gebhart/patrepeval huggingface dataset:
ICOS-Ligand Expression on Plasmacytoid Dendritic Cells Supports Breast Cancer Progression by Promoting the Accumulation of Immunosuppressive CD4+ T Cells (2012)

Human breast tumors are infiltrated by memory CD4(+) T cells along with increased numbers of regulatory T cells (Treg) and plasmacytoid dendritic cells (pDC) that facilitate immune escape and correlate with poor prognosis. Here, we report that inducible costimulatory molecule (ICOS), a T cell costimulatory molecule of the CTLA4/PD1/CD28 family, is expressed mostly by tumor-associated Treg in primary breast tumors. A large proportion of these ICOS(+) Treg were Ki67(+) and this evident proliferative expansion was found to rely on interactions with tumor-associated pDC. Indeed, tumor-associated Treg highly expanded in presence of pDC but failed to proliferate under CD3/CD28 signal. In vitro experiments revealed that the addition of a neutralizing anti-ICOS antibody blocked pDC-induced Treg expansion and interleukin-10 secretion by memory CD4(+) T cells, establishing a pivotal role for ICOS in this process. Supporting these findings, the presence of ICOS(+) cells in clinical specimens of breast cancer correlated with a poor prognosis. Together, our results highlight an important relationship between Treg and pDC in breast tumors, and show that ICOS/ICOS-L interaction is a central event in immunosuppression of tumor-associated memory CD4(+) T cells. These findings strongly rationalize antibody-mediated ICOS blockade as a powerful clinical strategy to correct immune escape and promote therapeutic responses in breast cancer.
The 26‐mer peptide released from SNAP‐25 cleavage by botulinum neurotoxin E inhibits vesicle docking (1998)

Botulinum neurotoxin E (BoNT E) cleaves SNAP-25 at the C-terminal domain releasing a 26-mer peptide. This peptide product may act as an excitation-secretion uncoupling peptide (ESUP) to inhibit vesicle fusion and thus contribute to the efficacy of BoNT E in disabling neurosecretion. We have addressed this question using a synthetic 26-mer peptide which mimics the amino acid sequence of the naturally released peptide, and is hereafter denoted as ESUP E. This synthetic peptide is a potent inhibitor of Ca2+-evoked exocytosis in permeabilized chromaffin cells and reduces neurotransmitter release from identified cholinergic synapses in in vitro buccal ganglia of Aplysia californica. In chromaffin cells, both ESUP E and BoNT E abrogate the slow component of secretion without affecting the fast, Ca2+-mediated fusion event. Analysis of immunoprecipitates of the synaptic ternary complex involving SNAP-25, VAMP and syntaxin demonstrates that ESUP E interferes with the assembly of the docking complex. Thus, the efficacy of BoNTs as inhibitors of neurosecretion may arise from the synergistic action of cleaving the substrate and releasing peptide products that disable the fusion process by blocking specific steps of the exocytotic cascade.
An approach to the multifunction graphic terminal for the ISDN environment (2003)

Presents an overview of the ISDN (integrated services digital network)-like services in advanced countries and describes a promising service menu, based on the ISDN (integrated services digital network) experiment in Japan. The authors propose the integration of various terminal functions into six categories of multifunction terminals that handle voice, data, graphics and video signals and can meet the needs of ISDN customers. They then present a multifunction graphic terminal that is capable of covering the great majority of conceivable ISDN services.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Cell Cycle in Vasculoproliferative Diseases (2001)

