gebhart/patrepeval huggingface dataset:
Inhibitors of 17alpha-hydroxylase/17,20-lyase (CYP17): potential agents for the treatment of prostate cancer. (1999)

Prostate cancer (PCa) is now the most prevalent cancer in men in the U.S.A. and Europe. At present the major treatment options include surgical or medical castration. These strategies depend on the abolition of the production of testosterone by the testes. However, as these procedures do not affect adrenal androgen production, they are frequently combined with androgen receptor antagonist to block their action. Inhibition of the key enzyme which catalyzes the biosynthesis of androgens from pregnane precursors, 17alpha-hydroxylase/17,20-lyase (hereafter referred to as CYP17 ) could prevent androgen biosynthesis from both sources. Thus total blockade of androgen production by CYP17 inhibitors may provide effective treatment of prostate cancer patients. Indeed, this strategy is now an area of intense interest within research institutions and the pharmaceutical industry. This review highlights development in the design and evaluation of both steroidal and non-steroidal CYP17 inhibitors since 1965. Major emphasis is given to the potent CYP17 inhibitors and those which may show clinical promise. The review could function as a comprehensive working reference of research accomplishment in the field and what problems remain to be tackled in the future.
Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways (2007)

Melanoma is one of the most aggressive cancers, and its incidence is increasing. These tumors derive from the melanocyte lineage and remain incurable after metastasis. Here we report that SONIC HEDGEHOG (SHH)-GLI signaling is active in the matrix of human hair follicles, and that it is required for the normal proliferation of human melanocytes in culture. SHH-GLI signaling also regulates the proliferation and survival of human melanomas: the growth, recurrence, and metastasis of melanoma xenografts in mice are prevented by local or systemic interference of HH-GLI function. Moreover, we show that oncogenic RAS-induced melanomas in transgenic mice express Gli1 and require Hh-Gli signaling in vitro and in vivo. Finally, we provide evidence that endogenous RAS-MEK and AKT signaling regulate the nuclear localization and transcriptional activity of GLI1 in melanoma and other cancer cells. Our data uncover an unsuspected role of HH-GLI signaling in melanocytes and melanomas, demonstrate a role for this pathway in RAS-induced tumors, suggest a general integration of the RAS/AKT and HH-GLI pathways, and open a therapeutic approach for human melanomas.
Heterogeneous nuclear ribonucleoprotein K is over expressed, aberrantly localised and is associated with poor prognosis in colorectal cancer (2006)

Heterogeneous ribonucleoprotein K (hnRNP K) is a member of the hnRNP family which has several different cellular roles including transcription, mRNA shuttling, RNA editing and translation. Several reports implicate hnRNP K having a role in tumorigenesis, for instance hnRNP K increases transcription of the oncogene c-myc and hnRNP K expression is regulated by the p53/MDM 2 pathway. In this study comparing normal colon to colorectal cancer by proteomics, hnRNP K was identified as being overexpressed in this type of cancer. Immunohistochemistry with a monoclonal antibody to hnRNP K (which we developed) on colorectal cancer tissue microarray, confirmed that hnRNP K was overexpressed in colorectal cancer (P<0.001) and also showed that hnRNP K had an aberrant subcellular localisation in cancer cells. In normal colon hnRNP K was exclusively nuclear whereas in colorectal cancer the protein localised both in the cytoplasm and the nucleus. There were significant increases in both nuclear (P=0.007) and cytoplasmic (P=0.001) expression of hnRNP K in Dukes C tumours compared with early stage tumours. In Dukes C patient's good survival was associated with increased hnRNP K nuclear expression (P=0.0093). To elaborate on the recent observation that hnRNP K is regulated by p53, the expression profiles of these two proteins were also analysed. There was no correlation between hnRNP K and p53 expression, however, patients who presented tumours that were positive for hnRNP K and p53 had a poorer survival outcome (P=0.045).
Structure-Guided Design of a Series of MCL-1 Inhibitors with High Affinity and Selectivity (2015)

Myeloid cell leukemia 1 (MCL-1) is a BCL-2 family protein that has been implicated in the progression and survival of multiple tumor types. Herein we report a series of MCL-1 inhibitors that emanated from a high throughput screening (HTS) hit and progressed via iterative cycles of structure-guided design. Advanced compounds from this series exhibited subnanomolar affinity for MCL-1 and excellent selectivity over other BCL-2 family proteins as well as multiple kinases and GPCRs. In a MCL-1 dependent human tumor cell line, administration of compound 30b rapidly induced caspase activation with associated loss in cell viability. The small molecules described herein thus comprise effective tools for studying MCL-1 biology.
An oligosaccharide-tetanus toxoid conjugate vaccine against type III group B Streptococcus. (1990)

