gebhart/patrepeval huggingface dataset:
Local infusion of urokinase for the lysis of thrombosis associated with permanent central venous catheters in cancer patients. (1987)

We assessed the efficacy of local fibrinolytic therapy in 35 axillary-subclavian vein thromboses (SVT) that occurred in cancer patients with percutaneous central venous catheters (CVC). These catheters were indwelling for a median of 1 month (range, one day to 10 months) before thrombosis developed. Urokinase was administered at a dose of 500 to 2,000 U/kg/h. Complete lysis occurred in 25 of 30 thrombi that were directly infused, after a median of four days. Complete lysis occurred in one of 12 thrombi that could not be directly infused with urokinase and in two of six with associated phlebitis. Eighty-one percent of the thrombi that were symptomatic for less than 1 week before treatment resolved, compared with 56% present for longer than 1 week. Sixteen patients who had complete (12) or partial (four) thrombolysis did not have their CVCs removed. All four patients with partial thrombolysis had recurrent thrombosis at a median of eight days (range, one to 90). Only two patients who had complete thrombolysis had recurrent thrombosis, at 8 and 16 months. Only minor hemorrhagic toxicity was seen.
Isotype distribution of ANTI–CYCLIC citrullinated peptide antibodies in undifferentiated arthritis and rheumatoid arthritis reflects an ongoing immune response (2006)

These data indicate development of the anti-CCP isotype repertoire into full usage early in the course of arthritis. The sustained presence of IgM anti-CCP indicates ongoing recruitment of new B cells into the anti-CCP response, reflecting a continuous (re)activation of the RA-specific anti-CCP response during the course of anti-CCP-positive arthritis.
Human cytomegalovirus US3 and UL36-38 immediate-early proteins regulate gene expression (1992)

We have established the ability of the human cytomegalovirus (HCMV) UL36-38 and US3 immediate-early (IE) gene products to alter gene expression in human cells by using transient transfection assays. The cellular heat shock protein 70 (hsp70) promoter was transactivated following cotransfection with the HCMV IE regions in nonpermissive HeLa cells by UL36-38, US3, or IE1 and in permissive human diploid fibroblasts (HFF) by IE1 or IE2. Moreover, hsp70 expression was synergistically increased in HeLa cells cotransfected with US3 and UL36, with US3 and UL37, or with US3 and UL37x1. The synergistic transactivation of hsp70 expression by US3 and UL36-38 was not observed in HFF cells. Synergy was also not observed in HeLa cells between US3 and UL38, an early gene product encoded by the UL36-38 IE locus. Synergistic transactivation of hsp70 expression in HeLa cells required the syntheses of UL36-38 and US3 IE proteins, since nonsense mutants were not functional. hsp70 expression increased with increasing amounts of transfected US3 and UL37 DNA and occurred at the level of stable hsp70-promoted RNA. In contrast to the broad hsp70 response, promoters from the HCMV UL112 early gene and another cellular gene, brain creatine kinase, both responded strongly only to singly transfected IE2 in HeLa cells. Nevertheless, IE2 transactivation of the UL112 promoter was further stimulated by cotransfection of IE1 or of UL36-38 in both HeLa and HFF cells. Thus, different patterns of promoter transactivation and interactions between HCMV IE gene products in transactivation were found in HFF cells and in HeLa cells. These results establish the ability of the HCMV US3 and UL36-38 proteins to alter cellular and viral gene expression and are consistent with involvement of cellular transcription factors in HCMV IE regulation of gene expression.
Serotonergic Stimulation of Corticotropin‐Releasing Hormone and Pro‐Opiomelanocortin Gene Expression (2002)

