gebhart/patrepeval huggingface dataset:
A Membrane-Proximal Region of the Interleukin-2 Receptor γ c Chain Sufficient for Jak Kinase Activation and Induction of Proliferation in T Cells (1996)

The interleukin-2 (IL-2) receptor (IL-2R) consists of three distinct subunits (alpha, beta, and gamma c) and regulates proliferation of T lymphocytes. Intracellular signalling results from ligand-mediated heterodimerization of the cytoplasmic domains of the beta and gamma c chains. To identify the residues of gamma c critical to this process, mutations were introduced into the cytoplasmic domain, and the effects on signalling were analyzed in the IL-2-dependent T-cell line CTLL2 and T-helper clone D10, using chimeric IL-2R chains that bind and are activated by granulocyte-macrophage colony-stimulating factor. Whereas previous studies of fibroblasts and transformed T cells have suggested that signalling by gamma c requires both membrane-proximal and C-terminal subdomains, our results for IL-2-dependent T cells demonstrate that the membrane-proximal 52 amino acids are sufficient to mediate a normal proliferative response, including induction of the proto-oncogenes c-myc and c-fos. Although gamma c is phosphorylated on tyrosine upon receptor activation and could potentially interact with downstream molecules containing SH2 domains, cytoplasmic tyrosine residues were dispensable for mitogenic signalling. However, deletion of a membrane-proximal region conserved among other cytokine receptors (cytoplasmic residues 5 to 37) or an adjacent region unique to gamma c (residues 40 to 52) abrogated functional interaction of the receptor chain with the tyrosine kinase Jak3. This correlated with a loss of all signalling events analyzed, including phosphorylation of the IL-2R beta-associated kinase Jak1, expression of c-myc and c-fos, and induction of the proliferative response. Thus, it appears in T cells that Jak3 is a critical mediator of mitogenic signaling by the gamma c chain.
Apoptosis or growth arrest: Modulation of tumor suppressor p53's specificity by bacterial redox protein azurin (2004)

The tumor suppressor protein p53 is known to induce either apoptosis or growth arrest depending on cellular background. We have previously reported that a bacterial redox protein azurin induces apoptosis in J774 cell line-derived macrophages whereas a site-directed mutant M44KM64E azurin shows very little cytotoxicity and fails to induce apoptosis in J774 cells. We now report that purified M44KM64E mutant azurin protein can enter both J774 cells as well as the human breast cancer MCF-7 cells. Entry of M44KM64E mutant azurin in J774 cells causes strong inhibition of cell-cycle progression at the G1 to S phase and a higher level of transcription of the p21 gene. Corresponding to high p21 levels, the levels of cyclins and cyclin-dependent kinases were greatly lowered in M44KM64E mutant azurin-treated J774 cells. Interestingly, M44KM64E mutant azurin protein failed to elicit inhibition of cell-cycle progression in MCF-7 cells, presumably because of mutation at the retinoblastoma tumor suppressor protein that allows functional E2F formation in MCF-7 cells even in the presence of high intracellular p21 level. Thus, the WT azurin induces apoptosis but little inhibition of cell-cycle progression whereas the M44KM64E mutant azurin is deficient in the induction of apoptosis but mediates strong inhibition of cell-cycle progression, demonstrating the role of a single bacterial protein and its hydrophobic patch in modulating two important functions of p53.
Phase II Study of Carboplatin, Paclitaxel, and Bevacizumab With Maintenance Bevacizumab As First-Line Chemotherapy for Advanced Müllerian Tumors (2009)