We have developed an oligosaccharide-tetanus toxoid conjugate vaccine against type III group B Streptococcus. Purified group B streptococcal type III capsular polysaccharide was depolymerized by enzymatic digestion using endo-beta-galactosidase produced by Citrobacter freundii. Following enzymatic digestion, oligosaccharides were fractionated by gel filtration chromatography on Sephadex G-75. An oligosaccharide pool of average Mr = 14,500 (corresponding to 13.6 repeating units of the type III polysaccharide) was used for conjugation to tetanus toxoid. Tetanus toxoid was covalently coupled via a synthetic spacer molecule to the reducing end of the oligosaccharide by reductive amination. The oligosaccharide-tetanus toxoid conjugate elicited type III-specific anticapsular antibodies (measured in enzyme-linked immunosorbent assay) in three out of three rabbits whereas the unconjugated native type III polysaccharide was nonimmunogenic. Antiserum from rabbits vaccinated with the oligosaccharide-protein conjugate protected mice against lethal challenge with live group B streptococci (16 out of 16 mice survived) and opsonized group B streptococci for phagocytosis in vitro. No protection was conferred by preimmune serum nor by serum from rabbits vaccinated with unconjugated native type III polysaccharide. An oligosaccharide-protein conjugate vaccine of this design may prove to be an effective immunogen for protection against group B streptococcal infection in humans. In addition, the approach to vaccine design utilized in these studies will facilitate further definition of the structural parameters that determine immune response to glycoconjugate vaccines.
Prospective Randomized Study on the Management of Moyamoya Disease with Hemorrhagic Onset: Japan Adult Moyamoya (JAM) Trial. (2002)

The prospective effect of bypass surgery against recurrent bleedings should be statistically evaluated to establish treatment guidelines for moyamoya disease with hemorrhagic onset. Twelve Japanese centers have combined to evaluate the benefits of direct anastomotic bypass surgery in randomized patients who have experienced hemorrhagic episodes related to moyamoya disease and who have received either best medical treatment alone or best medical treatment plus extracranial-intracranial bypass surgery. This prospective study (Japan Adult moyamoya ‹JAM› Trial) was initiated in January 2001.
Induction of Clinical and Endoscopic Remission of Mild to Moderately Active Ulcerative Colitis With Budesonide MMX® 9 mg: Analysis of Pooled Data from Two Phase 3 Studies (2011)

Purpose: To evaluate the efficacy and safety of budesonide MMX® (B-MMX) 6 mg and 9 mg oral tablets in patients (pts) with active mild to moderate ulcerative colitis (UC), when administered for 8 weeks, compared to placebo (PBO). Methods: Pooled data from two Phase 3 studies evaluating patients achieving clinical and endoscopic remission with B-MMX 9 mg or 6 mg tablets once daily compared with PBO over an 8 week period were analyzed. The primary endpoint was induction of clinical and endoscopic remission; defined by strict criteria with a UCDAI score ≤1 after 8 weeks with scores of 0 for rectal bleeding and stool frequency, no mucosal friability after full colonoscopy, and a ≥1-point reduction from baseline in the endoscopic index score. Clinical improvement (≥3 point reduction in UCDAI), endoscopic improvement (≥1 point reduction in the UCDAI mucosal appearance subscore), and symptom resolution (score of 0 for rectal bleeding and stool frequency from UCDAI) were also evaluated at week 8. Results: 672 patients from the pooled modified intent-to-treat (mITT) population, which included randomized patients who received ≥1 dose of study drug, were treated with PBO, B-MMX 9 mg, or B-MMX 6 mg. The mITT population excluded patients without histological evidence of active disease at baseline or with major eligibility or GCP violations according to ICH E9 Guidelines. Clinical and endoscopic remission for B-MMX 9 mg vs. PBO was 17.7% vs. 6.2% (p=0.0002). Symptom resolution was 26.3% vs. 14.3%, respectively (p=0.0018). Clinical improvement and endoscopic improvement were both numerically greater for B-MMX 9 mg than PBO but not statistically different (Table). Treatment related adverse events, including potential glucocorticoid effects, occurred with similar frequencies across study groups.Table: No Caption available.Conclusion: Pooled data showed that B-MMX 9 mg given once daily is safe and effective for inducing clinical and endoscopic remission and symptom resolution in patients with mild to moderately active UC. Disclosure: Dr. Sandborn- Consultant: Cosmo Pharmaceuticals, Santarus Dr. Travis- Consultant: Cosmo Pharmaceuticals, Santarus Dr. Moro- Employee: Cosmo Pharmaceuticals, Dr. Bala- Investigator: Santarus Dr. Danese- Investigator: Cosmo Pharmaceuticals, Dr. Ballard- Employee: Santarus Dr. Bagin-Employee: Santarus Ms. Gautille- Employee: Santarus Dr. Huang- Employee: Santarus. This research was supported by an industry grant from Cosmo Pharmaceuticals and Santarus.
Reduction of Image Artifacts in Mice by Bladder Flushing with a Novel Double-Lumen Urethral Catheter (2006)