The neurotransmitter serotonin (5-HT) stimulates adrenocorticotropic hormone (ACTH) secretion from the anterior pituitary gland via activation of central 5-HT1 and 5-HT2 receptors. The effect of 5-HT is predominantly indirect and may be mediated via release of hypothalamic corticotropin-releasing hormone (CRH). We therefore investigated the possible involvement of CRH in the serotonergic stimulation of ACTH secretion in male rats. Increased neuronal 5-HT content induced by systemic administration of the precursor 5-hydroxytryptophan (5-HTP) in combination with the 5-HT reuptake inhibitor fluoxetine raised CRH mRNA expression in the paraventricular nucleus (PVN) by 64%, increased pro-opiomelanocortin (POMC) mRNA in the anterior pituitary lobe by 17% and stimulated ACTH secretion five-fold. Central administration of 5-HT agonists specific to 5-HT1A, 5-HT1B, 5-HT2A or 5-HT2C receptors increased CRH mRNA in the PVN by 15-50%, POMC mRNA in the anterior pituitary by 15-27% and ACTH secretion three- to five-fold, whereas a specific 5-HT3 agonist had no effect. Systemic administration of a specific anti-CRH antiserum inhibited the ACTH response to 5-HTP and fluoxetine and prevented the 5-HTP and fluoxetine-induced POMC mRNA response in the anterior pituitary lobe. Central or systemic infusion of 5-HT increased ACTH secretion seven- and eight-fold, respectively. Systemic pretreatment with the anti-CRH antiserum reduced the ACTH responses to 5-HT by 80% and 64%, respectively. It is concluded that 5-HT via activation of 5-HT1A, 5-HT2A, 5-HT2C and possibly also 5-HT1B receptors increases the synthesis of CRH in the PVN and POMC in the anterior pituitary lobe, which results in increased ACTH secretion. Furthermore, the results indicate that CRH is an important mediator of the ACTH response to 5-HT.
A phase II trial of the multitargeted kinase inhibitor lenvatinib (E7080) in advanced medullary thyroid cancer (MTC). (2012)

5591 Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ. In phase I studies of lenvatinib partial responses (PR) were observed in thyroid as well as melanoma, endometrial, and renal cancers. Methods: Patients (pts) with unresectable MTC and disease progression demonstrated by RECIST during the prior 12 months were enrolled. Pts may have received prior VEGFR targeted therapy. Pts were treated with a starting dose of lenvatinib 24 mg once daily in 28 day cycles until disease progression or development of unmanageable toxicities. Primary end point was Response Rate (RR) by RECIST. Tumor genetic analysis and circulating cytokine and angiogenic factors (CAF) analysis were performed. Results: 59 pts were enrolled (med age: 52; Male: 63%;) and are evaluable for response. 54% of pts required dose reduction for management of toxicity, and 22% were withdrawn from therapy due to toxicity. The most common treatment-related adverse events were proteinuria 58% (Gr3: 2%), diarrhea 56% (Gr3: 5%), hypertension 48% (Gr3: 7%), fatigue 44% (Gr3: 5%), decreased appetite 41% (Gr3: 5%), nausea 34% (Gr3: 0), and weight decreased 32% (Gr3: 3%). No Gr4 events were reported for these event categories. Confirmed PRs were observed in 21pts (RR: 36%, 95% CI: 24-49) based on independent imaging review (IIR) and 29 pts (RR: 49%, 95% CI: 36-62) based on investigator assessment. For pts who received prior VEGFR-directed treatment (n=26) RR=35% (IIR); with no prior VEGFR-directed treatment (n=33) RR=36 % (IIR). Median PFS by IRR is 9.0 mo (95% CI: 7.0-) (based on minimum 8 mo. f/u, 46% events observed). There was no clear difference in treatment response between RET-mutant (RET-mu) and RET-wild type (RET-wt) patients. Low baseline levels of ANG2, sTie-2, HGF and IL-8 were associated with greater tumor shrinkage and prolonged PFS whereas high baseline levels of VEGF and sVEGFR3 were associated with greater tumor shrinkage. Conclusions: Lenvatinib administered orally at a dose of 24 mg once daily to patients with MTC is associated with manageable toxicity and a RR of 36%, identifying lenvatinib as a promising new potential therapeutic agent for treating patients affected with this disease.
Phase I study of oral suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, in patients (pts) with advanced leukemias or myelodysplastic syndromes (MDS) (2004)

