gebhart/patrepeval huggingface dataset:
Oxidative breakdown of octanoic acid is maintained in patients with cirrhosis despite advanced disease (2003)

As an octanoic acid 13CO2 breath test is frequently used to test gastric emptying of solid food, the purpose of the present study was to study whether oxidative breakdown of octanoic acid is affected by severe liver disease. The design of our study was twofold. First, cirrhotic patients (n = 82) of varying severity were compared with healthy controls (n = 17). Values of half-time, time point of maximal expiration and cumulative recovery of octanoic acid breath tests (OBT) were not significantly different between them. Secondly, cirrhotic patients (n = 10) were studied before placement of transjugular intrahepatic portosystemic shunt, 4-7 days later and 1-2 months later. Values of half-time, time point of maximal expiration and cumulative recovery of consecutive OBTs did not change significantly. The OBT may therefore be a suitable test in the future to detect delayed gastric emptying of solids in cirrhotic patients with reduced liver function and portal hypertension.
A colon-specific drug-delivery system based on drug glycosides and the glycosidases of colonic bacteria (1984)

Steroid glycosides and the unique glycosidase activity of the colonic microflora form the basis of a new colon-specific drug-delivery system. Drug glycosides are hydrophilic and, thus, poorly absorbed from the small intestine. Once such a glycoside reaches the colon it can be cleaved by bacterial glycosidases, releasing the free drug to be absorbed by the colonic mucosa. This concept was illustrated with dexamethasone 21-beta-D-glucoside (1) and prednisolone 21-beta-D-glucoside (2), two prodrugs that may be useful in treating inflammatory bowel disease. Hydrolysis of the prodrugs by beta-glucosidase and fecal homogenates in vitro released the free steroids. Glucosides 1 and 2 were administered to rats intragastrically to determine when and where the free steroids were released. Unmodified dexamethasone (3) and prednisolone (4) were also given to rats intragastrically to compare absorption of the glucosides with the free steroids. Both glucosides were found to reach the rat lower intestine in 4-5 h, where they were rapidly hydrolyzed, releasing the free steroids. Delivery of steroid 3 (via glucoside 1) was more specific than that of steroid 4 (via glucoside 2): nearly 60% of an oral dose of glucoside 1 reached the cecum, whereas less than 15% of glucoside 2 reached the cecum. When free steroids 3 and 4 were administered orally, they were almost exclusively absorbed in the small intestine: less than 1% of an oral dose of each reached the cecum.
PDX:PBX complexes are required for normal proliferation of pancreatic cells during development (2001)

The homeobox factor PDX-1 is a key regulator of pancreatic morphogenesis and glucose homeostasis; targeted disruption of the PDX-1 gene leads to pancreatic agenesis in pdx-1(-/-) homozygotes. Pdx-1 heterozygotes develop normally, but they display glucose intolerance in adulthood. Like certain other homeobox proteins, PDX-1 contains a consensus FPWMK motif that promotes heterodimer formation with the ubiquitous homeodomain protein PBX. To evaluate the importance of PDX-1:PBX complexes in pancreatic morphogenesis and glucose homeostasis, we expressed either wild-type or PBX interaction defective PDX-1 transgenes under control of the PDX-1 promoter. Both wild-type and mutant PDX-1 transgenes corrected glucose intolerance in pdx-1 heterozygotes. The wild-type PDX-1 transgene rescued the development of all pancreatic lineages in pdx-1(-/-) animals, and these mice survived to adulthood. In contrast, pancreata from pdx-1(-/-) mice expressing the mutant PDX-1 transgene were hypoplastic, and these mice died within 3 weeks of birth from pancreatic insufficiency. All pancreatic cell types were observed in pdx-1(-/-) mice expressing the mutant PDX-1 transgene; but the islets were smaller, and increased numbers of islet hormone-positive cells were noted within the ductal epithelium. These results indicate that PDX-1:PBX complexes are dispensable for glucose homeostasis and for differentiation of stem cells into ductal, endocrine, and acinar lineages; but they are essential for expansion of these populations during development.
Arabidopsis REGULATOR OF AXILLARY MERISTEMS1Controls a Leaf Axil Stem Cell Niche and Modulates Vegetative Development (2006)

