gebhart/patrepeval huggingface dataset:
Expanded complexity of unstable repeat diseases (2012)

Unstable repeat diseases (URDs) share a common mutational phenomenon of changes in the copy number of short, tandemly repeated DNA sequences. More than 20 human neurological diseases are caused by instability, predominantly, expansion of microsatellite sequences. Changes in the repeat size initiate a cascade of pathological processes, frequently characteristic of a unique disease or a small subgroup of the URDs. Understanding of both the mechanism of repeat instability and molecular consequences of the repeat expansions is critical to developing successful therapies for these diseases. Recent technological breakthroughs in whole genome, transcriptome and proteome analyses will almost certainly lead to new discoveries regarding the mechanisms of repeat instability, the pathogenesis of URDs, and will facilitate development of novel therapeutic approaches. The aim of this review is to give a general overview of unstable repeats diseases, highlight the complexities of these diseases, and feature the emerging discoveries in the field.
An integrated approach for the systematic identification and characterization of heart-enriched genes with unknown functions (2009)

We conclude that DGSA is a versatile tool for database mining allowing efficient selection of uncharacterized genes for functional analysis.
Gemcitabine and Arabinosylcytosin Pharmacogenomics: Genome-Wide Association and Drug Response Biomarkers (2009)

Cancer patients show large individual variation in their response to chemotherapeutic agents. Gemcitabine (dFdC) and AraC, two cytidine analogues, have shown significant activity against a variety of tumors. We previously used expression data from a lymphoblastoid cell line-based model system to identify genes that might be important for the two drug cytotoxicity. In the present study, we used that same model system to perform a genome-wide association (GWA) study to test the hypothesis that common genetic variation might influence both gene expression and response to the two drugs. Specifically, genome-wide single nucleotide polymorphisms (SNPs) and mRNA expression data were obtained using the Illumina 550K(R) HumanHap550 SNP Chip and Affymetrix U133 Plus 2.0 GeneChip, respectively, for 174 ethnically-defined "Human Variation Panel" lymphoblastoid cell lines. Gemcitabine and AraC cytotoxicity assays were performed to obtain IC(50) values for the cell lines. We then performed GWA studies with SNPs, gene expression and IC(50) of these two drugs. This approach identified SNPs that were associated with gemcitabine or AraC IC(50) values and with the expression regulation for 29 genes or 30 genes, respectively. One SNP in IQGAP2 (rs3797418) was significantly associated with variation in both the expression of multiple genes and gemcitabine and AraC IC(50). A second SNP in TGM3 (rs6082527) was also significantly associated with multiple gene expression and gemcitabine IC50. To confirm the association results, we performed siRNA knock down of selected genes with expression that was associated with rs3797418 and rs6082527 in tumor cell and the knock down altered gemcitabine or AraC sensitivity, confirming our association study results. These results suggest that the application of GWA approaches using cell-based model systems, when combined with complementary functional validation, can provide insights into mechanisms responsible for variation in cytidine analogue response.
Bone regeneration: current concepts and future directions (2011)

Bone regeneration is a complex, well-orchestrated physiological process of bone formation, which can be seen during normal fracture healing, and is involved in continuous remodelling throughout adult life. However, there are complex clinical conditions in which bone regeneration is required in large quantity, such as for skeletal reconstruction of large bone defects created by trauma, infection, tumour resection and skeletal abnormalities, or cases in which the regenerative process is compromised, including avascular necrosis, atrophic non-unions and osteoporosis. Currently, there is a plethora of different strategies to augment the impaired or 'insufficient' bone-regeneration process, including the 'gold standard' autologous bone graft, free fibula vascularised graft, allograft implantation, and use of growth factors, osteoconductive scaffolds, osteoprogenitor cells and distraction osteogenesis. Improved 'local' strategies in terms of tissue engineering and gene therapy, or even 'systemic' enhancement of bone repair, are under intense investigation, in an effort to overcome the limitations of the current methods, to produce bone-graft substitutes with biomechanical properties that are as identical to normal bone as possible, to accelerate the overall regeneration process, or even to address systemic conditions, such as skeletal disorders and osteoporosis.
A modification of Hepatest, using the Terasaki plate, for the detection of HBSAg in blood donors. (1976)