3027 Background: SAHA is a histone deacetylase inhibitor with in vitro antileukemia activity. Methods: We present results of a phase I study in pts with leukemia/MDS given SAHA orally three times a day (TID) x 14 consecutive days every 21days. The TID schedule was developed to induce continuous histone hyperacetylation for 14 days. The initial dose level was 100 mg po TID with dose escalation in increments of 50 mg TID, using a 3+3 design. Eligibility included: relapsed/refractory leukemia/MDS, or untreated disease if pt not willing to proceed with standard therapy, preserved organ function and performance status. Results: 15 pts have been treated and are evaluable for toxicity. At dose level 1, 2 pts with AML and 1 CMML. At level 2, 1 pt with AML, 1 with ALL and 1 with CLL. At level 3, 4 with AML, 1 with MDS and 1 with ALL, at level 4, 2 with AML and 1 with CML. Median age is 71 years; median number of prior therapies 2. Dose level 3 was expanded from 3 to 6 pts, to better assess toxicity. No pt has experienced grade 3- 4 toxicity or death related to SAHA. The most commonly reported adverse events, regardless of causality, are nausea, vomiting, diarrhea, anorexia, headache, fatigue, dyspepsia, that resolved during the week of rest. Lab abnormalities included pancytopenia, hyperglycemia, hypokalemia, hypocalcemia, hypophosphatemia. Histone hyperacetylation was detected in pts treated at all dose levels. On dose level 1, one pt with AML achieved hematological improvement (marrow blasts less than 5%, ANC > 1x 109k/UL, but no recovery of platelets) and progressed in the marrow after 6 courses. On dose level 2, one CLL pt had reduction in the size of lymph nodes. On dose level 3, one elderly pt with untreated AML achieved a complete remission after 2 courses of therapy, now maintained after 4; two additional AML pts and one MDS pt had a decrease in marrow blasts to less than 10% without peripheral blood recovery. Conclusions: These results indicate that single agent SAHA is well tolerated up to doses of 250 mg po TID x 14 days every 21 days and has promising activity in pts with AML/MDS. Dose escalation continues. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aton Pharma Aton Pharma Aton Pharma
Virus-mediated induction of interferon A gene requires cooperation between multiple binding factors in the interferon alpha promoter region. (1993)

Transcriptional activation of interferon A (IFNA) gene in virus-infected cells is controlled by a 35-nucleotide inducible element that is cell type specific. Within this region, two elements, alpha F1 and IRF-1 binding sites, were shown by mutation analysis to play a crucial role in the expression of inducible element. In this study, we have analyzed the binding of nuclear proteins to the alpha F1 sequence and have shown that the induction is associated with the formation of a novel complex alpha F1/B, which contains at least two DNA binding proteins of 68 and 96 kDa. In contrast, no binding of the purified interferon regulatory factor 1 (IRF-1) either to the alpha F1 or IRF-1 binding sites could be detected in vitro. However, the oligonucleotides corresponding to alpha F1 or IRF-1 binding sites competed efficiently for the induction of IFNA4 promoter region in a transient transfection assay. We suggest that the induction of IFNA promoter region requires cooperation between alpha F1 binding proteins and IRF-1. Interestingly, our data also show that the inability of IFNA6 promoter to be expressed in infected L-cells may be a result of a viral-induced repressor, which could act by binding and inactivating alpha F1 or by competing for the IRF-1 binding site. These results suggest that cell-specific expression of IFNA genes results from core-cruitment of trans-acting factors that bind to alpha F1 and the IRF-1 binding site with the cell-specific virus-induced activator or repressor.
Prospective correction of affine motion for arbitrary MR sequences on a clinical scanner (2005)

The concept of prospective 3D affine motion correction was generalized, based on the Bloch equations, for signal excitation and sampling using arbitrary MR sequences. The technique was implemented on a clinical MRI scanner for Cartesian, radial, and spiral imaging sequences, as well as for 2D spatially selective RF excitation pulses. A patient-specific motion model steered by real-time navigators was employed to account for the additional degrees of freedom provided by the affine motion model. Different navigator concepts (multiple spatial and temporal navigators, quadratic navigators and other motion sensors) were investigated, with the aim of improving the correlation between navigator information and the motion model. Experiments on moving phantoms are presented to prove the technical feasibility of the approach. In vivo experiments on coronary MRA and renal MRI show the potential of the method for cardiac and abdominal applications hampered by respiratory motion.
Radical-mediated Dimerization and Oxidation Reactions for the Synthesis of Complex Alkaloids (2012)

Concise and general strategies for radical-based dimerization of cyclotryptamine and cyclotryptophan derivatives in addition to radical-based oxidation of structurally complex diketopiperazines are discussed. The impact of these radical-based chemistries on the rapid generation of molecular complexity is highlighted using representative examples from recent complex homodimeric alkaloid total syntheses. Additionally, a new and general strategy for radical-based directed heterodimerization of cyclotryptamine substructures via solvent-caged unsymmetrical diazene fragmentation is discussed.
Immunobiology of transplantation 1 (1996)

