/dry weight ratio (n = 6 rats/group). One-way ANOVA and Tukey's test were used for statistical analysis. The results indicated that E2 downregulated lung iNOS expression after trauma-hemorrhage. Protein concentration, LDH activity, and nitrate/nitrite and IL-6 levels in BALF and nitrate/nitrite and IL-6 levels in the lung increased significantly after trauma-hemorrhage; however, administration of DPN but not PPT significantly improved all parameters. Moreover, DPN treatment attenuated trauma-hemorrhage-mediated increase in iNOS mRNA/protein expression in the lung. In contrast, no significant change in the above parameters was observed with PPT. Thus the salutary effects of E2 on attenuation of lung injury are mediated via ER-beta, and ER-beta-induced downregulation of iNOS likely plays a significant role in the DPN-mediated lung protection after trauma-hemorrhage.
Towards Deeper Understanding of Variational Autoencoding Models (2017)

We propose a new family of optimization criteria for variational auto-encoding models, generalizing the standard evidence lower bound. We provide conditions under which they recover the data distribution and learn latent features, and formally show that common issues such as blurry samples and uninformative latent features arise when these conditions are not met. Based on these new insights, we propose a new sequential VAE model that can generate sharp samples on the LSUN image dataset based on pixel-wise reconstruction loss, and propose an optimization criterion that encourages unsupervised learning of informative latent features.
Doxazosin and Congestive Heart Failure (2002)

Doxazosin remains a commonly used antihypertensive medication, although its use has been tainted by recent findings from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT was a large, simple trial, designed in a fashion to closely mimic clinical practice as it occurs in high-risk hypertensive patients aged 55 years or older. Its goals were to determine whether the incidence of the primary outcome--a composite of fatal coronary heart disease and nonfatal myocardial infarction--differed between treatment with a diuretic (chlorthalidone) (12.5-25.0 mg/day) and treatment with each of three other types of antihypertensive drugs-a calcium-channel blocker (amlodipine), an angiotensin-converting enzyme inhibitor (lisinopril), and a peripheral alpha-adrenergic blocker (doxazosin) (2-8 mg/day). Doxazosin was recently withdrawn from this trial after an interim analysis showed the secondary end point of combined cardiovascular disease to be 25% greater in patients on doxazosin than in those assigned to treatment with chlorthalidone. This finding was largely driven by congestive heart failure. The practicing clinician should not abandon doxazosin completely because of the ALLHAT findings, although these findings are indisputably important. These results represent an interim analysis and their application to clinical practice needs to occur carefully. A valued member of our therapeutic armamentarium need not be laid entirely to rest; rather, doxazosin should now be viewed as a secondary or tertiary antihypertensive therapy pending a more complete review of the ALLHAT data.
Recombining sequence recombination in normal kappa-chain-expressing B cells (1997)

Recombining sequence (RS) recombination is a DNA rearrangement that deletes one or two C kappa alleles in a large proportion of lambda-expressing B cells. Since its discovery, this recombination has been suggested to play a role in activating lambda gene rearrangements. A model involving a positive signal generated by RS recombination seems to be excluded, but another model that is still under consideration proposes that RS recombination removes DNA sequences within the kappa locus that would interfere with lambda gene assembly. Using PCR assays, we have found that kappa-expressing cells account for the majority of RS rearrangements in mouse spleen. RS rearrangements were also detected by Southern blot in kappa-secreting hybridomas. Quantification of rearrangements indicates that approximately 12% of kappa cells bear an RS recombination. From this finding, we infer that once a cell has performed an RS recombination on one kappa allele, it has a 3 times higher probability of rearranging functionally its other kappa allele rather than one of the lambda genes. These data call into question the role of RS recombination in the switch from kappa to lambda and suggest another function for this nonproductive rearrangement.
Overview of hemostatic factors involved in atherosclerotic cardiovascular disease (2005)

