gebhart/patrepeval huggingface dataset:
Risk Factors for Sporadic Cryptosporidiosis among Immunocompetent Persons in the United States from 1999 to 2001 (2004)

Many studies have evaluated the role of Cryptosporidium spp. in outbreaks of enteric illness, but few studies have evaluated sporadic cryptosporidiosis in the United States. To assess the risk factors for sporadic cryptosporidiosis among immunocompetent persons, a matched case-control study was conducted in seven sites of the Foodborne Diseases Active Surveillance Network (FoodNet) involving 282 persons with laboratory-identified cryptosporidiosis and 490 age-matched and geographically matched controls. Risk factors included international travel (odds ratio [OR] = 7.7; 95% confidence interval [95% CI] = 2.7 to 22.0), contact with cattle (OR = 3.5; 95% CI = 1.8 to 6.8), contact with persons >2 to 11 years of age with diarrhea (OR = 3.0; 95% CI = 1.5 to 6.2), and freshwater swimming (OR = 1.9; 95% CI = 1.049 to 3.5). Eating raw vegetables was protective (OR = 0.5; 95% CI = 0.3 to 0.7). This study underscores the need for ongoing public health education to prevent cryptosporidiosis, particularly among travelers, animal handlers, child caregivers, and swimmers, and the need for further assessment of the role of raw vegetables in cryptosporidiosis.
Suppressive effect of Ixodes ricinus salivary gland extract on mechanisms of natural immunity in vitro. (1998)

Tick saliva has been shown to contain a variety of pharmacologically active molecules, including those with immunosuppressive activities. There is increasing evidence that the nonspecific suppression of host immunity by tick saliva is exploited by tick-borne pathogens, e.g. the saliva-activated transmission (SAT) of some tick-borne viruses. We have demonstrated the suppressive effect of the salivary gland extract (SGE) derived from partially fed (five days) Ixodes ricinus females on important mechanisms of innate immunity: natural killer (NK) cells, interferon and nitric oxide production. SGE reduced the interferon induction by polyinosinic-polycytidylic acid (poly I:C) or Escherichia coli lipopolysaccharide (LPS) in a culture of Balb/c mouse splenocytes by 94% and 62%, respectively. SGE suppressed the cytotoxicity of nonstimulated and in vivo poly I:C-stimulated mouse NK cells by up to 31% and 26%, respectively. The induction of NK activity in vitro by LPS but not by Concanavalin-A (Con-A) was also downregulated in the presence of SGE. The addition of SGE to cultures of mouse macrophages partially inhibited the production of nitric oxide, induced by LPS. These data suggest that the facilitating effect of SGE on the transmission of some tick-borne pathogens might be associated with the suppression of the host innate resistance mechanisms, represented by interferon, nitric oxide and NK cells.
Economic and social research council: research seminar series (2003)

"Economic and social research council: Research seminar series." Deafness & Education International, 5(2), pp. 130–131
High Efficiency CRISPR/Cas9-mediated Gene Editing in Primary Human T-cells Using Mutant Adenoviral E4orf6/E1b55k “Helper” Proteins (2016)

Many future therapeutic applications of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 and related RNA-guided nucleases are likely to require their use to promote gene targeting, thus necessitating development of methods that provide for delivery of three components-Cas9, guide RNAs and recombination templates-to primary cells rendered proficient for homology-directed repair. Here, we demonstrate an electroporation/transduction codelivery method that utilizes mRNA to express both Cas9 and mutant adenoviral E4orf6 and E1b55k helper proteins in association with adeno-associated virus (AAV) vectors expressing guide RNAs and recombination templates. By transiently enhancing target cell permissiveness to AAV transduction and gene editing efficiency, this novel approach promotes efficient gene disruption and/or gene targeting at multiple loci in primary human T-cells, illustrating its broad potential for application in translational gene editing.
Ritanserin, A 5-HT2 Receptor Blocker, as Add-on Treatment in Narcolepsy (1991)

