gebhart/patrepeval huggingface dataset:
Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir (1997)

Coadministration with the human immunodeficiency virus (HIV) protease inhibitor ritonavir was investigated as a method for enhancing the levels of other peptidomimetic HIV protease inhibitors in plasma. In rat and human liver microsomes, ritonavir potently inhibited the cytochrome P450 (CYP)-mediated metabolism of saquinavir, indinavir, nelfinavir, and VX-478. The structural features of ritonavir responsible for CYP binding and inhibition were examined. Coadministration of other protease inhibitors with ritonavir in rats and dogs produced elevated and sustained plasma drug levels 8 to 12 h after a single dose. Drug exposure in rats was elevated by 8- to 46-fold. A > 50-fold enhancement of the concentrations of saquinavir in plasma was observed in humans following a single codose of ritonavir (600 mg) and saquinavir (200 mg). These results indicate that ritonavir can favorably alter the pharmacokinetic profiles of other protease inhibitors. Combination regimens of ritonavir and other protease inhibitors may thus play a role in the treatment of HIV infection. Because of potentially substantial drug level increases, however, such combinations require further investigation to establish safe regimens for clinical use.
Integrative Phosphoproteomics Links IL-23R Signaling with Metabolic Adaptation in Lymphocytes (2016)

Interleukin (IL)-23 mediated signal transduction represents a major molecular mechanism underlying the pathology of inflammatory bowel disease, Crohn's disease and ulcerative colitis. In addition, emerging evidence supports the role of IL-23-driven Th17 cells in inflammation. Components of the IL-23 signaling pathway, such as IL-23R, JAK2 and STAT3, have been characterized, but elements unique to this network as compared to other interleukins have not been readily explored. In this study, we have undertaken an integrative phosphoproteomics approach to better characterise downstream signaling events. To this end, we performed and compared phosphopeptide and phosphoprotein enrichment methodologies after activation of T lymphocytes by IL-23. We demonstrate the complementary nature of the two phosphoenrichment approaches by maximizing the capture of phosphorylation events. A total of 8202 unique phosphopeptides, and 4317 unique proteins were identified, amongst which STAT3, PKM2, CDK6 and LASP-1 showed induction of specific phosphorylation not readily observed after IL-2 stimulation. Interestingly, quantitative analysis revealed predominant phosphorylation of pre-existing STAT3 nuclear subsets in addition to translocation of phosphorylated STAT3 within 30 min after IL-23 stimulation. After IL-23R activation, a small subset of PKM2 also translocates to the nucleus and may contribute to STAT3 phosphorylation, suggesting multiple cellular responses including metabolic adaptation.
Conversion of Mature Human β-Cells Into Glucagon-Producing α-Cells (2013)

Conversion of one terminally differentiated cell type into another (or transdifferentiation) usually requires the forced expression of key transcription factors. We examined the plasticity of human insulin-producing β-cells in a model of islet cell aggregate formation. Here, we show that primary human β-cells can undergo a conversion into glucagon-producing α-cells without introduction of any genetic modification. The process occurs within days as revealed by lentivirus-mediated β-cell lineage tracing. Converted cells are indistinguishable from native α-cells based on ultrastructural morphology and maintain their α-cell phenotype after transplantation in vivo. Transition of β-cells into α-cells occurs after β-cell degranulation and is characterized by the presence of β-cell-specific transcription factors Pdx1 and Nkx6.1 in glucagon(+) cells. Finally, we show that lentivirus-mediated knockdown of Arx, a determinant of the α-cell lineage, inhibits the conversion. Our findings reveal an unknown plasticity of human adult endocrine cells that can be modulated. This endocrine cell plasticity could have implications for islet development, (patho)physiology, and regeneration.
Literature Review: Silicone Applications in Health Care (2014)