Shoot branching is a major determinant of variation in plant stature. Branches, which form secondary growth axes, originate from stem cells activated in leaf axils. The initial steps by which axillary meristems (AMs) are specified and their stem cells organized are still poorly understood. We identified gain- and loss-of-function alleles at the Arabidopsis thaliana REGULATOR OF AXILLARY MERISTEMS1 (RAX1) locus. RAX1 is encoded by the Myb-like transcription factor MYB37 and is an Arabidopsis homolog of the tomato (Solanum lycopersicum) Blind gene. RAX1 is transiently expressed in a small central domain within the boundary zone separating shoot apical meristem and leaf primordia early in leaf primordium development. RAX1 genetically interacts with CUP-SHAPED COTYLEDON (CUC) genes and is required for the expression of CUC2 in the RAX1 expression domain, suggesting that RAX1 acts through CUC2. We propose that RAX1 functions to positionally specify a stem cell niche for AM formation. RAX1 also affects the timing of developmental phase transitions by negatively regulating gibberellic acid levels in the shoot apex. RAX1 thus defines a novel activity that links the specification of AM formation with the modulation of the rate of progression through developmental phases.
APC truncation and increased β-catenin levels in a human breast cancer cell line (2000)

Mutations in the Adenomatous Polyposis Coli ( APC ) tumor suppressor gene or the β- catenin gene are present in most colon cancers and less frequently in other tumor types. In this study, we screened 24 human breast cancer cell lines and three immortalized human breast epithelial cell lines for alterations in β- and γ-catenin and APC by western blotting, protein truncation assay and DNA sequence analysis. In one cell line (DU 4475), an APC mutation was identified (E1577stop) that resulted in expression of truncated APC. This mutation was associated with elevated cytosolic β-catenin levels, probably due to loss of APC function, as in colon cancers. No mutations were found in exon 3 of the β- or γ- catenin genes. We conclude that APC mutations and β-catenin upregulation may occur with low frequency in human breast cancer cells.
P-glycoprotein mediates profound resistance to bisantrene. (1994)

Bisantrene, mitoxantrone, and anthracyclines are anthracene derivatives that interact with DNA and are used for the treatment of cancers. The mechanisms of resistance to bisantrene are unknown. Here we show that cells that overexpress low levels of P-glycoprotein or are transfected with human MDR1 have approximately 10-fold greater resistance to bisantrene compared to vinblastine, doxorubicin, or colchicine. Furthermore, bisantrene can be used to select for high-level P-glycoprotein-mediated multiple drug resistance in a human colon carcinoma cell line, LS 174T, and the drug blocks photoaffinity labeling of P-glycoprotein. The data suggest that bisantrene is an excellent substrate for P-glycoprotein. These findings could influence subsequent clinical evaluation of bisantrene for the treatment of cancer.
Understanding the Nature of the DNA-Assisted Separation of Single-Walled Carbon Nanotubes Using Fluorescence and Raman Spectroscopy (2004)

Certain DNA sequences form a highly stable monolayer at the surface of single-walled carbon nanotubes, enabling their dispersion in aqueous solution. Ion-exchange chromatography can be used to separate these systems on the basis of their diameter in distinct, eluted fractions. Raman and fluorescence spectroscopy are used to characterize the nature of the separation by a comparison of radial breathing mode intensities at 457-, 532-, 633-, and 785-nm excitation wavelengths. Trends reveal a strong diameter dependence of the fractions, with larger diameters eluting later than smaller diameters. Average diameters of each fraction varied from 0.816 and 1.084 nm for the first and last eluted fractions, respectively. This conclusion is supported by a systematic shifting of the Raman tangential mode with increasing elution as well as changes in the relative intensities of radial breathing modes. Fluorescence emission from each fraction reveals the absence of relative shifting or broadening and hence uniformity in the chemical environment and the absence of doping-related complications for each fraction. The separation also reveals the fine structure of the G‘ two-phonon mode, which is described using a composite model with contributions from transition-dependent phonons.
Local cytokine expression in the progression toward B cell malignancy in Sjögren's syndrome. (1995)

Many cytokines may be involved in the evolution of prelymphomatous to definite B cell malignant lesions in SS, as well as in the development of SS unrelated B cell non-Hodgkin's lymphomas. A putative pathobiological role of the IL-12/IL-4 balance, in the presence of cytokines that may sustain B cell proliferation (i.e., IL-3, IL-6, IL-10), may represent a major point for future research. Finally, our data reinforce the view of SS as a human model of B cell lymphomagenesis.
A small region of the mouse mammary tumor virus long terminal repeat confers glucocorticoid hormone regulation on a linked heterologous gene. (1983)

