gebhart/patrepeval huggingface dataset:
Induction of apoptosis of integrin-expressing human prostate cancer cells by cyclic Arg-Gly-Asp peptides. (2001)

Prostate cancer is the second most common cause of cancer deaths among men in the United States. We have investigated the effect of cyclo-(Arg-Gly-Asp-D-Phe-Val; cRGDfV), Arg-Gly-Asp, or Arg-Gly-Asp-Ser, on survival of human prostate cancer (LNCaP and PC-3) and normal (HEL) cells in vitro. Addition of cRGDfV (20 microg/ml) but not the linear Arg-Gly-Asp or Arg-Gly-Asp-Ser peptide induced significant (approximately 84%) killing of LNCaP cells expressing alphavbeta3 integrins on their surfaces. In contrast, none of these peptides had any major effect on the growth of PC-3 or HEL cells, which express little alphavbeta3 integrin on their surfaces. Treatment of LNCaP but not of PC-3 or HEL cells with cRGDfV resulted in cleavage of focal adhesion kinase, a key player in integrin-mediated signal transduction pathway. The evidence we present here suggests that the killing of LNCaP cells after cRGDfV treatment was attributable to apoptosis or programmed cell death. This is evidenced by activation of at least two caspases (caspase-3 and caspase-9) as detected by cleavage of poly(ADP-ribose) polymerase and partial blocking of apoptosis by a selective inhibitor of caspase-9. Our results suggest that cRGDfV may be an effective treatment for some human prostate cancers by inducing apoptosis through interference with the regulation of integrin/focal adhesion kinase-mediated signal transduction pathway necessary for cell survival.
Grb4/Nckβ Acts as a Nuclear Repressor of v-Abl-induced Transcription from c-jun/c-fosPromoter Elements (2001)

Grb4 is an adaptor protein consisting of three src homology (SH) 3 domains and a single SH2 domain. We previously cloned Grb4 as a direct interacting partner of Bcr-Abl and v-Abl via the Grb4 SH2 domain. We now show that overexpression of Grb4 results in significant inhibition of v-Abl-induced transcriptional activation from promitogenic enhancer elements such as activator protein 1 (AP-1) and serum-responsive element (SRE). We demonstrate that the inhibitory activity of Grb4 is independent of the direct interaction of v-Abl and Grb4: a Grb4 mutant that lacks a functional SH2 domain shows an even more pronounced inhibition of AP-1/SRE. Further mutational analysis revealed that the first two SH3 domains primarily mediate the inhibitory function. The inhibitory activity of Grb4 is specific for c-jun/c-fos-regulated promoter elements and is located downstream of MEKK1 and JNK because co-expression of Grb4 resulted in down-regulation of MEKK1-induced AP-1 activity without affecting JNK activity. Thus, the nuclear pool of Grb4 is likely to mediate this inhibition. Indeed, cell fractionation and fluorescence microscopy studies revealed that the stronger inhibitory potential of the Grb4 SH2 mutant occurred in conjunction with increased nuclear localization of this mutant. Our results suggest a novel role for Grb4 in the inhibition of promitogenic enhancer elements such as 12-O-tetradecanoylphorbol-13-acetate-responsive element and SRE.
Shear stress and the role of high molecular weight von Willebrand factor multimers in thrombus formation (2005)

High molecular weight von Willebrand factor (VWF) multimers have an important role in the formation of platelet thrombi under conditions of high shear stress resulting from rapid blood flow. Laboratory studies conducted using an endothelial cell system have shown that ultra-large VWF multimers (ULVWF) attach to the surface of histamine-stimulated endothelial cells and form large string-like structures to which platelets adhere. Platelet attachment is mediated through the interaction of the glycoprotein (Gp) Ibalpha subunit of the platelet GpIb-IX-V complex with the A1 domain of VWF. These platelet-ULVWF strings are rapidly cleaved by the addition of normal human plasma or the purified plasma metalloprotease ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type I motifs domains). Cleaving activity is absent from the plasma of patients with the congenital or acquired forms of thrombotic thrombocytopenic purpura (TTP) and from mixtures of normal plasma with plasma from patients with acquired TTP. The interaction of VWF with P-selectin is at least partially responsible for the attachment of the VWF strings to the endothelium. Increased tensile stress on ULVWF multimers resulting from the tethering of ULVWF strings to the endothelial surface by P-selectin in flowing blood may expose the cleavage site on the A2 domain of VWF, facilitating multimer degradation by ADAMTS-13. These studies have important implications in bleeding and thrombotic disorders, including von Willebrand disease and TTP.
The General Applicability of in Situ Transesterification for the Production of Fatty Acid Esters from a Variety of Feedstocks (2007)