A simple modification of Hepatest (Wellcome Reagents) is described, which lends itself to the rapid large-scale screening of blood donors. The technique uses 4 mul of HBSAb coated turkey cells (Cayzer et al., 1974), and Terasaki plates (Hopkins and Das, 1973), in contrast to the 25 mul used in the microtitre tray technique. This results in a considerable saving on the cost of reagents, the cost per test being reduced to 16% of the cost of the recommended method. In our hands, this modification is as convenient to use as the manual microtitre tray technique. Positive sera from the screen test are also tested for non-specificity using horse IgG coated turkey control cells. The falso positive screen test rate has been reduced by the adoption of a modified buffer containing turkey serum.
Successful and Rapid Treatment of Blue and Green Tattoo Pigment With a Novel Picosecond Laser (2012)

While additional future studies are needed, we believe that this new technology is more effective in targeting blue and green pigment, resulting in expedited clearance with less collateral injury to surrounding tissue.
Two Dynamin-2 Genes Are Required for Normal Zebrafish Development (2013)

Dynamin-2 (DNM2) is a large GTPase involved in clathrin-mediated endocytosis and related trafficking pathways. Mutations in human DNM2 cause two distinct neuromuscular disorders: centronuclear myopathy and Charcot-Marie-Tooth disease. Zebrafish have been shown to be an excellent animal model for many neurologic disorders, and this system has the potential to inform our understanding of DNM2-related disease. Currently, little is known about the endogenous zebrafish orthologs to human DNM2. In this study, we characterize two zebrafish dynamin-2 genes, dnm2 and dnm2-like. Both orthologs are structurally similar to human DNM2 at the gene and protein levels. They are expressed throughout early development and in all adult tissues examined. Knockdown of dnm2 and dnm2-like gene products resulted in extensive morphological abnormalities during development, and expression of human DNM2 RNA rescued these phenotypes. Our findings suggest that dnm2 and dnm2-like are orthologs to human DNM2, and that they are required for normal zebrafish development.
Zyxin and cCRP: two interactive LIM domain proteins associated with the cytoskeleton. (1992)

Interaction with extracellular matrix can trigger a variety of responses by cells including changes in specific gene expression and cell differentiation. The mechanism by which cell surface events are coupled to the transcriptional machinery is not understood, however, proteins localized at sites of cell-substratum contact are likely to function as signal transducers. We have recently purified and characterized a low abundance adhesion plaque protein called zyxin (Crawford, A. W., and M. C. Beckerle. 1991. J. Biol. Chem. 266:5847-5853; Crawford, A. W., J. W. Michelsen, and M. C. Beckerle. 1992. J. Cell Biol. 116:1381-1393). We have now isolated and sequenced zyxin cDNA and we report here that zyxin exhibits an unusual proline-rich NH2-terminus followed by three tandemly arrayed LIM domains. LIM domains have previously been identified in proteins that play important roles in transcriptional regulation and cellular differentiation. LIM domains have been proposed to coordinate metal ions and we have demonstrated by atomic absorption spectroscopy that purified zyxin binds zinc, a result consistent with the idea that zyxin has zinc fingers. In addition, we have discovered that zyxin interacts in vitro with a 23-kD protein that also exhibits LIM domains. Microsequence analysis has revealed that the 23-kD protein (or cCRP) is the chicken homologue of the human cysteine-rich protein (hCRP). By double-label indirect immunofluorescence, we found that zyxin and cCRP are extensively colocalized in chicken embryo fibroblasts, consistent with the idea that they interact in vivo. We conclude that LIM domains are zinc-binding sequences that may be involved in protein-protein interactions. The demonstration that two cytoskeletal proteins, zyxin and cCRP, share a sequence motif with proteins important for transcriptional regulation raises the possibility that zyxin and cCRP are components of a signal transduction pathway that mediates adhesion-stimulated changes in gene expression.
Allopurinol Attenuates Left Ventricular Remodeling and Dysfunction After Experimental Myocardial Infarction (2004)

The present study reveals a novel beneficial effect of treatment with allopurinol, ie, a marked attenuation of LV remodeling processes and dysfunction after experimental MI. Allopurinol treatment therefore represents a potential novel strategy to prevent LV remodeling and dysfunction after MI.
New plate medium for facilitated differentiation of Salmonella spp. from Proteus spp. and other enteric bacteria (1990)