Expression of mouse mammary tumor virus (MMTV) proviruses is transcriptionally regulated by glucocorticoid hormones. We have linked the MMTV long terminal repeat (LTR) to the coding region of the herpes simplex virus thymidine kinase gene and used this construction to characterize sequences within the LTR that are involved in glucocorticoid regulation. Our results show that 290 base pairs (bp) of the MMTV LTR, including 190 bp upstream from the start site for transcription, are sufficient to confer regulation on the downstream gene. Deletion of an additional 50 bp, leaving sequences from position -140 to +100, eliminates the response. However, the constitutive level of expression is maintained even after deletion of sequences upstream from position -80, indicating that sequences required for the hormone response can be distinguished from those required for basal expression. We also have shown, by making a 4-bp insertion or a 20-bp deletion around position -107, that the distance between the putative signal for hormone response and the start site of transcription can be varied without affecting regulation. Furthermore, replacement of MMTV sequences from position -59 to +100 with analogous sequences from the Rous sarcoma virus LTR does not change the regulation.
THE EFFECT OF ORGAN PRESERVATION ON TISSUE INJURY IN TRANSPLANTATION (2004)

P81 Aims: To examine the effectiveness of current organ preservation strategies to minimise tissue injury during cold and warm ischaemia, and to develop a preservation strategy that reduces fluid influx with associated cellular oedema that promotes post transplant inflammatory reactions which contributes to tissue injury. Methods: Proximal renal tubules were isolated from rabbit kidneys and maintained in Euro-Collins, Marshalls, UW and Phosphate Buffered Sucrose solutions for 0-72hrs cold ischaemia. At 24hr intervals tubules were then placed in warm perfusion fluids containing strophanthidin to inhibit ATPase dependent cell volume regulation to model transplant ischaemia. In addition, whole kidneys were perfused with preservation solutions for similar time points and reperfused over 2 hours. Renal function was assessed by creatinine and urea levels, and by sodium reabsorption. Histological analysis of perfused organs was performed using H&E, PAS and electron microscopy. Results: The isolated tubule studies demonstrated that a phosphate buffered sucrose solution (PBS) significantly (P<0.05) diminished cellular oedema as a result of cold ischaemia when compared to Euro-Collins, Marshalls, or UW. In addition, subsequent increases in tubule cell volume as a result of warm ischaemia were also significantly (P<0.05) reduced in PBS solutions. Modifications to the PBS based solution were made to include blockade of calcium influx, cyclo-oxygenase inhibition, and anti-oxidants. This modified solution was assessed in perfused whole organs and demonstrated improved organ function parameters when compared to Euro-Collins and Marshalls and UW. Histology revealed comparative maintenance of renal architecture with less histological signs of cellular oedema with modified PBS and UW compared with tissues preserved in Euro-Collins or Marshalls solutions. Conclusions: Data has accumulated suggesting that mediators of inflammation, such as complement C3, may be upregulated following organ transplantation (Pratt et al. Am. J. Path.157: 815-823. 2000) and that such factors can both help initiate acute rejection (Pratt et al. Nature Medicine 8: 582-587. 2002) through interaction with specific receptors on subsets of T cells responsible for signal transduction, and are sensitive to therapeutic inhibition (Am. J. Path163: 1457-65. 2003). Control of these mechanisms may be possible through minimising organ preservation injury, which this study would suggest could be achieved with a modified PBS type solution. Data from this study will be used to inform the UK discussion forum on organ preservation (www.bts.org.uk/forums). This is designed to gain consensus on organ preservation strategies to protect tissues from injury that limits long-term outcomes, and to improve the management of donor organs in clinical transplantation.
TGF-β1 Gene Silencing for Treating Liver Fibrosis (2009)