In electron paramagnetic resonance imaging (EPRI), the accumulation of contrast agent in the bladder can create a very large source of signal, often far greater than that of the organ of interest. Mouse model images have become increasingly important in preclinical testing. To minimize bladder accumulation on mouse images, we developed a novel, minimally invasive, MRI/EPRI-friendly procedure for flushing a female mouse bladder. It is also applicable to other imaging techniques, for example, PET, SPECT, etc., where contrast agent accumulation in the bladder is also undesirable. A double-lumen urethral catheter was developed, using a standard IV catheter with a silicone tube extension, having a polyethylene tube threaded into the IV catheter. Flushing of the bladder provides a substantial reduction in artifacts, as shown in images of tumors in mice.
Low‐intensity oral anticoagulation in sickle‐cell disease reverses the prethrombotic state: promises for treatment? (1995)

Increased plasma levels of prothrombin fragment 1 + 2 (F1 + 2) found in patients with sickle-cell disease reflect enhanced endogenous thrombin generation. We postulate that hypercoagulability contributes to vaso-occlusion. The intensity of acenocoumarol treatment required to reduce the F1 + 2 level to 50% of pretreatment level was investigated in seven patients with symptomatic sickle-cell anaemia during steady-state disease for a period of 2 months. All patients had increased levels of F1 + 2 compared with an age-matched control group. Normalization of the F1 + 2 was achieved at a median INR of 1.64 (range 1.18-2.2). It is concluded that low-intensity oral anticoagulation normalizes the hypercoagulability in sickle-cell disease.
PROTECTION OF ISLETS OF LANGERHANS FROM ANTIBODIES BY MICROENCAPSULATION WITH ALGINATE-POLY-L-LYSINE MEMBRANES1 (1993)

Microencapsulation of islets has been proposed to prevent their immune destruction following transplantation. An indirect immunofluorescence technique has been developed and used to study the permeability of the alginate-poly-L-lysine microcapsules to antibodies. Wistar rat islets were incubated with the R2D6 monoclonal mouse IgM antibody against rat islets, microencapsulated, and incubated with fluorescein-labeled goat IgG antibodies against mouse IgG and IgM. For the negative controls, the first antibody was omitted or both antibodies were omitted. The positive controls included islets incubated with both antibodies before they were encapsulated. Our study demonstrated that the alginate-poly-L-lysine membranes are not permeable to IgG when poly-L-lysine of molecular weights ranging from 21,000 to 390,000 are used. This simple immunofluorescence technique demonstrated the nonpermeability of the microcapsules to IgG, and could be useful for the initial evaluation of new types of membranes.
In vitro paracrine regulation of human keratinocyte growth by fibroblast‐derived insulin‐like growth factors (1992)

Human keratinocytes isolated from a skin biopsy and cultured in vitro on a feeder-layer of irradiated fibroblasts reconstitute a stratified squamous epithelium suitable for grafting onto patients suffering from large burn wounds. Since conditioned medium from 3T3-J2 cells can partially substitute for the intact feeder-layer, we studied the possible involvement of insulin-like growth factors acting in a paracrine fashion. IGFs were measured (after Sephadex G-50 gel-chromatography in acid conditions) in media conditioned by a feeder-layer of lethally irradiated 3T3-J2 fibroblasts on which keratinocytes were grown. Immunoreactive (IR) IGF-I, IGF-II, and IGF binding activity were present in the medium conditioned by the feeder-layer. The medium conditioned by keratinocytes showed nearly undetectable amounts of IR IGF-I and IGF-II, suggesting that keratinocytes are unable to synthesize IGFs peptides. Recombinant IGF-I and IGF-II, and conditioned medium from 3T3-J2 cells, caused a dose-dependent increase of 3H-thymydine incorporation in cultured keratinocytes. The stimulatory effect of IGF and of 3T3-J2 conditioned medium was inhibited by the MoAb Sm 1.2, which recognizes both IGF-I and IGF-II but not insulin, and by the MoAb alpha IR-3, which is a specific antagonist of type-I IGF receptor. Fetal mouse-derived 3T3-J2 cells and adult human skin fibroblasts were equally able to sustain keratinocyte growth and in both cases addition of Sm 1.2 MoAb causes a 50% decrease in the keratinocyte number. When the non-IGF-producing BALB/c 3T3 cells were used as a feeder-layer, the keratinocytes number was similar to that observed with 3T3-J2 and with human fibroblasts plus the Sm 1.2 MoAb. IGF-I and IGF-II restored the BALB/c 3T3 growth promoting activity to the level of 3T3-J2 and of normal human fibroblasts. Our results suggest that fetal mouse 3T3-J2 and human fibroblasts synthesize IGF peptides, while keratinocytes do not. Fibroblast-derived IGFs stimulate keratinocyte growth in a paracrine fashion, suggesting their role in the regulation of keratinocyte proliferation in skin growth and in wound healing.
Biochemical Consequences of Type 2 Adenovirus and Simian Virus 40 Double Infections of African Green Monkey Kidney Cells (1970)