Despite major advances resulting from the development of new immunosuppressive drugs in recent years, the field of clinical transplantation is currently limited by inadequate organ availability, chronic rejection, and complications of chronic, nonspecific immunosuppressive therapy. Because of the organ shortage, extensive research has recently focused on the potential to use donors from other species, i.e., xenotransplantation. The best way to avoid the problems of chronic rejection and complications of immunosuppressive therapy, and to overcome the considerable immunologic barriers to xenotransplantation, would be to induce a state of systemic tolerance to the donor in the recipient. Recent developments in the understanding of mechanisms of central and peripheral T cell tolerance have led to new strategies for inducing tolerance in experimental models, some of which are already being evaluated clinically.
First Principles Study of the LiâBiâF Phase Diagram and Bismuth Fluoride Conversion Reactions with Lithium (2009)

First principles calculations have been used to explore the LiâBiâF ternary phase diagram. Our results confirm the thermodynamic stability of previously observed phases and find no new phases in this system. Electrochemical voltage profiles for the reaction of Li and BiF3 are in reasonable agreement with experiment. The driving force to form ternary LiâBiâF intermediates is small. We also investigated the effect of particle size on the reaction voltage and find a potential decrease when nanoscale vs bulk Bi forms upon reacting BiF3 with Li.
ORIGINAL ARTICLE: Tumor Necrosis Factor (TNF)–TNF Receptor Gene Polymorphisms and Their Serum Levels in Korean Women with Endometriosis (2008)

The haplotype alleles of the TNT-alpha and TNFR2 gene polymorphisms are genetic factors associated with endometriosis, and circulating sTNFR rather than TNT-alpha, may be involved in the development of endometriosis in Korean women.
Uncertainty principles and ideal atomic decomposition (2001)

Suppose a discrete-time signal S(t), 0/spl les/t<N, is a superposition of atoms taken from a combined time-frequency dictionary made of spike sequences 1/sub {t=/spl tau/}/ and sinusoids exp{2/spl pi/iwt/N}//spl radic/N. Can one recover, from knowledge of S alone, the precise collection of atoms going to make up S? Because every discrete-time signal can be represented as a superposition of spikes alone, or as a superposition of sinusoids alone, there is no unique way of writing S as a sum of spikes and sinusoids in general. We prove that if S is representable as a highly sparse superposition of atoms from this time-frequency dictionary, then there is only one such highly sparse representation of S, and it can be obtained by solving the convex optimization problem of minimizing the l/sup 1/ norm of the coefficients among all decompositions. Here "highly sparse" means that N/sub t/+N/sub w/</spl radic/N/2 where N/sub t/ is the number of time atoms, N/sub w/ is the number of frequency atoms, and N is the length of the discrete-time signal. Underlying this result is a general l/sup 1/ uncertainty principle which says that if two bases are mutually incoherent, no nonzero signal can have a sparse representation in both bases simultaneously. For the above setting, the bases are sinusoids and spikes, and mutual incoherence is measured in terms of the largest inner product between different basis elements. The uncertainty principle holds for a variety of interesting basis pairs, not just sinusoids and spikes. The results have idealized applications to band-limited approximation with gross errors, to error-correcting encryption, and to separation of uncoordinated sources. Related phenomena hold for functions of a real variable, with basis pairs such as sinusoids and wavelets, and for functions of two variables, with basis pairs such as wavelets and ridgelets. In these settings, if a function f is representable by a sufficiently sparse superposition of terms taken from both bases, then there is only one such sparse representation; it may be obtained by minimum l/sup 1/ norm atomic decomposition. The condition "sufficiently sparse" becomes a multiscale condition; for example, that the number of wavelets at level j plus the number of sinusoids in the jth dyadic frequency band are together less than a constant times 2/sup j/2/.
Fast atom bombardment mass spectral analyses of Photofrin II® and its synthetic analogs (1990)

Fast atom bombardment (FAB) mass spectroscopy was used to characterize the components of Photofrin II. The data indicate that the oligomeric components of Photofrin II contain up to nine porphyrin units. In order to elucidate the nature of covalent linkages between porphyrin units, Photofrin II methyl ester and a porphyrin derivative-2 (2A) were synthesized and characterized by FAB mass spectroscopy. Model studies were also performed by analyzing possible components of Photofrin II, namely, porphyrin dimers 3, 4, 5, 6 and timer 7 with ether or ester linkages. The higher porphyrin oligomers joined by only ether linkages were also synthesized and characterized by FAB mass spectroscopy. The model studies indicate that the porphyrin units in Photofrin II are linked with ether or ether/ester linkages.
Molecular mechanism controlling the incorporation of fluorescent nucleotides into DNA by PCR (1997)