In a double-blind placebo-controlled trial, ritanserin (a 5-HT2 receptor blocker) 5 mg/day or placebo was added to the usual medication in 28 patients with narcolepsy during 4 wk. The effect was assessed by means of polysomnography, daily and weekly subjective evaluations, and Multiple sleep latency tests (MSLT). During the night ritanserin increased the amount of nonrapid eye movement slow wave sleep and reduced wakefulness after sleep onset. It improved the feeling of being refreshed in the morning after awakening and reduced subjective daytime sleepiness. The drug did not significantly influence sleep latency in the MSLT.
Anti‐OX40 stimulation in vivo enhances CD8+ memory T cell survival and significantly increases recall responses (2006)

There is growing evidence that engagement of OX40 (CD134), a member of the TNF receptor superfamily, can directly stimulate antigen-specific CD8+ T cells. It has been shown that CD8+ T cells express OX40 following activation, but the response of antigen-specific CD8+ T cells to OX40 stimulation has not been fully characterized. We utilized an antigen-specific transgenic CD8+ T cell model (OT-I) to determine if OX40 engagement can boost the generation of antigen-specific CD8+ T cell memory. Our results demonstrate that enhanced OX40 costimulation, via an agonist anti-OX40 antibody, increases CD25 and phospho-Akt expression on the antigen-specific CD8+ T cells and significantly increases the generation of long-lived antigen-specific CD8+ memory T cells. The increased numbers of memory CD8+ T cells generated via anti-OX40 treatment still required the presence of CD4+ T cells for their long-term maintenance in vivo. In addition, anti-OX40 costimulation greatly enhanced antigen-specific CD8+ T cell recall responses. These data show that OX40 engagement in vivo increases the number of antigen-specific CD8+ memory T cells surviving after antigen challenge and has implications for the development of more potent vaccines against pathogens and cancer.
Phosphoinositide-3 kinase binds to a proline-rich motif in the Na + ,K + -ATPase α subunit and regulates its trafficking (2000)

Endocytosis of Na(+),K(+)-ATPase molecules in response to G protein-coupled receptor stimulation requires activation of class I(A) phosphoinositide-3 kinase (PI3K-I(A)) in a protein kinase C-dependent manner. In this paper, we report that PI3K-I(A), through its p85alpha subunit-SH3 domain, binds to a proline-rich region in the Na(+),K(+)-ATPase catalytic alpha subunit. This interaction is enhanced by protein kinase C-dependent phosphorylation of a serine residue that flanks the proline-rich motif in the Na(+),K(+)-ATPase alpha subunit and results in increased PI3K-I(A) activity, an effect necessary for adaptor protein 2 binding and clathrin recruitment. Thus, Ser-phosphorylation of the Na(+),K(+)-ATPase catalytic subunit serves as an anchor signal for regulating the location of PI3K-I(A) and its activation during Na(+),K(+)-ATPase endocytosis in response to G protein-coupled receptor signals.
Characteristics of long-term survivors in a randomized phase III trial (NAPOLI-1) of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with liposomal irinotecan (nal-IRI; MM-398) + 5-FU/LV. (2017)

293 Background: nal-IRI, a liposomal formulation of irinotecan, plus 5-FU/LV is approved in the United States and Taiwan for patients (pts) with mPDAC previously treated with gemcitabine-based therapy. Primary analysis of the NAPOLI-1 trial (NCT01494506) showed that nal-IRI+5-FU/LV significantly improved median overall survival vs 5-FU/LV (6.1 vs 4.2 months; HR, 0.67; 95% CI, 0.49-0.92; P = 0.012; Wang-Gillam et al, Lancet. 2016). Herein we report baseline characteristics of pts surviving ≥1 year (data cutoff, Nov 2015). Methods: This analysis includes 117 pts assigned to treatment with nal-IRI 70 mg/m 2 (free base) + 5-FU/LV 2400/400 mg/m 2 q2w, and 119 pts assigned to treatment with 5-FU/LV 2000/200 mg/m 2 weekly for weeks 1-4 q6w. Results: A total of 29 (25%) pts in the nal-IRI+5-FU/LV arm and 17 (14%) in the 5-FU/LV arm survived ≥1 year. These pts typically had better performance status, lower CA19-9 (U/mL) levels, and were less likely to have liver metastases at baseline, compared with the overall population (Table). For long-term survivors in the nal-IRI+5-FU/LV arm, a higher proportion of pts had neutrophil-to-lymphocyte ratio (NLR) &gt;5, a marker of poor prognosis, suggesting that higher NLR may potentially be predictive of survival outcome with nal-IRI+5-FU/LV. Conclusions: More pts receiving nal-IRI+5-FU/LV versus 5-FU/LV were alive beyond 1 year. The most prominent prognostic markers of survival ≥1 year included lower CA19-9, KPS ≥90 and absence of liver metastases. These analyses may be limited by small sample sizes. Clinical trial information: NCT01494506. [Table: see text]
Genetically‐defined ovarian cancer mouse models (2015)