Early in the 20<sup>th</sup> century, the term ‘silicone’ was coined by Professor Frederic Stanley Kipping, a British chemist and one of the founding fathers of silicon chemistry. The word was given to describe new compounds containing a Si-O linkage (siloxane bond) and basic chemical formula R<sub>2</sub>-Si-O. In industry, silicone usually refers to linear polydimethylsiloxane (PDMS), the most basic silicone polymer containing only methyl groups as substituents in the polymeric structure. However, the term silicone can also be used to describe complex polymer structures that feature a wide range of functional groups, branching or crosslinking. “The properties of basic PDMS materials can be changed by replacing some methyl groups with other organic groups or atoms.” Substitution of this type is useful when specific physical and chemical properties are required of the material, such as adhesion or compatibility with a certain substrate.
9-(2-Sulfo)fluorenylmethyloxycarbonyl chloride, a new reagent for the purification of synthetic peptides (1978)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXT9-(2-Sulfo)fluorenylmethyloxycarbonyl chloride, a new reagent for the purification of synthetic peptidesR. B. Merrifield and Anita E. BachCite this: J. Org. Chem. 1978, 43, 25, 4808–4816Publication Date (Print):December 1, 1978Publication History Published online1 May 2002Published inissue 1 December 1978https://pubs.acs.org/doi/10.1021/jo00419a021https://doi.org/10.1021/jo00419a021research-articleACS PublicationsRequest reuse permissionsArticle Views1122Altmetric-Citations66LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Myocardial 99m Tc-Tetrofosmin Uptake During Adenosine-Induced Vasodilatation With Either a Critical or Mild Coronary Stenosis (1997)

In this canine model, relative underperfusion with adenosine stress is better resolved with 201Tl than with 99mTc-tetrofosmin and may be explained by the lower EF for 99mTc tetrofosmin. With clinical imaging, greater 201Tl attenuation and redistribution may lessen this advantage.
Transition-metal-catalyzed reactions of diazo compounds. 1. Cyclopropanation of double bonds (1980)

peer reviewed
Recombinant activated factor VII for the treatment of life-threatening haemorrhage (2003)

To describe the use of recombinant activated factor VII (rFVIIa) in patients with life-threatening haemorrhage. We report a case series of Australian patients with life-threatening haemorrhage who were treated with rFVIIa prior to August 2002 namely 21 patients, median age 45 years (range 22-79 years), 33% (seven of 21) female. The major causes for bleeding were multi-trauma, cardiac or vascular surgery, or orthoptic liver transplantation. In the 24 h prior to the administration of rFVIIa, the median blood usage was 22 U packed cells (range 3-66 U), the median International Normalized Ratio was 1.6 (range 1.4-3.6) and the median activated partial thromboplastin time was 55 s (range 31-180 s). During the 24 h after administration of rFVIIa, the median blood usage was 2 U packed cells (range 0-16 U), the median International Normalized Ratio was 1.0 (range 0.9-1.2) and the median activated partial thromboplastin time was 40 s (range 30-94 s); P < 0.001 for each comparison. Sixteen of the 21 patients were discharged from hospital or were alive at 30 days. There were no thrombotic complications following the administration of rFVIIa. These uncontrolled data suggest a role for rFVIIa as an adjunctive haemostatic measure in surgical patients with life-threatening haemorrhage for whom conventional measures to achieve haemostasis have failed.
Actin Assembly Plays a Variable, but not Obligatory Role in Receptor‐Mediated Endocytosis (2000)

Three cell-permeant compounds, cytochalasin D, latrunculin A and jasplakinolide, which perturb intracellular actin dynamics by distinct mechanisms, were used to probe the role of filamentous actin and actin assembly in clathrin-mediated endocytosis in mammalian cells. These compounds had variable effects on receptor-mediated endocytosis of transferrin that depended on both the cell line and the experimental protocol employed. Endocytosis in A431 cells assayed in suspension was inhibited by latrunculin A and jaspiakinolide, but resistant to cytochalasin D, whereas neither compound inhibited endocytosis in adherent A431 cells. In contrast, endocytosis in adherent CHO cells was more sensitive to disruption of the actin cytoskeleton than endocytosis in CHO cells grown or assayed in suspension. Endocytosis in other cell types, including nonadherent K562 human erythroleukemic cells or adherent Cos-7 cells was unaffected by disruption of the actin cytoskeleton. While it remains possible that actin filaments can play an accessory role in receptor-mediated endocytosis, these discordant results indicate that actin assembly does not play an obligatory role in endocytic coated vesicle formation in cultured mammalian cells.
Effect of Multiple Mutations in the Hemoglobin- and Hemoglobin-Haptoglobin-Binding Proteins, HgpA, HgpB, and HgpC, of Haemophilus influenzae Type b (1999)