The efficiency and yield of incorporation of fluorescent nucleotides into DNA by polymerase chain reaction (PCR) have been investigated with linear amplification (PCR with single-stranded template and single primer). In the present study, we prepared single-stranded templates with defined sequences and used dUTP attached to the fluorescent label with linkers of different lengths. Incorporation and yield of the modified dUTP were reduced when the sequence demanded that multiple dyes be inserted at adjacent sites. The interactions between the polymerase and cyanine-labeled sites on the extending strand probably terminated the chain extension. Thus, because labeling density was increased, the yield of PCR was reduced. We also found that the interactions between the primer and dye-labeled sites on template disturb primer annealing and lead to a decrease in PCR yield.
Ribozyme-mediated inhibition of bcr-abl gene expression in a Philadelphia chromosome-positive cell line (1993)

The bcr-abl fusion gene is the molecular counterpart of the Philadelphia chromosome (Ph1) and is directly involved in the pathogenesis of Ph1+ leukemia. Inhibition of bcr-abl gene expression may have profound effects on the cell biology of Ph1+ cells, as recent experiments with antisense oligonucleotides have shown. In this study we have designed and synthesized a unique ribozyme that is directed against bcr-abl mRNA. The ribozyme cleaved bcr-abl mRNA in a cell-free in vitro system. A DNA-RNA hybrid ribozyme was then incorporated into a liposome vector and transfected into EM-2 cells, a cell line derived from a patient with blast crisis of chronic myelogenous leukemia. The ribozyme decreased levels of detectable bcr-abl mRNA in these cells, inhibited expression of the bcr-abl gene product, p210bcr-abl, and inhibited cell growth. This anti-bcr-abl ribozyme may be a useful tool to study the cell biology of Ph1+ leukemia and may ultimately have therapeutic potential in treating patients with Ph1 leukemias.
A phase II trial of lenvatinib in patients with advanced or recurrent endometrial cancer: Angiopoietin-2 as a predictive marker for clinical outcomes. (2013)

5520 Background: Lenvatinib is an oral receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT, and PDGFRβ. The importance of angiogenesis in endometrial cancer (EC) highlights the need to understand clinical mechanisms of escape (eg, angiopoietin-2 [Ang-2]) from antiangiogenic therapy. Methods: Patients (pts) had metastatic/unresectable EC after 1 or 2 prior platinum-based treatments (Tx), ≤2 prior chemotherapies, and ECOG PS ≤2. Pts received lenvatinib 24 mg once daily until disease progression or development of unmanageable toxicities. Primary endpoint was objective response rate (ORR: complete + partial response [CR+PR]) by RECIST 1.1. Archival tumor tissue and baseline (BL) and post-Tx plasma samples were collected for molecular analyses (reported elsewhere). Results: 133 pts were treated (median age: 62 y) and evaluated for safety, efficacy, and molecular correlative analysis. Dose reduction (31%) or Tx discontinuation (31%) occurred for toxicity. Median Tx duration was 112 days. The most common adverse events were hypertension 55% (Gr 3/4: 33%), fatigue 42% (Gr 3: 12.8%), diarrhea 35% (Gr 3: 5.3%), decreased appetite 35% (Gr 3: 2.3%), and nausea 32% (Gr 3: 3%); 1 pt had Gr 5 asthenia. Bowel obstruction, fistula formation, and perforation occurred in 3.8%, 2.3%, and 1.5%, respectively. Confirmed CR+PRs were observed in 19 pts (14.3%) by independent review (IRR) and 29 pts (21.8%) by investigator assessment (Inv). mPFS was 5.4 mos and mOS was 10.6 mos. Among 50 serum factors tested, only BL plasma Ang-2 correlated with maximal tumor shrinkage, R = 0.36 (Spearman), p &lt; 0.001; ORR; PFS; and OS. The 24 pts with low BL Ang-2 plasma levels (cut-off value &lt;2082 pg/mL) were compared with the 98 pts with high BL Ang-2 (&gt;2082 pg/mL) and improved ORR (61% vs 18%), mPFS (9.5 vs 3.7 mos), and mOS (23 vs 8.9 mos) were observed. Conclusions: Lenvatinib in this population was tolerable and resulted in a 14.3% (IRR) and 21.8% (Inv) ORR and mOS of 10.6 mos.Low BL Ang-2 level appears to predict clinical benefit in a subset of pts with advanced EC who may achieve high response rates and prolonged overall survival. Further assessment is warranted. Clinical trial information: NCT01111461.