PURPOSE New strategies are needed to improve outcomes for patients with advanced ovarian cancer. Bevacizumab is a recombinant humanized monoclonal antibody that neutralizes vascular endothelial growth factor but is associated with GI perforations (GIPs) in patients with recurrent disease. PATIENTS AND METHODS An open-label, phase II clinical trial was conducted in newly diagnosed patients with stage > or = IC epithelial müllerian tumors. Patients received intravenous (IV) carboplatin (area under the curve = 5), paclitaxel (175 mg/m(2) IV), and bevacizumab (15 mg/kg IV) for six to eight cycles on day 1 every 21 days. Bevacizumab was omitted in the first cycle and continued as a single agent for 1 year. Results Sixty-two women participated in this study. Fifty-one patients (82%) were optimally surgically cytoreduced before treatment. The median age was 58 years (range, 18 to 77 years). Forty-five women (73%) had ovarian cancer, 10 (16%) had peritoneal cancer, four (6%) had fallopian tube cancers, and three (5%) had uterine papillary serous tumors. The majority of patients (90%) had stage III or IV disease. A median of 17 maintenance cycles (range, 0 to 25+ cycles) of bevacizumab (556 cycles) were administered with mild toxicity. Treatment was associated with two pulmonary embolisms and two GIPs, all occurring during the chemotherapy phase of treatment (364 total cycles). No grade 4 toxicities were seen during maintenance bevacizumab treatment. Radiographic responses were documented in 21 (75%) of 28 women with measurable disease (11 complete responses and 10 partial responses), with CA-125 responses in 76% of patients (11 complete responses, 21%; and 35 partial responses, 55%). The progression-free survival rate at 36 months was 58%. CONCLUSION The regimen of carboplatin, paclitaxel, and bevacizumab with maintenance bevacizumab is feasible, safe, and worthy of future study in advanced ovarian cancer.
Functional Changes of Carboxymethyl Potato Starch by Conjugating with Amino Acids (1995)

Amino acid-carboxymethyl starch granule (AA-CMS) conjugates were prepared by using water-soluble carbodiimide (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) to improve the functions of starch. Slightly modified potato CMS was dispersed in a 5% water-soluble carbodiimide solution. An amino acid (Glu, Cys, Lys, Gly, Leu, or Phe) solution was added, and the reaction mixture was incubated at 24°C for 5 h, resulting in the formation of an acid-amide bond between CMS and the amino acid. Each AA-CMS conjugate was recovered after thoroughly washing with distilled water and air-drying. The functional changes of the starch were investigated by microscopic observation, differential scanning calorimetry (DSC), solubility, and digestibility with α-amylase or β-amylase. The swelling and solubility of the AA-CMS conjugates were much lower than those of CMS. Data from DSC shows that the conjugates gelatinized at a higher temperature than CMS and were difficult to retrograde, especially the conjugates with hydrophobic amino acids. The digestibility of the conjugates with α-amylase or β-amylase was markedly decreased as compared
Financing private infrastructure projects : emerging trends from IFC's experience (1994)

The last few years have seen an unprecedented increase world-wide in private participation in infrastructure financing. The International Finance Corporation (IFC), which has been involved in the financing of infrastructure projects for nearly three decades, has played an active role in these developments. To date, the Corporation has undertaken the financing of nearly 90 such projects in 26 developing countries, many of them in only the past few years. Its pipeline on new infrastructure projects has moreover continued to grow rapidly. This paper reviews the preliminary lessons emerging from IFC's experience with infrastructure financing in the developing world.
Cytotrophoblasts Up-Regulate Soluble Fms-Like Tyrosine Kinase-1 Expression under Reduced Oxygen: An Implication for the Placental Vascular Development and the Pathophysiology of Preeclampsia (2004)

Sufficient cytotrophoblast (CT) invasion into the uterine wall and subsequent remodeling of maternal uterine vasculature is critical to establish uteroplacental circulation. The production of vascular endothelial growth factor (VEGF) family molecules is confirmed in placental cells including CTs, but it is not elucidated how the VEGF system in CTs is controlled by oxygen tension and how it is involved in the development of placental circulation. To address this, we explored the effect of oxygen tension on the expression of VEGF, placenta growth factor (PlGF), and their antagonist, soluble fms-like tyrosine kinase-1 (sFlt-1) using ELISA and real-time PCR in a primary CT cell culture. For comparison, the same was conducted in parallel using other cells comprising placenta, such as human umbilical vein endothelial cells (HUVECs) and villous fibroblasts (VFs). Reduced oxygen resulted in a pronounced increase in sFlt-1 mRNA amount and sFlt-1 release into the culture media in CTs, whereas this was not the case with HUVECs and VFs. Free (not bound to sFlt-1) VEGF was not detected in CT culture media regardless of oxygen concentration, even though VEGF expression was stimulated by reduced oxygen in CTs, which was similar to the stimulation in HUVECs and VFs. Free PlGF was also diminished in CT culture media by reduced oxygen. These results implicate that CTs possess a unique property to enhance sFlt-1 production under reduced oxygen, which could consequently antagonize angiogenic activity of VEGF and PlGF. The presented findings might provide a framework with which to understand the mechanism of uterine vascular remodeling and its perturbations as exemplified in preeclampsia.
Present Status and Future Prospects for HIV Therapies (1993)