Haemophilus influenzae requires heme for growth and can utilize hemoglobin and hemoglobin-haptoglobin as heme sources. We previously identified two hemoglobin- and hemoglobin-haptoglobin-binding proteins, HgpA and HgpB, in H. influenzae HI689. Insertional mutation of hgpA and hgpB, either singly or together, did not abrogate the ability to utilize or bind either hemoglobin or the hemoglobin-haptoglobin complex. A hemoglobin affinity purification method was used to isolate a protein of approximately 120 kDa from the hgpA hgpB double mutant. We have cloned and sequenced the gene encoding this third hemoglobin/hemoglobin-haptoglobin binding protein and designate it hgpC. Insertional mutation of hgpC did not affect the ability of the strain to utilize either hemoglobin or hemoglobin-haptoglobin. An hgpA hgpB hgpC triple mutant constructed by insertional mutagenesis showed a reduced ability to use the hemoglobin-haptoglobin complex but was unaltered in the ability to use hemoglobin. A second class of mutants was constructed in which the entire structural gene of each of the three proteins was deleted. The hgpA hgpB hgpC complete-deletion triple mutant was unable to utilize the hemoglobin-haptoglobin complex and showed a reduced ability to use hemoglobin. We have identified three hemoglobin/hemoglobin-haptoglobin-binding proteins in Haemophilus influenzae. Any one of the three proteins is sufficient to support growth with hemoglobin-haptoglobin as the heme source, and expression of at least one of the three is essential for hemoglobin-haptoglobin utilization. Although the three proteins play a role in hemoglobin utilization, an additional hemoglobin acquisition mechanism(s) exists.
Tramadol in post-herpetic neuralgia: a randomized, double-blind, placebo-controlled trial (2003)

The efficacy and safety of sustained-release tramadol compared to placebo in the treatment of post-herpetic neuralgia were evaluated in a multicenter, randomized, double-blind, parallel-group study in 127 outpatients. Treatment was administrated for 6 weeks. The dose of tramadol could be increased from 100 mg/day to 400 mg/day (300 mg/day in patients more than 75 years old). Groups were compared on changes in pain intensity on a Visual Analogue Scale (VAS) between inclusion and the 6th week of treatment (covariance analysis as main analysis and repeated measures analysis as complementary analysis) in the per protocol (PP) population. The randomized population comprised 127 patients aged 35-85 years, mostly females (72.4%). Groups were comparable at inclusion both in the intent to treat (ITT) population (63 patients in the tramadol group and 62 patients in the placebo group) and in the PP population (53 patients in the tramadol group and 55 patients in the placebo group). Mean pain intensity on day 43 adjusted on day 1 (covariance analysis) was significantly lower in the tramadol group than in the placebo group in both the PP (P=0.0499), and the ITT (P=0.031) populations. The two groups significantly differed on change in pain intensity over time (repeated measures analysis) in the ITT population (P=0.012). The percentage of pain relief over the 6th week was significantly higher in the tramadol group than in the placebo group (P=0.017). During the 6th week, patients in the tramadol group required less rescue medication than patients in the placebo group (P=0.022). No significant difference was found between groups either in pain intensity on a 5-point Verbal Scale (VRS) or in quality of life measurements. Tramadol was administered at an average dosage of 275.5 (89.7) mg/day after a 1-week dose-adaptation period. Tramadol was well tolerated. No notable difference appeared between groups either in the percentage of patients with treatment-associated adverse events (TAAE) (29.7% in the tramadol group and 31.8% in the placebo group) or in the total number of TAAE (31 in the tramadol group and 28 in the placebo group).
A fusion peptide directs enhanced systemic dystrophin exon skipping and functional restoration in dystrophin-deficient mdx mice (2009)