Atherosclerosis and restenosis of epicardial vessels are among the greatest challenges facing the clinical cardiologist, and phenotypic modulation and proliferation of smooth muscle cells are major components of the vasculoproliferative response. Proliferation is regulated by the interplay of regulatory proteins at checkpoints in the cell cycle that alter cellular growth. Activation of the cell cycle and the genetic control of its progression are final common pathways in this process. Investigators have postulated that cell-cycle inhibition using drugs and genetic or physical methods has the potential to reverse or prevent the vasculoproliferative process. The current challenge is to translate in vitro data demonstrating the efficacy of cell-cycle inhibition to clinical trials. At present, the steps that must be taken to meet this goal are (1) to design methods of delivery of these agents to specific sites, (2) to identify appropriate cellular targets to elicit cell-cycle arrest, and (3) to improve the therapeutic ratio by minimizing potential side effects. This review discusses current concepts of the cell cycle, target-regulating mechanisms, and possible interventions in vasculoproliferative diseases. We also discuss ongoing clinical trials that use antiproliferative agents in the hope of limiting the course of these diseases, as well as the promise that antiproliferative therapy holds in the coming decade.
Network security architecture for intelligent networks (2002)

This paper focuses on a network security architecture and the requirements of such an architecture. These requirements are necessary to attain a level of security that meaningfully protects its operators, end users, and itself, while maintaining a reasonable level of security-transparency. Those requirements are: registration; identification and authentication; data integrity and confidentiality; firewalls and parental control; and enabling e-commerce.
Lipolytic Enzymes (1974)

A major group of lipolytic enzymes typified by pancreatic lipase consists of nonspecific esterases probably of the serinehistidine type. Another group, the phospholipases 2 of exocrine glands, are calcium activated and have exacting stereo-specific substrate requirements. The enzymes of both groups hydrolyze water-insoluble esters. They must not only adsorb to oil—water or micelle—water interfaces but also must position their active sites toward the matrix (oil droplet, micelle, or membrane) in which the substrate molecules are imbedded, the "supersubstrate" It is postulated that lipolytic enzymes are hydrolases that have developed supersubstrate binding sites for attachment and orientation toward lipids. Such a binding site, which is topographically distinct from the substrate binding sites of the reactive center, may have hydrophobic or electrostatic character.
The immunologic detection of minimal residual disease in acute leukemia [published erratum appears in Blood 1990 Nov 1;76(7):1901] (1990)

Certain combinations of differentiation antigens are expressed on leukemia blasts and are absent or extremely rare among normal progenitors in the fetal liver and fetal and regenerating bone marrow. These combinations include cCD3/TdT, a thymic feature retained on thymic-acute lymphoblastic leukemia (T-ALL) blasts outside the thymus, and the coexpression of TdT and myeloid markers (CD13, CD33) on a proportion of ALL and acute myeloid leukemia (AML). Thus, double marker immunofluorescence assays are operationally leukemia-specific and can be applied in 35% of acute leukemias for detecting minimal disease at a less than 10(-4) level; only rare cases, 2 of 35 in our study, switch these relevant features during relapse. The sensitivity and specificity of these assays was tested as follows. First, bone marrow samples taken from patients who had originally presented with blasts expressing the leukemia-associated combinations but were in full morphologic remission were studied, and varying numbers (less than 0.01% to 10% of the mononuclear fraction) of cells with aberrant features were identified in 11.6% of the cases. Second, the outcome of 19 patients with minimal disease identified immunologically while in complete morphologic remission was investigated: all 19 patients have developed systemic relapse within 4 to 25 (median 14.5) weeks. In contrast, 17 of 25 patients also morphologically in complete remission and without residual disease identifiable immunologically after repeated testing are still in morphologic and immunologic remission (follow-up 17 to 114 weeks, median 28 weeks). Only eight patients in this group have relapsed so far: in two patients the relapse was localized in the cerebrospinal fluid, while in six patients a systemic relapse was observed 6 to 51 (median 21.5) weeks after the last negative immunologic bone marrow examination. In conclusion, no false-positive results were detected with these sensitive assays, and the introduction of appropriately planned prospective studies, including the immunologic detection of residual leukemia, is justified on the basis of these observations.
Vascular endothelial growth factor Trap-Eye for diabetic macular oedema (2009)

Diabetic macular oedema (DMO) is the leading cause of visual loss in working-aged Americans, and as such successful treatment is of major public health importance. The gold standard is laser photocoagulation based on the landmark Early Treatment Diabetic Retinopathy Study (ETDRS).1 In the ETDRS, laser treatment reduced the 3-year risk of moderate visual loss by 50%; however, the standard teaching is that patients in the ETDRS rarely improved vision. In fact, in the published ETDRS manuscripts to date, only around 10% of patients gained more than three lines of vision. This led to the prevailing thinking that laser prevents vision loss, but rarely results in visual improvement. Thus, newer therapies have been explored in an effort to improve outcomes in this common and devastating condition.