Since the discovery of human immunodeficiency virus (HIV) in 1983, significant progress has been made toward the discovery, development, and licensing of anti-HIV drugs. In vitro screens against whole virus are now being complemented by screens against specific viral targets, resulting in the development of clinical candidates acting at several critical stages of the viral life cycle. Despite these advances, clinical therapy remains largely palliative. In addition, it has recently been recognized that HIV resistance to most drugs may pose even greater obstacles. Moreover, emerging data on immunopathogenesis raise the possibility that even if virus was eliminated from an infected individual, the patient's immune system might not be capable of restoration to normal function. In the face of such obstacles, deeper insights into the pathogenic mechanisms of disease, aggressive exploitation of those mechanisms for therapeutic gain, and continued commitment of both public and private sectors to support and collaborate in this research are needed.
Nanomedicine for targeted drug delivery (2009)

In recent years, nanoparticles have played an ever increasing role in biomedical research and clinical applications. The unique physical properties of nanomaterials are being exploited in the field of nanomedicine for applications as diverse as drug delivery and targeting, MRI contrast enhancement, gene therapy, biomarkers, targeted hyperthermia and many others. This review focuses on the design, synthesis and unique properties of nanoparticles used in nanomedicine as well as on clinical uses for both diagnosis and treatment of disease.
Sequence variability in the 5' non-coding region of hepatitis C virus: identification of a new virus type and restrictions on sequence diversity (1993)

We have analysed the pattern of nucleotide sequence variability in the 5' non-coding region (5' NCR) of geographically dispersed variants of hepatitis C virus (HCV). Phylogenetic analysis of sequences in this region indicated the existence of a new virus type, provisionally termed type 4, the identity of which was confirmed by further analysis of the more variable part of the HCV core protein coding region. The geographical distribution of HCV type 4 was distinct from that of other HCV types, it being particularly widespread in Africa and absent or rare in Europe and the Far East. Much of the variability in the 5' NCR appears to be constrained by a requirement for specific secondary structures in the viral RNA. In one of the most variable regions of the 5' NCR (positions -169 to -114), most of the nucleotide changes that are characteristic of different HCV types were covariant, with complementary substitutions at other positions. According to the proposed secondary structure of the 5' NCR, such changes preserved base pairing within a stem-loop structure, whereas the nucleotide insertions found in a proportion of 5' NCR sequences, including those of type 4, localized exclusively to the non-base-paired terminal loop. The specific nucleotide substitutions in the 5' NCR that differentiate each of the four HCV types can be detected by restriction enzyme cleavage, providing a rapid and reliable method for virus typing.
Sleeping Beauty Transposon‐mediated Engineering of Human Primary T Cells for Therapy of CD19+ Lymphoid Malignancies (2008)

We have reported earlier that the non-viral Sleeping Beauty (SB) transposon system can mediate genomic integration and long-term reporter gene expression in human primary peripheral blood (PB) T cells. In order to test whether this system can be used for genetically modifying both PB T cells and umbilical cord blood (UCB) T cells as graft-versus-leukemia effector cells, an SB transposon was constructed to coexpress a single-chain chimeric antigen receptor (CAR) for human CD19 and CD20. PB and UCB were nucleofected with the transposon and a transposase plasmid, activated and then expanded in culture using anti-CD3/CD28 beads. Stable dual-gene expression was confirmed in both T-cell types, permitting enrichment by positive selection with Rituxan. The engineered CD4(+) T cells and CD8(+) T cells both exhibited specific cytotoxicity against CD19(+) leukemia and lymphoma cell lines, as well as against CD19 transfectants, and produced high-levels of antigen-dependent Th1 (but not Th2) cytokines. The in vivo adoptive transfer of genetically engineered T cells significantly reduced tumor growth and prolonged the survival of the animal. Taken together, these data indicate that T cells from PB and UCB can be stably modified using a non-viral DNA transfer system, and that such modified T cells may be useful in the treatment of refractory leukemia and lymphoma.
Abnormal synthesis of mannose 1-phosphate derived carbohydrates in carbohydrate-deficient glycoprotein syndrome type I fibroblasts with phosphomannomutase deficiency (1998)