Epithelial ovarian cancer (EOC), the deadliest of gynaecological cancers, is a disease that remains difficult to detect early and treat efficiently. A significant challenge for researchers in the field is that the aetiology of EOC and the molecular pathways important for its development are poorly understood. Moreover, precursor lesions have not been readily identifiable, making the mechanisms of EOC progression difficult to delineate. In order to address these issues, several genetically-defined ovarian mouse models have been generated in the past 15 years. However, because of the recent suggestion that most EOCs may not originate from the ovarian surface 'epithelium', but from other tissues of the female genital tract, some models may need to be re-evaluated within this new paradigm. In this review, we examine several genetically-defined EOC models and discuss how the new paradigm may explain some of the features of these models. A better understanding of the strengths and limitations of the current EOC mouse models will undoubtedly allow us to utilize these tools to better understand the biology of the disease and develop new approaches for EOC prevention, detection, and treatment.
Activation of the ERK1/2 and p38 Mitogen-activated Protein Kinase Pathways Mediates Fibroblast Growth Factor-induced Growth Arrest of Chondrocytes (2004)

Fibroblast growth factors (FGFs) regulate long bone development by affecting the proliferation and differentiation of chondrocytes. FGF treatment inhibits the proliferation of chondrocytes both in vitro and in vivo, but the signaling pathways involved have not been clearly identified. In this report we show that both the MEK-ERK1/2 and p38 MAPK pathways, but not phospholipase C gamma or phosphatidylinositol 3-kinase, play a role in FGF-mediated growth arrest of chondrocytes. Chemical inhibitors of the MEK1/2 or the p38 MAPK pathways applied to rat chondrosarcoma (RCS) chondrocytes significantly prevented FGF-induced growth arrest. The retinoblastoma family members p107 and p130 were previously shown to be essential effectors of FGF-induced growth arrest in chondrocytes. The dephosphorylation of p107, one of the earliest events in RCS growth arrest, was significantly blocked by MEK1/2 inhibitors but not by the p38 MAPK inhibitors, whereas that of p130, which occurs later, was partially prevented both by the MEK and p38 inhibitors. Furthermore, by expressing the nerve growth factor (NGF) receptor, TrkA, and the epidermal growth factor (EGF) receptor, ErbB1, in RCS cells we show that NGF treatment of the transfected cells caused growth inhibition, whereas EGF did not. FGF- and NGF-induced growth inhibition is accompanied by a strong and sustained activation of ERK1/2 and p38 MAPK and a decrease of AKT phosphorylation, whereas EGF induces a much more transient activation of p38 and ERK1/2 and increases AKT phosphorylation. These results indicate that inhibition of chondrocyte proliferation by FGF requires both ERK1/2 and p38 MAPK signaling and also suggest that sustained activation of these pathways is required to achieve growth inhibition.
Discovery and Development of Veterinary Antiparasitic Drugs: Past, Present and Future (2011)