Hemostatic factors associated with the development of cardiovascular disease (CVD) include fibrinogen, von Willebrand factor, tissue plasminogen activator (tPA) antigen, plasminogen activator inhibitor-1 (PAI-1), and factor VII. Each SD increment of these increases the association by 24-30%. Most hemostatic factors are intercorrelated with inflammatory markers [e.g., C-reactive protein (CRP)] and LDL cholesterol. Fibrinogen seems the most fundamental hemostatic risk factor for CVD. The Framingham Study reaffirms the significant linear risk factor trends across fibrinogen tertiles (P< 0.001) for age, body mass index, smoking, diabetes mellitus, total cholesterol, HDL cholesterol, and TG in both sexes. Fibrinogen may also directly increase CVD risk because of its role in platelet aggregation, plasma viscosity, and fibrin formation. Fibrinogen is also an acute-phase reactant that is elevated in inflammatory states. Fibrinogen mediates the thrombogenic effect of other risk factors. Fibrinogen levels increase with the number of cigarettes smoked and quickly fall after smoking cessation. This rapid fibrinogen decline may be a mechanism for CVD risk reduction after smoking cessation. Weight loss is accompanied by reduced fibrinogen. The correlation between fibrinogen and LDL cholesterol suggests that lipid-imposed CVD risk is mediated partly through fibrinogen. Hyperreactive platelets of diabetics may result in part from their increased fibrinogen. Elevated fibrinogen and CRP of unstable angina suggest an acute-phase reaction. Prevalence, case-control, angiographic, and echocardiogram investigations incriminate hemostatic and inflammatory markers as strong independent risk factors for initial and recurrent CVD. Framingham Study data indicate that each SD increase in fibrinogen imposes a 20% independent increment in risk. It may be concluded that fibrinogen and CRP determination may be useful screening tools to identify individuals at added risk for thrombotic complications of CVD.
N-Cadherin Is Expressed by Putative Stem/Progenitor Cells and Melanocytes in the Human Limbal Epithelial Stem Cell Niche (2006)

Corneal epithelial stem cells are known to be localized to the basal layer of the limbal epithelium, providing a model system for epithelial stem cell biology; however, the mechanisms regarding the maintenance of these stem cells in their specialized niche remain poorly understood. N-cadherin is a member of the classic cadherin family and has previously been demonstrated to be expressed by hematopoietic stem cells. In the present study, we demonstrate that N-cadherin is expressed by putative stem/progenitor cells, as well as melanocytes, in the human limbal epithelial stem cell niche. In addition, we demonstrate that upon in vitro culture using 3T3 feeder layers, loss of N-cadherin expression occurs with cell proliferation. These results indicate that N-cadherin may be a critical cell-to-cell adhesion molecule between corneal epithelial stem/progenitor cells and their corresponding niche cells in the limbal epithelium.
Filter-response line shapes of resonant waveguide gratings (1996)

The line shape symmetry properties of planar dielectric resonant waveguide-grating filters are theoretically characterized for both TE and TM polarization. Classical antireflection theory is applied to the design of guided-mode resonance filters and it is shown that the symmetry of the line-shape response is determined by the location of the resonance relative to the minimum of the antireflection band. The conditions that allow a single dielectric layer to simultaneously function as both a waveguide grating and as an antireflection thin film are presented. Single-layer antireflection waveguide gratings are shown to yield highly symmetrical filter-response line shapes with suppressed sideband reflectivity and 100% reflectivity at the resonance wavelength. The parametric locations of the symmetrical line-shape responses are predicted approximately by solving the resonance-location equation with the grating thickness set equal to a multiple of a half-resonance-wavelength. Graphical representations of these solutions are provided. Symmetric waveguide-grating filters are shown to yield symmetrical line shapes with near-zero sideband reflectivity, whereas asymmetric filters produce symmetrical line shapes but suffer from increased sideband reflectance that increases as the asymmetry of the filter grows. Numerous calculated examples are presented to demonstrate that ideal reflection filters can be designed by combining thin-film antireflection effects and resonance effects in a single dielectric layer.
MULTICENTER TRIAL EXPLORING CALCINEURIN INHIBITORS AVOIDANCE IN RENAL TRANSPLANTATION (2001)

This CNI avoidance study in immunologic low-risk patients, while only partially successful in preventing acute rejection, provided benefits to a sizable minority of patients who have not required chronic CNI therapy. However, wide acceptance of a CNI-sparing immunosuppression regimen may require a lower rate of acute rejection, possibly through the addition of a non-nephrotoxic dose of CNI. However, because complete IL-2Ralpha blockade was present during rejection, it can be assumed that alternative pathways, such as IL-15, may be responsible for the rejection; thus, the incorporation of non-nephrotoxic immunosuppressive agents, such as sirolimus, may provide a more strategic approach.
Partial Splenectomy for Gaucherʼs Disease (1987)