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene that abolish the synthesis of dystrophin protein. Antisense oligonucleotides (AOs) targeted to trigger excision of an exon bearing a mutant premature stop codon in the DMD transcript have been shown to skip the mutated exon and partially restore functional dystrophin protein in dystrophin-deficient mdx mice. To fully exploit the therapeutic potential of this method requires highly efficient systemic AO delivery to multiple muscle groups, to modify the disease process and restore muscle function. While systemic delivery of naked AOs in DMD animal models requires high doses and is of relatively poor efficiency, we and others have recently shown that short arginine-rich peptide-AO conjugates can dramatically improve in vivo DMD splice correction. Here we report for the first time that a chimeric fusion peptide (B-MSP-PMO) consisting of a muscle-targeting heptapeptide (MSP) fused to an arginine-rich cell-penetrating peptide (B-peptide) and conjugated to a morpholino oligomer (PMO) AO directs highly efficient systemic dystrophin splice correction in mdx mice. With very low systemic doses, we demonstrate that B-MSP-PMO restores high-level, uniform dystrophin protein expression in multiple peripheral muscle groups, yielding functional correction and improvement of the mdx dystrophic phenotype. Our data demonstrate proof-of-concept for this chimeric peptide approach in DMD splice correction therapy and is likely to have broad application.
Catalytic Enantioselective Synthesis of Quaternary Stereocenters via Intermolecular C-Acylation of Silyl Ketene Acetals:  Dual Activation of the Electrophile and the Nucleophile (2003)

A nucleophile-catalyzed asymmetric intermolecular C-acylation of silyl ketene acetals by anhydrides has been developed, furnishing quaternary stereocenters with high enantioselectivity. Mechanistic studies support the hypothesis that the reaction involves activation both of the silyl ketene acetal (generation of an enolate) and of the anhydride (formation of an acylpyridinium ion).
Comparison of four cytokine regimens for mobilization of peripheral blood stem cells: IL-3 alone and combined with GM-CSF or G-CSF. (1996)

Improved methods for mobilization may reduce the number of aphereses required to collect adequate numbers of peripheral blood stem cells (PBSC) and hasten engraftment following high-dose therapy. Mobilization with cytokines alone enables engraftment after myeloablative therapy. The optimal cytokine regimen for mobilization has not been established. The study evaluated the effects of four interleukin-3-containing cytokine regimens administered during steady state hematopoiesis on PBSC mobilization in 30 patients with breast cancer or lymphoid malignancies. These regimens included IL-3 alone (Arm 1), sequential IL-3 --> G-GSF (Arm 2), sequential IL-3 --> GM-CSF (Arm 3) and combined IL-3 + G-CSF (Arm 4). Consecutive days of apheresis were performed until a target of 4-6 x 10(8) mononuclear cells/kg were collected. All patients received intravenous GM-CSF after PBSC infusion. Median days to an ANC > or = 500/ microliters in Arm 3(22 days) was significantly slower than for patients in Arm 2 (13 days) but not significantly different from patients in Arm 1 or Arm 4. There was no significant difference in platelet engraftment or days of hospitalization between the study arms. Addition of GM-CSF to IL-3-containing mobilization regimens results in collection of PBSC that lead to delayed engraftment. Further development of Arms 1, 2, and 4 appear warranted.
Fixed-slope universal lossy data compression (1997)

Corresponding to any lossless codeword length function l, three universal lossy data compression schemes are presented: one is with a fixed rate, another is with a fixed distortion, and a third is with a fixed slope. The former two universal lossy data compression schemes are the generalization of Yang-Kieffer's (see ibid., vol.42, no.1, p.239-45, 1995) results to the general case of any lossless codeword length function l, whereas the third is new. In the case of fixed-slope /spl lambda/>0, our universal lossy data compression scheme works as follows: for any source sequence x/sup n/ of length n, the encoder first searches for a reproduction sequence y/sup n/ of length n which minimizes a cost function n/sup -1/l(y/sup n/)+/spl lambda//spl rho//sub n/(x/sup n/, y/sup n/) over all reproduction sequences of length n, and then encodes x/sup n/ into the binary codeword of length l(y/sup n/) associated with y/sup n/ via the lossless codeword length function l, where /spl rho//sub n/(x/sup n/, y/sup n/) is the distortion per sample between x/sup n/ and y/sup n/. Under some mild assumptions on the lossless codeword length function l, it is shown that when this fixed-slope data compression scheme is applied to encode a stationary, ergodic source, the resulting encoding rate per sample and the distortion per sample converge with probability one to R/sub /spl lambda// and D/sub /spl lambda//, respectively, where (D/sub /spl lambda//, R/sub /spl lambda//) is the point on the rate distortion curve at which the slope of the rate distortion function is -/spl lambda/. This result holds particularly for the arithmetic codeword length function and Lempel-Ziv codeword length function. The main advantage of this fixed-slope universal lossy data compression scheme over the fixed-rate (fixed-distortion) universal lossy data compression scheme lies in the fact that it converts the encoding problem to a search problem through a trellis and then permits one to use some sequential search algorithms to implement it. Simulation results show that this fixed-slope universal lossy data compression scheme, combined with a suitable search algorithm, is promising.
Association of adenovirus early-region 1A proteins with cellular polypeptides. (1986)