Despite investment in programs to manage the development of resistance to existing agents, this continues to drive the need for discovery of novel antiparasitic agents for veterinary medicine. Historically, antiparasitic drug discovery was driven by empirical screening, but technological advances have lead to an increased focus on mechanism-based approaches to drug discovery and this is projected to increase as our capabilities advance to improve both the throughput of assays and the quality of data generated. Investment in the development of combination products with novel agents is increasing and, despite regulatory hurdles in some regions, efforts to globally harmonize regulations will aid in delivering safe, efficacious drugs to help in resistance management and integrated parasite control programs.
Kinase domain of the muscle-specific receptor tyrosine kinase (MuSK) is sufficient for phosphorylation but not clustering of acetylcholine receptors: Required role for the MuSK ectodomain? (1997)

Formation of the neuromuscular junction (NMJ) depends upon a nerve-derived protein, agrin, acting by means of a muscle-specific receptor tyrosine kinase, MuSK, as well as a required accessory receptor protein known as MASC. We report that MuSK does not merely play a structural role by demonstrating that MuSK kinase activity is required for inducing acetylcholine receptor (AChR) clustering. We also show that MuSK is necessary, and that MuSK kinase domain activation is sufficient, to mediate a key early event in NMJ formation-phosphorylation of the AChR. However, MuSK kinase domain activation and the resulting AChR phosphorylation are not sufficient for AChR clustering; thus we show that the MuSK ectodomain is also required. These results indicate that AChR phosphorylation is not the sole trigger of the clustering process. Moreover, our results suggest that, unlike the ectodomain of all other receptor tyrosine kinases, the MuSK ectodomain plays a required role in addition to simply mediating ligand binding and receptor dimerization, perhaps by helping to recruit NMJ components to a MuSK-based scaffold.
Intracerebral Clysis in a Rat Glioma Model (2000)

The C6 glioma model can be easily modified to study aspects of interstitial delivery via ICC and the application of ICC to the screening of potential antitumor agents for safety and efficacy.
Targeting the MAPK–RAS–RAF signaling pathway in cancer therapy (2012)

Inhibitors of MEK and particularly of RAF kinases have shown effectiveness in clinical trials with manageable side effects. RAS and BRAF genes need to be analyzed for mutations as markers of response to treatments and to avoid paradoxical effects. Further characterization of the RAS-MAPK molecular mechanisms regulation in malignant cells or underlying the acquired resistance to RAF inhibitors will facilitate development of novel combination therapies.
Characteristics of Patients With Type 2 Diabetes in Mexico (2003)

Diabetes affects a large proportion of Mexican adults (8.18%). This figure may be underestimated. The majority of the subjects had modifiable risk factors for the chronic complications of diabetes. Only a few achieved adequate blood pressure control and other treatment goals.
Buprenorphine Pharmacokinetics: Relative Bioavailability of Sublingual Tablet and Liquid Formulations (1999)

Buprenorphine is an effective new treatment for opiate dependence. This study compared the bioavailability of buprenorphine from a tablet to that from a reference solution. Six men experienced with, but not dependent on, opiates (DSM-III-R) were each administered 7.7 mg of buprenorphine in liquid form and 8 mg in tablet form 1 week apart in a balanced crossover design. Plasma levels were measured by electron capture capillary gas chromatography (GC), and concentration-time curves were constructed. Pharmacokinetic data were analyzed by analysis of variance. The bioavailability from the tablet was approximately 50% that from the liquid and was not affected by saliva pH. Lower bioavailability from the tablet may be due to slow dissolution.
Rapid nuclear translocation and increased activity of cyclin-dependent kinase 6 after T cell activation (1997)