Abstract We previously described a method for fatty acid methyl ester (FAME) production wherein acylglycerol transesterification was achieved by reacting flaked full fat soybeans with alkaline methanol to create a product that met ASTM specifications for biodiesel. In the present work we explore the general applicability of this approach, termed in situ transesterification, to feedstocks other than soybeans. Materials investigated were distillers dried grains with solubles (DDGS), which is a co‐product of the production of ethanol from corn, and meat and bone meal (MBM), a product of animal rendering. For both feedstocks, reaction conditions giving maximum lipid transesterification were predicted by statistical experimental design and response surface regression analysis, and then verified experimentally. Successful transesterification was achieved at ambient pressure and 35 °C. For DDGS, partial drying markedly reduced the methanol requirement to achieve a high degree (91.1% of maximum theoretical) of transesterification. Elevated reaction temperatures (to 55 °C was explored) caused little or no shortening of the time to completion. Protein was not removed from the DDGS during this treatment. For MBM, drying was not required to achieve a high degree (93.3%) of transesterification. The remaining meal retained approximately 90% of the protein originally present. Coupled with the previous work with soybeans, the data presented here indicate that in situ transesterification is generally applicable to lipid‐bearing materials, which could substantially increase the supply of biodiesel.
A combination of platelet‐derived and insulin‐like growth factors enhances periodontal regeneration (1989)

The combination of platelet-derived growth factor (PDGF) and insulin-like growth factor one (IGF-1) has previously been shown to enhance repair of soft tissue wounds. Here we report initial observations following application of PDGF and IGF-1 to periodontitis-affected teeth in beagle dogs. 1 micrograms of PDGF and IGF-1 in an aqueous gel was applied to the root surfaces of test teeth following open flap debridement. Control sites received the gel alone. Block biopsies of the teeth and surrounding bone were taken 2 weeks after treatment. Histologic analyses of control specimens revealed a long junctional epithelial attachment, and no new bone or cementum formation. In contrast, growth factor treated sites exhibited significant amounts of new bone and cementum formation. A nearly continuous layer of osteoblasts lined the newly formed bone, and there was a dense cellular "front" at the coronal extent of the new bone. These preliminary results suggest that in vivo application of the combination of PDGF and IGF-1 may enhance regeneration of the periodontal structures.
CTLA-4 dysregulation of self/tumor-reactive CD8+ T-cell function is CD4+ T-cell dependent (2006)

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) maintains peripheral tolerance by suppressing T-cell activation and proliferation but its precise role in vivo remains unclear. We sought to elucidate the impact of CTLA-4 expression on self/tumor-reactive CD8(+) T cells by using the glycoprotein (gp) 100-specific T-cell receptor (TCR) transgenic mouse, pmel-1. pmel-1 CLTA-4(-/-) mice developed profound, accelerated autoimmune vitiligo. This enhanced autoimmunity was associated with a small but highly activated CD8(+) T-cell population and large numbers of CD4(+) T cells not expressing the transgenic TCR. Adoptive transfer of pmel-1 CLTA-4(-/-) CD8(+) T cells did not mediate superior antitumor immunity in the settings of either large established tumors or tumor challenge, suggesting that the mere absence of CTLA-4-mediated inhibition on CD8(+) T cells did not directly promote enhancement of their effector functions. Removal of CD4(+) T cells by crossing the pmel-1 CLTA-4(-/-) mouse onto a Rag-1(-/-) background resulted in the complete abrogation of CD8(+) T-cell activation and autoimmune manifestations. The effects of CD4(+) CLTA-4(-/-) T cells were dependent on the absence of CTLA-4 on CD8(+) T cells. These results indicated that CD8(+) CLTA-4(-/-) T-cell-mediated autoimmunity and tumor immunity required CD4(+) T cells in which the function was dysregulated by the absence of CTLA-4-mediated negative costimulation.
Treatment of disseminated granuloma annulare with fumaric acid esters (2002)