Extracts from adenovirus-transformed human 293 cells were immunoprecipitated with monoclonal antibodies specific for the early-region 1A (E1A) proteins. In addition to the E1A polypeptides, these antibodies precipitated a series of proteins with relative molecular weights of 28,000, 40,000, 50,000, 60,000, 80,000, 90,000, 110,000, 130,000, and 300,000. The two most abundant of these polypeptides are the 110,000-molecular-weight protein (110K protein) and 300K protein. Three experimental approaches have suggested that the 110K and 300K polypeptides are precipitated because they form stable complexes with the E1A proteins. The 110K and 300K polypeptides do not share epitopes with the E1A proteins, they copurify with a subset of the E1A proteins, and they bind to the E1A proteins following mixing in vitro. The 110K and 300K polypeptides are not adenoviral proteins, but are encoded by cellular DNA. Both the 12S and the 13S E1A proteins bind to the 110K and 300K species, and these complexes are found in adenovirus-transformed and -infected cells.
Cutting Edge: NKG2D Receptors Induced by IL-15 Costimulate CD28-Negative Effector CTL in the Tissue Microenvironment (2001)

Unlike primary T cells in lymph nodes, effector CD8(+) CTL in tissues do not express the costimulatory receptor CD28. We report that NKG2D, the receptor for stress-induced MICA and MICB molecules expressed in the intestine, serves as a potent costimulatory receptor for CTL freshly isolated from the human intestinal epithelium. Expression and function of NKG2D are selectively up-regulated by the cytokine IL-15, which is released by the inflamed intestinal epithelium. These findings identify a novel CTL costimulatory pathway regulated by IL-15 and suggest that tissues can fine-tune the activation of effector T cells based on the presence or absence of stress and inflammation. Uncontrolled secretion of IL-15 could lead to excessive induction of NKG2D and thus contribute to the development of autoimmune disease by facilitating the activation of autoreactive T cells.
A comparative evaluation of conventional and pretargeted radioimmunotherapy of CD20-expressing lymphoma xenografts (2001)

Radioimmunotherapy with anti-CD20 monoclonal antibodies is a promising new treatment approach for patients with relapsed B-cell lymphomas. However, the majority of patients treated with conventional radiolabeled anti-CD20 antibodies eventually have a relapse because the low tumor-to-blood and tumor-to-normal organ ratios of absorbed radioactivity limit the dose that can be safely administered without hematopoietic stem cell support. This study assessed the ability of a streptavidin-biotin "pretargeting" approach to improve the biodistribution of radioactivity in mice bearing Ramos lymphoma xenografts. A pretargeted streptavidin-conjugated anti-CD20 1F5 antibody was infused, followed 24 hours later by a biotinylated N-acetylgalactosamine-containing "clearing agent" and finally 3 hours later by (111)In-labeled DOTA-biotin. Tumor-to-blood ratios were 3:1 or more with pretargeting, compared with 0.5:1 or less with conventional (111)In-1F5. Tumor-to-normal organ ratios of absorbed radioactivity up to 56:1 were observed with pretargeting, but were 6:1 or less with conventional (111)In-1F5. Therapy experiments demonstrated that 400 microCi (14.8 MBq) or more of conventional (90)Y-1F5 was required to obtain major tumor responses, but this dose was associated with lethal toxicity in 100% of mice. In marked contrast, up to 800 microCi (29.6 MBq) (90)Y-DOTA-biotin could be safely administered by the pretargeting approach with only minor toxicity, and 89% of the mice were cured. These data suggest that anti-CD20 pretargeting shows great promise for improving current therapeutic options for B-cell lymphomas and warrants further preclinical and clinical testing.