Vascular endothelial growth factor (VEGF) was one of the first cytokines implicated in diabetic retinopathy and DMO with elevated VEGF levels found in patients with active disease.2 Increased retinal capillary permeability due to breakdown of the blood–retina barrier have been shown to be mediated by VEGF.3 Thus, VEGF appears to be a good target to prevent DMO and progression of diabetic retinopathy.

Several anti-VEGF agents have been evaluated in off-label case series and small-scale clinical trials to treat DMO. In a randomised, phase 2 clinical trial of 172 patients, …
Engraftment and survival after unrelated-donor bone marrow transplantation: a report from the National Marrow Donor Program (2000)

We analyzed engraftment of unrelated-donor (URD) bone marrow in 5246 patients who received transplants facilitated by the National Marrow Donor Program between August 1991 and June 1999. Among patients surviving at least 28 days, 4% had primary graft failure (failure to achieve an absolute neutrophil count &gt; 5 × 108/L before death or second stem-cell infusion). Multivariate logistic regression analysis showed that engraftment was associated with marrow matched at HLA-A, HLA-B, and DRB1; higher cell dose; younger recipient; male recipient; and recipient from a non–African American ethnic group. More rapid myeloid engraftment was associated with marrow serologically matched at HLA-A and HLA-B, DRB1 match, higher cell dose (in non-T-cell–depleted cases), younger recipient, recipient seronegativity for cytomegalovirus (CMV), male donor, no methotrexate for graft-versus-host disease prophylaxis, and transplantation done in more recent years. A platelet count higher than 50 × 109/L was achieved by 47% of patients by day 100. Conditional on survival to day 100, survival at 3 years was 61% in those with platelet engraftment at day 30, 58% in those with engraftment between day 30 and day 100, and 33% in those without engraftment at day 100 (P &lt; .0001). Factors favoring platelet engraftment were higher cell dose, DRB1 allele match, recipient seronegativity for CMV, HLA-A and HLA-B serologically matched donor, and male donor. Secondary graft failure occurred in 10% of patients achieving initial engraftment, and 18% of those patients are alive. These data demonstrate that quality of engraftment is an important predictor of survival after URD bone marrow transplantation.
Genetic Targeting or Pharmacologic Inhibition of NADPH Oxidase Nox4 Provides Renoprotection in Long-Term Diabetic Nephropathy (2014)

Diabetic nephropathy may occur, in part, as a result of intrarenal oxidative stress. NADPH oxidases comprise the only known dedicated reactive oxygen species (ROS)-forming enzyme family. In the rodent kidney, three isoforms of the catalytic subunit of NADPH oxidase are expressed (Nox1, Nox2, and Nox4). Here we show that Nox4 is the main source of renal ROS in a mouse model of diabetic nephropathy induced by streptozotocin administration in ApoE(-/-) mice. Deletion of Nox4, but not of Nox1, resulted in renal protection from glomerular injury as evidenced by attenuated albuminuria, preserved structure, reduced glomerular accumulation of extracellular matrix proteins, attenuated glomerular macrophage infiltration, and reduced renal expression of monocyte chemoattractant protein-1 and NF-κB in streptozotocin-induced diabetic ApoE(-/-) mice. Importantly, administration of the most specific Nox1/4 inhibitor, GKT137831, replicated these renoprotective effects of Nox4 deletion. In human podocytes, silencing of the Nox4 gene resulted in reduced production of ROS and downregulation of proinflammatory and profibrotic markers that are implicated in diabetic nephropathy. Collectively, these results identify Nox4 as a key source of ROS responsible for kidney injury in diabetes and provide proof of principle for an innovative small molecule approach to treat and/or prevent chronic kidney failure.
Accumulation of Glucosylceramides in Multidrug-resistant Cancer Cells (1996)