A new agar medium for the differentiation of Salmonella spp. from other members of the family Enterobacteriaceae is described. This medium exploits a novel phenotypic characteristic of Salmonella spp.: the formation of acid from propylene glycol. This characteristic may be used in combination with a chromogenic indicator of beta-galactosidase to differentiate Salmonella spp. from Proteus spp. and the other members of the Enterobacteriaceae. Desoxycholate may be included in the plate medium as an inhibitor of gram-positive organisms. Non-typhi Salmonella spp. yield distinct, bright red colonies on this medium, allowing facilitated identification and unambiguous differentiation from Proteus spp.
The Role of ErbB2 Signaling in the Onset of Terminal Differentiation of OligodendrocytesIn Vivo (2003)

The knock-out analyses of neuregulin and its receptors have indicated that they play essential roles in Schwann cell development. However, the role they play in oligodendrocyte development in vivo has remained unclear, because such knock-out animals die before CNS myelination begins. We examined the role of neuregulin signaling in the CNS by generating transgenic mice that express a dominant-negative mutant of the ErbB2 receptor among oligodendrocytes, using an MBP promoter. The transgenic mice exhibited widespread hypomyelination, resulting from a reduction in oligodendrocyte differentiation. The number of progenitors was conversely increased in the transgenic mice. We report that a reduction in oligodendrocyte differentiation is attributed in part to apoptosis of oligodendrocyte progenitors as they exit the cell cycle. A significant reduction in the number of p27+ oligodendrocyte precursors in the transgenic mice supports this conclusion. Taken together, these data suggest that for oligodendrocyte progenitors, ErbB2 signaling plays a role in governing a properly timed exit from the cell cycle during development into myelinating oligodendrocytes.
Lung cancer: New biological insights and recent therapeutic advances (2011)

Approximately 1.6 million new cases of lung cancer are diagnosed each year throughout the world. In many countries, the mortality related to lung cancer continues to rise. The outcomes for patients with all stages of lung cancer have improved in recent years. The use of systemic therapy in conjunction with local therapy has led to improved cure rates in both resectable and unresectable patient groups. For patients with advanced stage disease, modest but real improvements in overall survival and quality of life have been achieved with systemic chemotherapy. A major focus of research has been the development of molecularly targeted agents and the identification of biomarkers for patient selection. Patients with non-small cell lung cancer with mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain achieve response rates of greater than 70% and superior progression-free survival when treated with an EGFR tyrosine kinase inhibitor compared with standard chemotherapy. This has now emerged as the preferred therapeutic approach for the subset of patients with a mutation in exons 19 or 21 of the EGFR. Another promising targeted approach involves the use of an anaplastic lymphoma kinase (ALK) inhibitor in patients with a translocation involving the echinoderm microtubule-associated protein-like 4 (EML4) and -ALK genes. Finally, a paradigm shift in favor of maintenance therapy for patients with advanced stage disease has gained strength from recent data. All of these advances have been made possible by developing a greater understanding of the biology, the discovery of novel anticancer agents, and improved supportive care measures. This article reviews the major strides made in the treatment of lung cancer in the recent past.
Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations (2003)

Heterozygous mutations in the coding region of the serpentine Melanocortin 4 receptor are the most common genetic cause of human obesity described to date. There are still conflicting data regarding the overall prevalence of such mutations in obesity and limited information is available on the functional defects caused by most obesity-associated MC4R mutations. We report here the screening for mutations in the coding region of the MC4R of a new cohort of 172 patients presenting with severe childhood obesity and a family history of obesity. Three heterozygous MC4R mutations (Ser127Leu, Ala244Glu and Pro299His) were found in three patients of this cohort (1.74%), confirming that such mutations are implicated in a significant number of childhood obesity cases. A functional analysis of these mutant receptors, in addition to 11 other childhood obesity-associated MC4R mutations, indicates that they all alter the activation of the receptor by the endogenous agonist alpha-MSH. To further examine the functional defects caused by childhood obesity-associated MC4R mutations, we developed a novel, sensitive technique to quantitatively analyze the effect of a mutation on MC4R cell surface expression. Using this method we analyzed the cell surface expression of all the 14 described childhood obesity-associated MC4R missense mutations. We demonstrate that 81.3% of childhood obesity-associated heterozygous MC4R mutations lead to intracellular retention of the receptor. This result has implications for the potential pharmacologic rescue of childhood obesity-associated MC4R mutations and for the treatment of patients presenting with this condition.
Abstract P4-14-28: XMT-1522 induces tumor regressions in pre-clinical models representing HER2-positive and HER2 low-expressing breast cancer (2016)