In fibroblasts from five patients with carbohydrate-deficient glycoprotein syndrome type 1, the incorporation of [2-3H] mannose into mannose phosphates, GDP-mannose, GDP-fucose, dolichol-P-mannose, lipid-linked oligosaccharides, and glycoprotein fraction was determined. We observed a 3- to 5-fold reduction of incorporation of radioactivity into mannose 1-phosphate, GDP-mannose, GDP-fucose, dolichol-P-mannose, and nascent glycoproteins. The incorporation of radioactivity into mannose 6-phosphate was normal. The formation of lipid linked oligosaccharides was only slightly affected (</=20%), but their size was severely reduced, mostly containing five or fewer residues. As a consequence, truncated oligosaccharides were transferred to newly synthesized glycoproteins. The metabolic changes can be explained by a deficiency of phosphomannomutase activity, which was reduced to </=10% of control.
Laminin-induced Acetylcholine Receptor Clustering: An Alternative Pathway (1997)

The induction of acetylcholine receptor (AChR) clustering by neurally released agrin is a critical, early step in the formation of the neuromuscular junction. Laminin, a component of the muscle fiber basal lamina, also induces AChR clustering. We find that induction of AChR clustering in C2 myotubes is specific for laminin-1; neither laminin-2 (merosin) nor laminin-11 (a synapse-specific isoform) are active. Moreover, laminin-1 induces AChR clustering by a pathway that is independent of that used by neural agrin. The effects of laminin-1 and agrin are strictly additive and occur with different time courses. Most importantly, laminin- 1-induced clustering does not require MuSK, a receptor tyrosine kinase that is part of the receptor complex for agrin. Laminin-1 does not cause tyrosine phosphorylation of MuSK in C2 myotubes and induces AChR clustering in myotubes from MuSK-/- mice that do not respond to agrin. In contrast to agrin, laminin-1 also does not induce tyrosine phosphorylation of the AChR, demonstrating that AChR tyrosine phosphorylation is not required for clustering in myotubes. Laminin-1 thus acts by a mechanism that is independent of that used by agrin and may provide a supplemental pathway for AChR clustering during synaptogenesis.
UV laser modification and selective ion‐beam etching of amorphous vanadium pentoxide thin films (2009)

Abstract We present the results on excimer laser modification and patterning of amorphous vanadium pentoxide films. Wet positive resist‐type and Ar ion‐beam negative resist‐type etching techniques were employed to develop UV‐modified films. V 2 O 5 films were found to possess sufficient resistivity compared to standard electronic materials thus to be promising masks for sub‐micron lithography. (© 2009 WILEY‐VCH Verlag GmbH &amp; Co. KGaA, Weinheim)
Cytokines in atopic diseases: revisiting the Th2 dogma. (2006)

In the field of allergic diseases, extensive research has demonstrated the implication of a strong TH2 activation that both initiates and maintains in situ inflammation with the help of TH2 cytokines. However, as anti-TH2 cytokines therapy is not sufficient to suppress the disease, a more complex immunological mechanism is suspected. In this review, we will revisit the TH2 dogma in allergic diseases, propose a possible implication of TH1 inflammation correlated with the severity of atopic disease, to conclude with the therapeutic solutions envisaged.
B30.2-like domain proteins: update and new insights into a rapidly expanding family of proteins (1998)