Multidrug-resistant (MDR) tumors and cancer cell lines demonstrate a wide variety of biochemical changes. In this study we used drug-sensitive wild-type (wt) cancer cell lines and respective MDR subclones, and we demonstrate the accumulation of distinct lipids in MDR cells. These lipids were either absent or present at very low levels in drug-sensitive cells. The compounds, termed lipid-1 and lipid-2, migrated on thin-layer chromatography as a doublet. They could be radiolabeled by incubating MCF-7-AdrR (Adriamycin-resistant) breast cancer cells with [3H]serine, [3H]palmitic acid, or [3H]galactose. Utilization of these precursors by MCF-7-wt cells for synthesis of lipid-1 and -2 was minimal. Two inhibitors of sphingolipid biosynthesis, L-cycloserine and fumonisin B1, prevented the observed accumulation of the lipid compounds. An inhibitor of glucosylceramide synthesis, 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol, completely abolished the formation of lipid-1 and -2 in MCF-7-AdrR cells and, to a lesser extent, inhibited the formation of lactosylceramides and gangliosides. Utilizing mass spectrometry, the multidrug resistance-associated lipids were further characterized as monoglycosylceramides of two major species that contained either 16-carbon (palmitic) or 24-carbon (lignoceric and nervonic) fatty acids. The carbohydrate head group of glycosylceramides was identified as glucose, not galactose, thus designating the accumulated lipids as glucosylceramides. Incorporation of [3H]palmitic acid into glucosylceramide was strikingly higher (8-10 times) in MCF-7-AdrR cells compared with MCF-7-wt cells. Since the rate of glucosylceramide degradation in MCF-7-AdrR cells was not attenuated, accelerated glycosphingolipid synthesis in MDR cells is suggested. Glucosylceramide also accumulated in KB-V-1, a vinblastine-resistant epidermoid carcinoma but not in KB-3-1, drug-sensitive wt cells. MDR ovarian adenocarcinoma cells (NIH:OVCAR-3) also contained elevated levels of glucosylceramide. Our results demonstrate a correlation between cellular drug resistance and alterations in glucosylceramide metabolism.
Glycobiology of neuromuscular disorders (2003)

There has been a recent explosion in the identification of neuromuscular diseases caused by mutations in genes that affect carbohydrate metabolism or protein glycosylation. A number of these findings relate to defects in the glycosylation of alpha dystroglycan. Alpha dystroglycan is an essential component of the dystrophin-glycoprotein complex, and aberrant glycosylation of alpha dystroglycan is associated with multiple forms of muscular dystrophy in mice and humans. We review the evidence that defects in dystroglycan glycosylation cause muscular dystrophy. In addition, we review evidence that glycobiology is important in other disorders that affect muscle, including hereditary inclusion body myopathy type II and congenital disorders of glycosylation. Finally, we discuss the long-term potential of glycotherapies for muscle disorders.
Locoregional treatment of low-grade B-cell lymphoma with CD3�CD19 bispecific antibodies and CD28 costimulation: II. Assessment of cellular immune responses (2001)

Ten patients with advanced B-cell lymphoma were treated with a single locoregional injection of CD3xCD19 bispecific and costimulating CD28 monospecific antibodies to activate tumor-infiltrating T-lymphocytes. Antibodies were administered at 4 different dose levels (30 microg, 270 microg, 810 microg, 1,600 microg of each antibody) either by intratumoral or intralymphatic injection. Most patients developed responses within different compartments of the immune systems (T cells, NK cells) subsequent to the antibody application. Comparative studies in 2 patients of which treated as well as untreated lymph nodes were available revealed the up-regulation of T-cell activation markers induced by the antibody injection. Additionally, in 1 patient the induction of apoptosis of lymphoma B cells in the antibody-treated lymph node was observed. Specificity analyses of peripheral blood T cells by means of IFN-gamma ELISpot measurement indicated the recruitment of idiotype-specific T cells, as in 1 out of 3 investigated patients an increased T-cell response toward autologous idiotype peptides could be demonstrated. We conclude that a single injection of CD3xCD19 bispecific antibodies is capable to induce an activation of autologous T lymphocytes if simultaneous costimulatory signaling by CD28 antibodies is provided. Furthermore, our data suggest that at least in some patients lymphoma-specific T cells can be recruited by this immunotherapeutic approach toward B-cell lymphoma.
Total Synthesis of (+)‐Haplophytine (2009)