Abstract XMT-1522 is an anti-HER2 antibody-drug conjugate (ADC) comprised of a novel anti-HER2 antibody (HT-19) and the Dolaflexin ADC platform, which allows for conjugation of 12-15 proprietary auristatin drug payload molecules per antibody without aggregation or detrimental impact on pharmacokinetics. The HT-19 antibody binds to a novel HER2 extracellular domain epitope and does not compete for HER2 binding with trastuzumab or pertuzumab. In vitro, XMT-1522 has sub-nanomolar potency in cell lines expressing as few as 25,000 HER2 antigens per cell, and is ∼100X more potent than ado-trastuzumab emtansine (T-DM1) across a panel of 25 cell lines representing a range of tumor indications and HER2 expression levels. In the BT-474 HER2-positive breast cancer model, treatment with the HT-19 antibody alone at a single 5 mg/kg dose is inactive, while XMT-1522 ADC at a single 2 mg/kg or 5 mg/kg dose induces durable complete tumor regression, indicating that the primary mechanism of XMT-1522 is cytotoxic payload delivery, not inhibition of HER2 signaling. T-DM1 at a single 5 mg/kg dose in the same model is inactive, consistent with the significant improvement in potency of XMT-1522 compared to T-DM1. Biodistribution studies using a HER2-targeted Dolaflexin ADC in the BT-474 model demonstrate accumulation of intact ADC and released active drug payload in tumor at levels significantly higher than normal tissues. In a HER2-positive patient-derived xenograft (PDX) model, XMT-1522 induces durable complete tumor regression after a single 1 mg/kg dose, while T-DM1 at a 10 mg/kg dose achieves tumor growth delay without regression. In a HER2 1+ PDX model without HER2 gene amplification, a single 3 mg/kg dose of XMT-1522 achieves partial tumor regression where a 10 mg/kg dose of T-DM1 is inactive. Combination of XMT-1522 with trastuzumab does not block the ability of the ADC to bind HER2 or efficiently internalize, and in vivo the combination of low dose XMT-1522 with full dose trastuzumab and pertuzumab is synergistic in a HER2-driven model. The exposure achieved with XMT-1522 at well-tolerated doses in cynomolgus monkey is several fold higher than the exposure needed in mice to achieve complete tumor regressions across models representing a range of HER2 expression and tumor indications. Based on these data, XMT-1522 will soon enter clinical testing in breast cancer patients with both HER2-positive tumors and HER2 low-expressing (IHC 1+ and 2+/FISH-) tumors. Citation Format: Bergstrom DA, Bodyak N, Park PU, Yurkovetskiy A, DeVit M, Yin M, Poling L, Thomas JD, Gumerov D, Xiao D, Ter-Ovanesyan E, Qin L, Uttard A, Johnson A, Lowinger TB. XMT-1522 induces tumor regressions in pre-clinical models representing HER2-positive and HER2 low-expressing breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-28.
Impaired CXCR4 Signaling Contributes to the Reduced Neovascularization Capacity of Endothelial Progenitor Cells From Patients With Coronary Artery Disease (2005)