The B30.2 domain is a conserved region of around 170 amino acids associated with several different protein domains, including the immunoglobulin folds of butyrophilin and the RING finger domain of ret finger protein. We recently reported several novel members of this family as well as previously undescribed protein families possessing the B30.2 domain. Many proteins have subsequently been found to possess this domain, including pyrin/marenostrin and the midline 1 (MID1) protein. Mutations in the B30.2 domain of pyrin/marenostrin are implicated in familial Mediterranean fever, and partial loss of the B30.2 domain of MID1 is responsible for Opitz G/BBB syndrome, characterized by developmental midline defects. In this study, we scrutinized the available sequence data bases for the identification of novel B30.2 domain proteins using highly sensitive database-searching tools. In addition, we discuss the chromosomal localization of genes in the B30.2 family, since the encoded proteins are likely to be involved in other forms of periodic fever, autoimmune, and genetic diseases.
Sequence Specific Double-Strand Cleavage of DNA by Fe-Bleomycin. 1. The Detection of Sequence-Specific Double-Strand Breaks Using Hairpin Oligonucleotides (1995)

A new method is described for the evaluation of sequence-specific double-strand (ds) cleavage of DNA by Fe-bleomycin (BLM). The method uses high-resolution polyacrylamide gel electrophoresis to separate single-strand (ss) and ds-cleavage products derived from hairpin oligonucleotides that have been designed to contain a specific ds-cleavage site. The BLM induced ss/ds-cleavage ratios ranged from approximately 3.3 to approximately 5.8 at 4 degrees C, with the most efficient ds-cleavage involving the thymidines of a 5'-GTAC/5'-GTAC site. Double-strand cleavage was not detected at several sites that were shown to yield significant ss-breaks. A study of the ss/ds-cleavage ratio at the 5'-GTAC/5'-GTAC site revealed that the ratio remained constant over a 70-fold range in concentration of Fe-BLM and extent of DNA degradation. The ss/ds-cleavage ratios at three sites studied were not significantly affected by the presence of "inert" Co(III)-BLM. The results are consistent with the proposal of Steighner and Povirk (1990) that a single molecule of Fe-BLM is responsible for ds-cleavage. The use of these hairpin oligonucleotides has greatly facilitated quantitative analysis of the ds-cleavage process (Absalon et al., 1995).
K-ras Oncogene Mutations Indicate Malignancy in Cystic Tumors of the Pancreas (1998)

K-ras mutation analysis seems to be a powerful tool to determine the malignant potential of cystic pancreatic tumors before and after surgery. Dilatation of the main pancreatic duct on computed tomography or endoscopic retrograde cholangiopancreatography is highly suggestive for malignancy in these rare tumors.
Myocardial Infarction Causes Increased Expression But Decreased Activity of the Myocardial Na+—Ca2+ Exchanger in the Rabbit (2003)

Na+-Ca2+ exchanger (NCX) protein levels and activity were measured in myocardium from the basal region of the left ventricle of rabbit hearts with significant left ventricular dysfunction (LVD), 8-9 weeks after an apical infarction. NCX protein abundance was higher in the tissue homogenates (121 +/- 11%) and purified membrane fractions (143 +/- 12%) in the LVD compared to the sham-operated (sham) group. NCX mRNA was also higher in the LVD group (126%). Lower NCX protein expression was observed in the membrane fractions from the epicardium compared to the endocardium in both the sham and LVD groups. Transmembrane currents were recorded in isolated cardiomyocytes by single-electrode voltage clamp; [Ca2+]i was measured using Fura-2. Rapid application of 10 mmol l-1 caffeine was used to induce Ca2+ release from the sarcoplasmic reticulum. The subsequent NCX-mediated Ca2+ efflux rate constant was lower (70% of sham) in the LVD group. NCX currents were measured in cardiomyocytes dialysed with 250 nM Ca2+ (50 mmol l-1 EGTA). A lower NCX current (75% of sham) was observed in the LVD group. Lower NCX activity was also observed in cardiomyocytes isolated from the epicardium compared to the endocardium; a transmural difference that was also seen in the LVD group. Reduced activity despite increased protein expression may result from reduced Ca2+ sensitivity of the allosteric regulation of NCX. However, measurements indicated increased Ca2+ sensitivity in the LVD group. Cardiomyocytes from LVD hearts displayed a marked reduction in the transverse tubule area (59% of sham) and the surface area/volume ratio (80% of sham). Disrupted transverse tubule structure may contribute to the decrease in NCX activity despite increased protein expression in LVD.