Advancing alkaloid synthesis: (+)-Haplophytine (see structure) was the target of a total synthesis featuring a highly stereoselective intramolecular Mannich reaction, Friedel–Crafts alkylation, oxidative rearrangement, and Fischer indole synthesis. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Inhibition of Kupffer cell functions as an explanation for the hepatoprotective properties of silibinin (1996)

The flavonoid silibinin, the main compound extracted from the milk thistle Silybum marianum, displays hepatoprotective properties in acute and chronic liver injury. To further elucidate the mechanisms by which it acts, we studied the effects of silibinin on different functions of isolated rat Kupffer cells, namely the formation of superoxide anion radical (02-), nitric oxide (NO), tumor necrosis factor alpha (TNF-alpha), prostaglandin E(2) (PGE(2)), and leukotriene B(4) (LTB(4)). Production of 02- and NO were inhibited in a dose-dependent manner, with an 50 percent inhibitory concentration (IC(50)) value around 80 micro mol/L. No effect on TNF-alpha formation was detected. Opposite effects were found on the cyclooxygenase and 5-lipoxygenase pathway of arachidonic acid metabolism. Whereas no influence on PGE(2) formation was observed with silibinin concentrations up to 100 micro mol/L, a strong inhibitory effect on LTB(4) formation became evident. The IC(50)-value for inhibiting the formation of this eicosanoid was determined to be 15 micro mol/L silibinin. The strong inhibition of LTB(4), formation by silibinin was confirmed in experiments with phagocytic cells isolated from human liver. Hence, while rather high concentrations of silibinin are necessary to diminish free radical formation by activated Kupffer cells, significant inhibition of the 5-lipoxygenase pathway already occurs at silibinin concentrations which are achieved in vivo. Selective inhibition of leukotriene formation by Kupffer cells can at least partly account for the hepatoprotective properties of silibinin.
Thermotolerance and profile of protein synthesis in murine bone marrow cells after heat shock. (1985)

In this study, we first investigated the survival of colony-forming units, granulocyte and macrophage (CFU-GM), after a single heat treatment. We then examined the induction, development, and decay of thermotolerance in CFU-GM. Finally, we analyzed the profiles of protein synthesis in the total murine bone marrow population during the development of thermotolerance. Several salient features emerged from our study: (a) granulocyte-macrophage progenitors were very sensitive to heat as compared to other mammalian cell lines; (b) CFU-GM can develop thermotolerance after both prolonged heating at 41-42 degrees C or an acute heat treatment at 43 degrees C in vitro; (c) thermotolerance in CFU-GM can be induced in vivo; the kinetics of development of thermotolerance in vivo is similar to that in vitro; (d) in contrast to other cell lines where thermotolerance lasts for several days, tolerance acquired by CFU-GM disappeared within 24 h, regardless of the temperature or duration of the initial heat treatment. The difference between the kinetics of systemic thermotolerance and thermotolerance in CFU-GM in the same animal model shows that bone marrow stem cells, or at least CFU-GM, are not the critical targets for systemic thermal death. When protein synthesis profiles of the heat-shocked bone marrow cells were compared to those from nonheated controls by one- and two-dimensional gel electrophoresis, the rates of synthesis of the Mr 70,000 and 87,000 proteins were shown to be enhanced during the development of thermotolerance. The enhanced rate of synthesis of these polypeptides lasted only 2-4 h and then returned to the control value.