African green monkey kidney (AGMK) cells were nonpermissive hosts for type 2 adenovirus although the restriction was not complete; when only 3 plaque-forming units/cell was employed as the inoculum, the viral yield was about 0.1% of the maximum virus produced when simian virus 40 (SV40) enhanced adenovirus multiplication. The viral yield of cells infected only with type 2 adenovirus increased as the multiplicity of infection was increased. Type 2 adenovirus could infect almost all AGMK cells in culture; adenovirus-specific early proteins and DNA were synthesized in most cells, but small amounts of late proteins were made in relatively few cells. Even when cells were infected with both SV40 and adenovirus, only about 50% were permissive for synthesis of adenovirus capsid proteins. Approximately the same quantity of adenovirus deoxyribonucleic acid (DNA) was synthesized in the restricted as in the SV40-enhanced infection. However, in cells infected with SV40 and type 2 adenovirus, replication of SV40 DNA was blocked, multiplication of SV40 was accordingly inhibited, and synthesis of host DNA was not stimulated. To enhance propagation of type 2 adenovirus, synthesis of an early SV40 protein was essential; 50 mug of cycloheximide per ml prevented the SV40-induced enhancement of adenovirus multiplication, whereas 5 x 10(-6)m 5-fluoro-2-deoxyuridine did not abrogate the enhancing phenomenon.
Involvement of IL-5 in a Murine Model of Allergic Pulmonary Inflammation: Prophylactic and Therapeutic Effect of an Anti-IL-5 Antibody (1995)

Interleukin-5 (IL-5) is important in the control of differentiation, migration, and activation of eosinophils. In order to study the role of IL-5 in the development of eosinophilic inflammation of the airways, we have used a monoclonal antibody to murine IL-5 (TRFK-5) in a murine model of allergic pulmonary inflammation. B6D2F1 mice were sensitized with alum-precipitated ovalbumin and were challenged with aerosolized ovalbumin on day 12 after sensitization. Samples of bronchoalveolar lavage (BAL) fluid, lung tissue, blood, and bone marrow aspirate were collected at different times after ovalbumin challenge. Twenty-four hours after challenge there were significant increases in the number of eosinophils in the BAL fluid, lung tissue, and blood while bone marrow eosinophils were decreased. Treatment of sensitized mice with TRFK-5 (0.01-1 mg/kg, i.p.) 2 h before ovalbumin challenge reduced the numbers of eosinophils in the BAL fluid and lung tissue and prevented the decrease in bone marrow eosinophils in a dose-dependent fashion. The number of eosinophils in the BAL fluid, peribronchial and alveolar regions of the lung was also reduced when TRFK-5 (2 mg/kg, i.p.) was given up to 5 d after ovalbumin challenge. Furthermore, there was no evidence of increased epithelial damage, edema, or the presence of mucus that could have resulted from eosinophil apoptosis and release of toxic proteins after neutralization of IL-5. These results demonstrate an important role for IL-5 in the development of eosinophilic inflammation of the airways and for the migration of eosinophils from the bone marrow into blood in response to antigen challenge.(ABSTRACT TRUNCATED AT 250 WORDS)
Formulation and pharmacology of long-acting cabotegravir (2015)

The pharmacologic profile of long-acting cabotegravir supports its continued development for both treatment and prevention of HIV-1 infection.
Protein Biomarkers in Serum of Pediatric Patients with Severe Traumatic Brain Injury Identified by ICAT–LC-MS/MS (2007)