Our observation has demonstrated that FAE is a potentially beneficial therapeutic option for patients with recalcitrant DGA. However controlled trials are necessary to fully explore the efficacy, optimal dosage, and safety of FAE in the management of DGA.
mTOR Inhibitors at a Glance. (2015)

Mechanistic target of rapamycin (mTOR) is a conserved threonine and serine protein kinase that was identified more than two decades ago as the target of immunosuppressive drug rapamycin. Since then considerable amount of information has been learned about the function of this kinase. It is now well-established that mTOR plays a pivotal role in governing cell growth and proliferation, hence making mTOR a therapeutic target for disease conditions caused by deregulated cell proliferation, such as cancer. In the past decade, numerous mTOR inhibitors have been developed and many are currently in clinical trials for cancer treatment. This commentary is to provide a brief summary of these mTOR inhibitors.
Novel cancer antigens for personalized immunotherapies: latest evidence and clinical potential (2015)

The clinical success of monoclonal antibody immune checkpoint modulators such as ipilimumab, which targets cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and the recently approved agents nivolumab and pembrolizumab, which target programmed cell death receptor 1 (PD-1), has stimulated renewed enthusiasm for anticancer immunotherapy, which was heralded by Science as 'Breakthrough of the Year' in 2013. As the potential of cancer immunotherapy has been recognized since the 1890s when William Coley showed that bacterial products could be beneficial in cancer patients, leveraging the immune system in the treatment of cancer is certainly not a new concept; however, earlier attempts to develop effective therapeutic vaccines and antibodies against solid tumors, for example, melanoma, frequently met with failure due in part to self-tolerance and the development of an immunosuppressive tumor microenvironment. Increased knowledge of the mechanisms through which cancer evades the immune system and the identification of tumor-associated antigens (TAAs) and negative immune checkpoint regulators have led to the development of vaccines and monoclonal antibodies targeting specific tumor antigens and immune checkpoints such as CTLA-4 and PD-1. This review first discusses the established targets of currently approved cancer immunotherapies and then focuses on investigational cancer antigens and their clinical potential. Because of the highly heterogeneous nature of tumors, effective anticancer immunotherapy-based treatment regimens will likely require a personalized combination of therapeutic vaccines, antibodies and chemotherapy that fit the specific biology of a patient's disease.
Relationship between Plasma Cyclo (His-Pro), a Neuropeptide Common to Processed Protein-rich Food, and C-Peptide/Insulin Molar Ratio in Obese Women (2001)

Cyclo (His-Pro) (CHP) is a gut-brain peptide whose plasma levels in humans are increased after glucose ingestion and preferentially altered by oral glucose ingestion compared to intravenous administration in rats, suggesting a role in the enteroinsular response to nutrient ingestion. We were interested in examining levels of CHP in women of differing weights and comparing these levels to various parameters of insulin secretion. Plasma from 26 fasting, nondiabetic women ranging from 21 to 70 years of age and weighing 43 to 114 kg was assayed for CHP. Insulin and C-peptide levels were measured in 17 of the 26. Fasting CHP levels were elevated in obese compared to nonobese women (2075+/-144 vs. 905+/-187 pg/ml; p < 0.001) and were related by regression analysis to weight (r = 0.668, p < 0.001) and body mass index (r = 0.636, p = 0.001). The fasting C peptide/insulin molar ratio, which may be used as an estimate of hepatic insulin clearance (HIC), was inversely related to CHP levels (r = -0.568, p = 0.017). We conclude CHP levels are increased in obese women and inversely related to their C-peptide/insulin molar ratio. The elevation of CHP in those with a decrease in this estimate of HIC (obese) is interesting as the greater insulin response seen in normal persons after oral glucose compared to intravenous glucose has been postulated to be due to a decrease in HIC by some gut factor. The presence of such a factor in excess in the obese might explain part of their hyperinsulinemia.
5-(1-Piperazinyl)-1H-1,2,4-triazol-3-amines as antihypertensive agents (1989)

A series of 5-(1-piperazinyl)-1H-1,2,4-triazol-3-amines was synthesized and screened for antihypertensive and diuretic activity in spontaneously hypertensive rats (SHR). One compound, 5-[4-[(3-chlorophenyl)methyl]-1-piperazinyl]-1H-1,2,4-triazol-3-am ine (8), was selected to define the mechanism of its antihypertensive activity. Studies in SHR suggest ganglionic blocking activity. Short-lived antihypertensive activity was observed in conscious renal hypertensive dogs.
Gonadotropin-Releasing Hormone at Estrus: Luteinizing Hormone, Estradiol, and Progesterone during the Periestrual and Postinsemination Periods in Dairy Cattle1 (1986)