Gaucher's disease is an autosomal recessive disorder caused by deficiency of beta glucocerebrosidase, resulting in an accumulation of glucocerebroside in the reticuloendothelial system. These patients have massive splenomegaly and bone pain, but may have normal life expectancy. Traditionally, splenectomy has been used to treat hypersplenism, but may be associated with a high incidence of postsplenectomy sepsis and accelerated hepatic and bone lipid deposition. Two children are reported who had partial splenectomy for symptoms of Gaucher's disease. Both patients had laboratory evidence of hypersplenism. A 90% splenectomy was performed, and the residual splenic fragment was wrapped in Vicryl mesh. Both patients are currently asymptomatic with normal hematologic parameters. Postoperative radionuclide scans demonstrate increase in the size of the residual splenic fragment. Partial splenectomy may benefit patients with Gaucher's disease, but long-term follow-up care is necessary.
Electrocardiographic and radiographic changes in cats with hyperthyroidism: comparison of populations evaluated during 1992-1993 vs. 1979-1982 (1999)

Cardiovascular manifestations of feline hyperthyroidism were compared in two populations of cats diagnosed at The Animal Medical Center from 1992 to 1993 (n=202) and 1979 to 1982 (n = 131). The prevalence of sinus tachycardia and increased R-wave voltage in lead II were both lower in the 1993 population compared with the 1982 population (p less than 0.001). A low frequency of atrial and ventricular arrhythmias and intraventricular conduction abnormalities were recorded in both populations. No significant differences between populations were recorded in the number of cats with mild, moderate, and severe cardiomegaly seen on thoracic radiographs. The percentage of cats in which radiographs were deemed clinically necessary based upon history and clinical examination was 25% of the 1993 population, compared with 63% of the 1982 population. The number of cats with radiographic evidence of congestive heart failure was 8% in 1993 compared with 20% in 1982, although this difference was not statistically significant. In conclusion, the incidence and severity of certain thyrotoxic cardiovascular manifestations were reduced in cats diagnosed between 1992 and 1993 compared with those diagnosed between 1979 and 1982.
Culture of Helicobacter pylori: Effect of Preimmersion of Biopsy Forceps in Formalin (1996)

Preimmersion of biopsy forceps in formalin does not adversely affect the ability to culture H. pylori.
Transcriptional Repression of p53 by Human T-cell Leukemia Virus Type I Tax Protein (1995)

The human T-cell leukemia virus type I oncoprotein Tax transcriptionally deregulates a wide variety of viral and cellular genes. Tax deregulation of gene expression is mediated through interaction with a variety of structurally unrelated cellular transcription factors, as Tax does not bind DNA in a sequence-specific manner. Although most of these cellular transcription factors have been shown to mediate activation by Tax, we have recently demonstrated that members of the basic helix-loop-helix (bHLH) family of transcription factors, which play a critical role in progression through the cell cycle, mediate repression by Tax. In this report, we examined whether Tax might repress transcription of the tumor suppressor p53, as the p53 gene has recently been demonstrated to be regulated by the bHLH protein c-Myc. Furthermore, loss or inactivation of the p53 gene has been shown to be causally associated with oncogenic transformation. We show that Tax represses transcription of the p53 gene and that this repression is dependent upon the bHLH recognition element in the p53 promoter. Together, these results suggest that Tax may promote malignant transformation through repression of p53 transcription.
Hedgehog Signaling Pathway is a New Therapeutic Target for Patients with Breast Cancer (2004)

Abstract The Hedgehog (Hh) signaling pathway functions as an organizer in embryonic development. Genetic analysis has demonstrated a critical role for the Hh pathway in mammary gland morphogenesis. Disruption of Patched1, a component of the Hh pathway, results in abnormal growth of mammary duct. Recent studies have shown constitutive activation of the Hh pathway in various types of malignancies. However, it remains unclear whether this pathway is activated in human breast cancer. Here, we determined the expression of the components, including Sonic Hh, Patched1, and Gli1, of the Hh pathway by immunohistochemical staining in a series of 52 human breast carcinomas. All of 52 tumors display staining of high intensity for Gli1 when compared with adjacent normal tissue. The nuclear staining ratio of Gli1 correlates with expression of estrogen receptor and histologic type. Exposure to cyclopamine, a steroidal alkaloid that blocks the Hh pathway, suppresses expression of Gli1 and the growth of the Hh pathway-activated breast carcinoma cells. These data indicate that the Hh pathway is a new candidate for therapeutic target of breast cancer.
Apical polarity in three-dimensional culture systems: where to now? (2010)

Delineation of the mechanisms that establish and maintain the polarity of epithelial tissues is essential to understanding morphogenesis, tissue specificity and cancer. Three-dimensional culture assays provide a useful platform for dissecting these processes but, as discussed in a recent study in BMC Biology on the culture of mammary gland epithelial cells, multiple parameters that influence the model must be taken into account.