Small interfering RNA (siRNA) and short hairpin RNA (shRNA) targeting different regions of transforming growth factor beta1 (TGF-beta1) mRNA were designed and the silencing effect was determined after transfection into immortalized rat liver stellate cells (HSC-T6). There was not only significant decrease in TGF-beta1, tissue inhibitor of metalloproteinase 1 (TIMP-1), alpha-smooth muscle actin (alpha-SMA) and type I collagen after transfection with TGF-beta1 siRNAs, but also synergism in gene silencing when siRNAs targeting two different start sites were used as a pool for transfection. The two siRNA sequences which efficiently inhibited TGF-beta1 gene expression were converted to shRNAs via cloning into the pSilencer1.0. There was significant decrease in TGF-beta1 and TIMP-1 when HSC-T6 cells were transfected with pshRNA targeting the same regions of TGF-beta1 mRNA as siRNAs. Furthermore, TGF-beta1 gene silencing in HSC-T6 cells significantly decreased the levels of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1beta). In conclusion, both siRNA and shRNA showed sequence-specific and dose dependent TGF-beta1 gene silencing and have the potential to treat liver fibrosis.
Lack of Detection of Human Immunodeficiency Virus in Persistently Seronegative Homosexual Men with High or Medium Risks for Infection (1991)

Some studies have suggested that seronegative homosexual men who have practiced high-risk sexual behavior can carry the human immunodeficiency virus (HIV) in a silent state, detectable only by polymerase chain reaction (PCR) or selective viral culture. To assess this concept, blood specimens were studied from 59 homosexual men with recognized risk behaviors: unprotected anal receptive intercourse at least once and many lifetime sex partners. After extensive virologic studies and PCR analysis, only one virus-positive, antibody-negative individual was identified. These findings indicate that HIV virus-positive, seronegative individuals are rare.
A fraction of the mRNA 5' cap-binding protein, eukaryotic initiation factor 4E, localizes to the nucleus. (1992)

The 5' cap structure m7GpppN (where N is any nucleotide) is a ubiquitous feature of cellular eukaryotic mRNAs. The cap is multifunctional as it is involved in translation, nucleocytoplasmic transport, splicing, and stabilization of mRNA against 5' exonucleolytic degradation. The cap binding protein, eukaryotic initiation factor 4E (eIF-4E), is a translation initiation factor that binds to the cap structure and is part of a complex (eIF-4F) that promotes mRNA binding to ribosomes. Overexpression of eIF-4E in fibroblasts results in cell transformation. To test the hypothesis that some of the biological effects of eIF-4E might be effected by a nuclear function, we determined the cellular distribution of eIF-4E. By means of indirect immunofluorescence experiments using polyclonal and monoclonal antibodies against eIF-4E as well as transfected epitope-tagged eIF-4E, we demonstrate that a fraction of eIF-4E localizes to the nucleus. These results suggest that eIF-4E is also involved in a nuclear function.
Heat shock protein 90 regulates the expression of Wilms tumor 1 protein in myeloid leukemias (2010)

The aberrant overexpression of Wilms tumor 1 (WT1) in myeloid leukemia plays an important role in blast cell survival and resistance to chemotherapy. High expression of WT1 is also associated with relapse and shortened disease-free survival in patients. However, the mechanisms by which WT1 expression is regulated in leukemia remain unclear. Here, we report that heat shock protein 90 (Hsp90), which plays a critical role in the folding and maturation of several oncogenic proteins, associates with WT1 protein and stabilizes its expression. Pharmacologic inhibition of Hsp90 resulted in ubiquitination and subsequent proteasome-dependant degradation of WT1. RNAi-mediated silencing of WT1 reduced the survival of leukemia cells and increased the sensitivity of these cells to chemotherapy and Hsp90 inhibition. Furthermore, Hsp90 inhibitors 17-AAG [17-(allylamino)-17-demethoxygeldanamycin] and STA-9090 significantly reduced the growth of myeloid leukemia xenografts in vivo and effectively down-regulated the expression of WT1 and its downstream target proteins, c-Myc and Bcl-2. Collectively, our studies identify WT1 as a novel Hsp90 client and support the crucial role for the WT1-Hsp90 interaction in maintaining leukemia cell survival. These findings have significant implications for developing effective therapies for myeloid leukemias and offer a strategy to inhibit the oncogenic functions of WT1 by clinically available Hsp90 inhibitors.
The formation of methylglyoxal from triose phosphates (1993)