Administering gonadotropin-releasing hormone (GnRH) improved conception rates in our previous studies. Our objective was to determine if the effect of GnRH was mediated through serum luteinizing hormone (LH) and/or by altered secretion of serum progesterone (P) and estradiol-17 beta (E) during the periestrual and post-insemination periods. Cattle were given either GnRH (n = 54) or saline (n = 55) at 72 h and inseminated artificially (AI) 80 h after the second of two injections of either prostaglandin F2 alpha or its analog, cloprostenol. Progesterone and E were measured in blood serum collected during 3 wk after AI (estrus) from 60 females. Blood was collected for LH determinations via indwelling jugular cannulae from 14 cows and 11 heifers. Collections were taken every 4 h from 32 to 108 h after the second PGF injection (PGF-2) (periestrual period) and at more frequent intervals during 240 min after administration of GnRH (n = 18) or saline (n = 7). Ten females had a spontaneous preovulatory LH surge before GnRH treatment (GnRH-spontaneous), whereas GnRH induced the preovulatory LH surge in six females. A spontaneous LH surge appeared to be initiated in two heifers at or near the time of GnRH treatment (spontaneous and/or induced). The remaining seven cows had spontaneous LH surges with no subsequent change in LH after saline treatment. Serum P during the 21 days after estrus was lower (p less than 0.05) in both pregnant and nonpregnant (open) cattle treated previously with GnRH compared with saline. Serum P during the first week after estrus was greater (p less than 0.01) and increased (p less than 0.05) more rapidly in saline controls and in GnRH-spontaneous cattle than in those exhibiting GnRH-induced or GnRH-spontaneous and/or-induced surges of LH. Conception rate of cattle receiving GnRH was higher (p = 0.06) than that of saline-treated controls. These data suggest that GnRH treatment at insemination initiated the preovulatory LH surge in some cattle, but serum P in both pregnant and open cows was compromised during the luteal phase after GnRH treatment. Improved fertility may be associated with delayed or slowly rising concentrations of serum progesterone after ovulation.
Defective canalicular transport and toxicity of dietary ursodeoxycholic acid in the abcb11 −/− mouse: transport and gene expression studies (2013)

The bile salt export pump (BSEP), encoded by the abcb11 gene, is the major canalicular transporter of bile acids from the hepatocyte. BSEP malfunction in humans causes bile acid retention and progressive liver injury, ultimately leading to end-stage liver failure. The natural, hydrophilic, bile acid ursodeoxycholic acid (UDCA) is efficacious in the treatment of cholestatic conditions, such as primary biliary cirrhosis and cholestasis of pregnancy. The beneficial effects of UDCA include promoting bile flow, reducing hepatic inflammation, preventing apoptosis, and maintaining mitochondrial integrity in hepatocytes. However, the role of BSEP in mediating UDCA efficacy is not known. Here, we used abcb11 knockout mice (abcb11-/-) to test the effects of acute and chronic UDCA administration on biliary secretion, bile acid composition, liver histology, and liver gene expression. Acutely infused UDCA, or its taurine conjugate (TUDC), was taken up by the liver but retained, with negligible biliary output, in abcb11-/- mice. Feeding UDCA to abcb11-/- mice led to weight loss, retention of bile acids, elevated liver enzymes, and histological damage to the liver. Semiquantitative RT-PCR showed that genes encoding Mdr1a and Mdr1b (canalicular) as well as Mrp4 (basolateral) transporters were upregulated in abcb11-/- mice. We concluded that infusion of UDCA and TUDC failed to induce bile flow in abcb11-/- mice. UDCA fed to abcb11-/- mice caused liver damage and the appearance of biliary tetra- and penta-hydroxy bile acids. Supplementation with UDCA in the absence of Bsep caused adverse effects in abcb11-/- mice.
First Pass at Cancer Genome Reveals Complex Landscape (2006)

Scientists have long known that the sparks that kindle cancer are mutations in a cell's genes. But most cancer-causing mutations have been discovered by looking in obvious places, such as in the genes that control cell division. Now it seems these efforts have barely glimpsed the big picture.
Deregulated Expression of E2F Family Members Induces S-Phase Entry and Overcomes p16 INK4A -Mediated Growth Suppression (1996)