Transplantation of bone marrow cells as well as circulating endothelial progenitor cells (EPC) enhances neovascularization after ischemia. The chemokine receptor CXCR4 is essential for migration and homing of hematopoietic stem cells. Therefore, we investigated the role of CXCR4 and its downstream signaling cascade for the angiogenic capacity of cultured human EPC. Ex vivo, differentiated EPC derived from peripheral blood abundantly expressed CXCR4. Incubation of EPC from healthy volunteers with neutralizing antibodies against CXCR4 profoundly inhibited vascular endothelial growth factor- and stromal-derived factor-1-induced migration as well as EPC-induced angiogenesis in an ex vivo assay. Preincubation of transplanted EPC with CXCR4 antibody reduced EPC incorporation and impaired blood-flow recovery in ischemic hindlimbs of nude mice (57+/-4% of normal perfusion versus untreated EPC: 80+/-11%, P<0.001). Bone marrow mononuclear cells (BM-MNC) or EPC of heterozygous CXCR4(+/-) mice displayed reduced CXCR4 expression and disclosed impaired in vivo capacity to enhance recovery of ischemic blood flow in nude mice (blood flow 27+/-11% versus 66+/-25% using wild-type cells, P<0.01). Importantly, impaired blood flow in ischemic CXCR4(+/-) mice was rescued by injection of wild-type BM-MNC. Next, we investigated the role of CXCR4 for functional capacities of EPC from patients with coronary artery disease (CAD). Surface expression of CXCR4 was similar in EPC from patients with CAD compared with healthy controls. However, basal Janus kinase (JAK)-2 phosphorylation was significantly reduced and less responsive to stromal-derived factor-1 in EPC from patients with CAD compared with healthy volunteers, indicating that CXCR4-mediated JAK-2 signaling is dysregulated in EPC from patients with CAD. The CXCR4 receptor signaling profoundly modulates the angiogenic activity and homing capacity of cultured human EPC. Disturbance of CXCR4 signaling, as demonstrated by reduced JAK-2 phosphorylation, may contribute to functional impairment of EPC from patients with CAD. Stimulating CXCR4 signaling might improve functional properties of EPC and may rescue impaired neovascularization capacity of EPC derived from patients with CAD.
Tumor Necrosis Factor-α (2010)

In the Sabra rat, oxidative stress (OS) and inflammation precede the development of hypertension. Inhibition of the phagocytic NADPH oxidase attenuates the rise in blood pressure. The present study was set to identify possible priming agents for this enzyme and to test the hypothesis that the phagocytic NADPH oxidase contributes to OS and inflammation. Sabra salt-sensitive and Sabra salt-resistant rats were salt loaded or provided regular chow for 60 days with or without apocynin to inhibit NADPH oxidase. Levels of interleukin 6, tumor necrosis factor-alpha, and interferon-gamma served as indices of inflammation. Extracellular and intracellular levels of the polymorphonuclear leukocyte tumor necrosis factor-alpha receptors (p55 and p75) were assessed by flow cytometry in young and adult rats. NADPH oxidase activity and expression of p47phox were measured in polymorphonuclear leukocytes and aortic rings. Malondialdehyde and carbonylated fibrinogen served as indices of OS. Inflammatory and OS indices excluding interferon-gamma were higher in the hypertensive state and reduced by apocynin. Levels of malondialdehyde and tumor necrosis factor-alpha were elevated already in the prehypertensive state. No differences were found in the levels of p75. The extracellular expression of p55 was higher in adult Sabra salt-resistant compared with Sabra salt-sensitive rats (7.46+/-2.2% versus 2.1+/-0.5%; P<0.05), whereas levels of the intracellular p55 were higher in adult Sabra salt-sensitive rats (3.2+/-2% versus 1.1+/-0.5%; P<0.05). In young normotensive rats, the extracellular levels of p55 were higher in Sabra salt-sensitive compared with Sabra salt-resistant rats (10.6+/-5.2% versus 2.9+/-1.5%; P<0.01). Tumor necrosis factor-alpha plays a role in activation of the polymorphonuclear leukocyte NADPH oxidase, thereby contributing to systemic OS, inflammation, and the development of hypertension in this model.
The Updated NICE Guidelines: Cardiac CT as the First-Line Test for Coronary Artery Disease (2017)

NICE recommend cardiac CT as the first-line test for the evaluation of stable coronary artery disease in chest pain pathways.
Least squares fitting of parametric surfaces to measured data (2000)

The problem is considered of fitting surfaces to measured data using the least squares norm, where it is assumed that a parameterization of the surface is available. Examples of practical applications include the product design and quality assurance of manufactured parts. There has been much recent algorithmic development based on conventional fitting ideas, mainly orthogonal distance regression. A different approach is taken here which explicitly takes account of the measurement process, and this is illustrated by some examples.