This report is a feasibility study on the utility of gel-free proteomics in identifying peripheral biomarkers of brain injury. The study was performed in six pediatric patients admitted to the intensive care unit for severe traumatic brain injury (TBI). Serum samples collected at admission (less than 8 h after injury) were used for determining the levels of S100beta by enzyme-linked immunosorbent assay (ELISA) and for proteomics analyses. Serum samples were depleted of high abundant albumin and immunoglobulin, and were compared to a pooled reference from several healthy individuals. After labeling and separation on an ionic column, six different serum fractions were analyzed using Isotope-Coded Affinity Tag (ICAT), followed by tandem mass spectrometry (MS/MS) protein sequencing and identification. Ninety-five unique, differentially expressed proteins were identified, including several with a likely brain origin. Several proteins with pattern similarity to S100beta identified by hierarchical clustering could be considered for evaluation in a larger patient sample as potential peripheral markers of TBI.
[P3–240]: DEVELOPMENT OF DIGITAL ELISAS FOR ULTRASENSITIVE MEASUREMENT OF SERUM GLIAL FIBRILLARY ACID PROTEIN AND UBIQUITIN C‐TERMINAL HYDROLASE WITH CLINICAL UTILITIES IN HUMAN TRAUMATIC BRAIN INJURY (2017)

Several investigations have reported that traumatic brain injury (TBI) is a significant risk factor for neurodegenerative diseases including chronic traumatic encephalopathy, Alzheimer's disease, and Parkinson's diseases. There is a widely recognized need for sensitive, accurate and rapid blood-based biomarker assays to supplement computed tomography (CT) scans and functional assessments commonly used for acute diagnosis of TBI. Digital ELISA assays were developed using single molecule array (Simoa) technology with monoclonal antibodies chosen from screening for ultrasensitive measurement of serum glial fibrillary acid protein (GFAP) and ubiquitin C-terminal hydrolase (UCH-L1), respectively. These assays were used to quantify protein levels in a total of 90 serum samples from 30 mild-moderate TBI (mTBI) patients with a Glasgow Coma Scale (GCS) of 9–15, 30 severe TBI patients with a GCS of 8 or less, and 30 normal serum as control. The digital ELISAs measured GFAP and UCH-L1 with a limit of detection (LOD) of 0.11 pg/mL and 0.63 pg/mL and a lower limit of quantification (LLOQ) of 0.48 pg/mL and 0.98 pg/mL in neat serum, respectively. Dilutional linearity was evaluated for both calibrator spiked normal serum and pooled TBI positive samples using sample diluent, and ranged from 110% to 117% for GFAP and 114% to 125% for UCH-L1. The mean of spike recovery was 90% for both assays. Both intra- and inter-assay coefficients of variation (CV) were demonstrated with less than 10%. These digital ELISAs were able to quantify all of the samples tested. Mean serum levels of both proteins were found to be significantly higher in mTBI patients than in control (p< 0.0001), and were further elevated in severe TBI patients versus controls and mTBI patients (p< 0.0001 for GFAP and p=0.002 for UCH-L1). Analysis of receiver operating characteristic (ROC) curves showed both proteins to be promising biomarkers for diagnosis of mTBI with an area of 0.9733 (0.9401–1.006, 95% CI) for GFAP and 0.8456 (0.7216–0.9695, 95% CI) for UCH-L1. Digital ELISA assays with high sensitivity and accuracy in quantification of both serum GFAP and UCH-L1 provide potential utility in diagnosis of mTBI.
Starch purification after pin milling and air classification of waxy, normal, and high amylose barleys (1995)

Three barley cultivars with low (SB89528), normal (Condor), and high (Glacier) amylose starch contents were pin-milled and air-classified into coarse and fine fractions by two passes at a vane setting (particle-size cut) of 15 μm and a third pass at 30 μm. The coarse fractions from the final pass (C3) had 15-36% starch, 12-15% protein, and 13-24% β-glucan, whereas the fine fractions (F3) had 77-78% starch, 8-9% protein, and 6-8% β-glucan. The shifts in starch, protein, and β-glucan varied among the cultivars. Scanning electron microscopy of the pin-milled barleys and their air-classified fractions showed that the first two air-classifications separated small granule starch into fine I (F1) and fine 2 (F2) fractions ; the large granule starch was separated into coarse 1 (C1 and coarse 2(C2) fractions. The third pass yielded a fine fraction (F3) rich in large granule starch. Further purification of F3 fractions by a wet process yielded almost pure large granule starch with an extraction efficiency ∼30% higher than that obtained by conventional laboratory starch extraction from barley. Furthermore, the process yielded protein and β-glucan as by-products at high levels of purity.