The E2F family of transcription factors regulate genes, whose products are essential for progression through the mammalian cell cycle. The transcriptional activity of the E2Fs is inhibited through the specific binding of the retinoblastoma protein, pRB, and the pRB homologs p107 and p130 to their transactivation domains. Seven members of the E2F transcription factor family have been isolated so far, and we were interested in investigating the possible contribution of the various E2Fs to cell cycle control. By presenting the results of the generation of cell lines with tetracycline-controlled expression of E2F-1 and E2F-4 and microinjection of expression plasmids for all members of the E2F family, we demonstrate here that the pRB-associated ED2Fs (E2F-1, E2F-2, and E2F-3) all induce S phase in quiescent rate fibroblasts when expressed alone. In contrast, the p107/p130-associated E2Fs require the coexpression of the heterodimeric partner DP-1 to promote S-phase entry and accelerate G1 progression. Furthermore, the pRB-associated E2Fs were all able to overcome a G1 arrest mediated by the p16INK4 tumor suppressor protein, and E2F-1 was shown to override a G1 block mediated by a neutralizing antibody to cyclin D1. The p16INK4-induced G1 arrest was not affected by expression of E2F-4, E2F-5, or DP-1 alone, but simulataneous expression of E2F-4 and DP-1 could overcome this block. Our results demonstrate that the generation of E2F activity is rate limiting for G1 progession, is sufficient to induce S-phase entry, and overcomes a p16-mediated G1 block, and since E12F-1, E2F-2, and E2F-3 are associated with pRB, they are the most likely downstream effectors in the p126-cyclin D-pRB pathway. Furthermore, our date suggest that the two subsets of E2Fs are regulated by distinct mechanisms and/or that they have distinct functions in cell cycle control. Since E2F-4 and E2F-5 cannot promote S-phase entry by themselves, our results may provide an explanation for the apparent lack of aberrations in p107 or p130 in human cancer.
Somatic and Meiotic Chromosomal Recombination between Inverted Duplications in Transgenic Tobacco Plants. (1992)

Homologous recombination has been extensively studied in bacteria, yeast, and more recently in animal cells, but little is known about this process in plants. We present here an analysis of meiotic and somatic chromosomal recombination between closely linked inverted duplications located on a single chromosomal region in tobacco. Transgenic tobacco lines were constructed by Agrobacterium transformation with plasmid vectors containing a functional hygromycin phosphotransferase (hyg) selectable marker flanked by a pair of defective neomycin phosphotransferase (neo) genes positioned as inverted repeats. As each neo gene is mutated in a different site, recombination between the two defective genes can be detected following selection for kanamycin-resistant plant cells. The recombination substrates were designed to allow investigation into the nature of molecular events underlying homologous recombination by restriction endonuclease analysis. Chromosomal recombination was studied in mitotically dividing cells (cultured leaf mesophyll cells) and after meiosis (germinated seedlings). Spontaneous somatic recombinants were recovered at frequencies between ~3 x 10-5 to 10-6 events per cell. Low dose [gamma] irradiation of somatic cells resulted in a threefold maximum increase in the recovery of recombinants. Recombinants were also detected at low frequency when transgenic T3 seeds were germinated under kanamycin selection. DNA gel blot analyses demonstrated that homologous recombination occurred mainly as gene conversion unassociated with reciprocal exchange, although a variety of other events including gene coconversion were also observed.
Cyclin D1 and human neoplasia (1998)

Neoplasia is characterised by abnormal regulation of the cell cycle. Cyclin D1 is a protein derived from the PRAD1, CCND1 or bcl-1 gene on chromosome 11q13, which is involved in both normal regulation of the cell cycle and neoplasia. In the G1 (resting) phase of the cell cycle, cyclin D1 together with its cyclin dependent kinase (cdk) partner, is responsible for transition to the S (DNA synthesis) phase by phosphorylating the product of the retinoblastoma gene (pRB), which then releases transcription factors important in the initiation of DNA replication. Amplification of the CCND1 gene or overexpression of the cyclin D1 protein releases a cell from its normal controls and causes transformation to a malignant phenotype. Analysis of these changes provides important diagnostic information in mantle cell (and related) lymphomas, and is of prognostic value in many cancers. Knowledge of cyclin D1's role in malignancy at the various sites, provides a basis on which future treatment directed against this molecule can proceed.