In Krebs-Ringer phosphate buffer, the rate of formation of methylglyoxal from glycerone phosphate and glyceraldehyde 3-phosphate was first order with respect to the triose phosphate with rates constant values of 1.94 +/- 0.02 x 10(-5) s-1 (n = 18) and 1.54 +/- 0.02 x 10(-4) s-1 (n = 18) at 37 degrees C, respectively. The rate of formation of methylglyoxal from glycerone phosphate and glyceraldehyde 3-phosphate in the presence of red blood cell lysate was not significantly different from the non-enzymatic value (P > 0.05). Methylglyoxal formation from glycerone phosphate was increased in the presence of triose phosphate isomerase but this may be due to the faster non-enzymatic formation from the glyceraldehyde 3-phosphate isomerisation product. For red blood cells in vitro, the predicted non-enzymatic rate of formation of methylglyoxal from glycerone phosphate and glyceraldehyde 3-phosphate may account for the metabolic flux through the glyoxalase system. The reactivity of glycerone phosphate and glyceraldehyde 3-phosphate towards the non-enzymatic formation of methylglyoxal under physiological conditions suggests that methylglyoxal formation is unavoidable from the Embden-Meyerhof pathway.
Effects of Resveratrol on Acoustic Trauma (2003)

Results demonstrate that the resveratrol group showed reduced threshold shifts compared with the control group after noise exposure. These shifts were significantly different between groups at 6 and 9 kHz (P < 0.05), corresponding to the region most represented by the frequency of the traumatic noise.Conclusion/significance Initial studies in our laboratory as well as other investigators have shown the importance of specific antioxidant therapy in the prevention of ischemic, noise, and age related hearing loss. The current study demonstrates a protective effect of resveratrol on noise-induced hearing loss.
Inhibition of the Calcium-dependent Tyrosine Kinase (CADTK) Blocks Monocyte Spreading and Motility (2001)

Freshly isolated peripheral blood monocytes lack focal adhesion kinase (p125(FAK)) but activate a second member of this kinase family, calcium-dependent tyrosine kinase (CADTK; also known as Pyk2/CAKbeta/RAFTK/FAK2), upon adhesion or stimulation with chemokines. To study the role of CADTK in monocyte adherence and motility, we performed immunocytochemical localization that showed CADTK at the leading edge and ruffling lamellipodial structures in freshly isolated, adhered human monocytes. We next introduced CADTK/CAKbeta-related non-kinase (CRNK), the C-terminal noncatalytic domain of CADTK, into monocytes by electroporation and showed that it inhibited CADTK autophosphorylation. Introduction of the fusion protein glutathione S-transferase (GST)-CRNK also reduced (i) cell spreading, as reflected in a reduced cell area 30 min after adhesion, (ii) adhesion-induced phosphotyrosine increases and redistribution into lamellipodia, and (iii) adhesion-induced extracellular signal-regulated protein kinase (ERK) activation. In control experiments, introduction of GST or GST-C3 transferase (an inhibitor of RhoA GTPase activity) by electroporation did not affect these parameters. Monocytes adhered in the presence of autologous serum were highly motile even after introduction of GST (83% motile cells). However, only 26% of monocytes with introduced GST-CRNK were motile. In contrast, GST-CRNK-treated monocytes were fully capable of phagocytosis and adhesion-induced cytokine gene induction, suggesting that CADTK is not involved in these cellular activities and that GST-CRNK introduction does not inhibit global monocyte functions. These results suggest that CADTK is crucial for the in vitro monocyte cytoskeletal reorganization necessary for cell motility and is likely to be required in vivo for recruitment to sites of inflammation.
Growth-hormone-releasing hormone (1990)

Growth-hormone-releasing hormone (GHRH, somatoliberin) is the hypothalamic peptide hormone that specifically stimulates synthesis and release of growth hormone (GH, somatotropin) by somatotrope cells of the anterior pituitary gland. GHRH is the last of the classically postulated hypothalamic hormones to be characterized, synthesized, and used in clinical medicine. In this review of GHRH, I discuss the discovery and characterization of the peptide, its role in the regulation of GH secretion, and its clinical use in pathological states of GH excess and GH deficiency. The two most clinically useful aspects of GHRH are to establish the etiology of GH deficiency, most commonly the result of a hypothalamic GHRH deficiency, and to treat GH-deficient children. Use of GHRH as therapy for GH deficiency currently is experimental and, to date, results encourage the idea of a therapeutic role for this peptide in promoting endogenous GH secretion with resulting acceleration of linear growth.
PI3Kδ Inhibition by Idelalisib in Patients with Relapsed Indolent Lymphoma (2014)

In this single-group study, idelalisib showed antitumor activity with an acceptable safety profile in patients with indolent non-Hodgkin's lymphoma who had received extensive prior treatment. (Funded by Gilead Sciences and others; ClinicalTrials.gov number, NCT01282424.).