To elucidate the roles of cyclin-dependent kinase 6 (cdk6) in T cells, we examined its intracellular localization, kinase activity, and associated proteins in the Jurkat T lymphoblastoid cell line. Jurkat cells had a high level of cdk6, which was associated with cyclin D3, but not cyclin D2, the member of the cyclin D family. When stimulated by a combination of PHA and anti-CD28 mAb, cdk6 activity was up-regulated, as measured by an in vitro kinase assay using recombinant, truncated retinoblastoma tumor suppressor gene protein (Rb protein) as substrate. Activation was most prominent when cells were stimulated with the combination of PHA and anti-CD28, although significant increases were detected after stimulation with PHA alone. The combination also resulted in maximal activation of c-Jun kinase and IL-2 production. Costimulation resulted in a rapid translocation of cdk6 to the nucleus, as demonstrated by both confocal immunofluorescence microscopy and biochemical fractionation techniques. Cdk6 activation and nuclear translocation were also observed after stimulation of Jurkat cells using the anti-CD28 Ab in combination with a mAb to CD3 (OKT3). Furthermore, nuclear translocation was observed in normal human T lymphocytes isolated from peripheral blood and stimulated in vitro with PHA. Two potential endogenous cdk6 substrates (with apparent molecular masses of 75-80 and 55-60 kDa), which were immunoprecipitated with cdk6 and phosphorylated in the in vitro kinase assay, were also identified. These data demonstrate the rapid activation and intracellular translocation of cdk6, implicating this kinase in early signal transduction events in T cells.
Problems on Self-similar Sets and Self-affine Sets: An Update (2000)

Self-similar sets that satisfy a certain separation condition (the open set condition) are quite well understood. However, self-similar sets with “overlap”, and self-affine sets (with or without overlap) still retain many mysteries. We list a few of these unsolved problems, and give references for the relevant background.
AMP-activated protein kinase, a metabolic master switch: possible roles in Type 2 diabetes (1999)

Adenosine 5'-monophosphate-activated protein kinase (AMPK) now appears to be a metabolic master switch, phosphorylating key target proteins that control flux through metabolic pathways of hepatic ketogenesis, cholesterol synthesis, lipogenesis, and triglyceride synthesis, adipocyte lipolysis, and skeletal muscle fatty acid oxidation. Recent evidence also implicates AMPK as being responsible for mediating the stimulation of glucose uptake induced by muscle contraction. In addition, the secretion of insulin by insulin secreting (INS-1) cells in culture is modulated by AMPK activation. The net effect of AMPK activation is stimulation of hepatic fatty acid oxidation and ketogenesis, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipolysis and lipogenesis, stimulation of skeletal muscle fatty acid oxidation and muscle glucose uptake, and modulation of insulin secretion by pancreatic beta-cells. In skeletal muscle, AMPK is activated by contraction. Type 2 diabetes mellitus is likely to be a disease of numerous etiologies. However, defects or disuse (due to a sedentary lifestyle) of the AMPK signaling system would be predicted to result in many of the metabolic perturbations observed in Type 2 diabetes mellitus. Increased recruitment of the AMPK signaling system, either by exercise or pharmaceutical activators, may be effective in correcting insulin resistance in patients with forms of impaired glucose tolerance and Type 2 diabetes resulting from defects in the insulin signaling cascade.
Advanced Amperometric Respiration Assay for Antimicrobial Susceptibility Testing (2014)

A ferricyanide-based electrochemical cell respiration assay was adapted for use in broad-spectrum antimicrobial susceptibility testing (AST). Total bacterial respiration was converted into faradaic current by electro-oxidation of ferrocyanide, produced when ferricyanide is reduced by bacterial electron-transport. For Escherichia coli (E. coli), the signal was linear with 5-13 × 10(8) colony-forming units in measuring buffer. For AST, test cells were treated with drugs before ferricyanide addition; cell counts from the amperometric assay provided a measure of drug-induced cell death. Initial trials with six antimicrobial agents produced incorrect susceptibility classifications for drugs that were electroactive at the potential used to detect ferrocyanide or which affected cellular respiration rates. We therefore changed the procedure from drug-treatment and assay in the same buffer to sequential drug exposure in treatment buffer, centrifugal separation of surviving cells, cell resuspension, incubation in the presence of ferricyanide and finally ferrocyanide amperometry in drug-free buffer. Data analysis with E. coli led to an activity classification that agreed with cell culture-based ASTs, obtained by a quicker, more convenient procedure. The potential of this approach was confirmed by trials with the highly virulent bacterium Burkholderia pseudomallei, a particularly antimicrobial-resistant pathogen that is the cause of lethal melioidosis in tropical climates and is currently of concern as a potential bioterrorism agent.
Cyclin D1 Expression Is Regulated Positively by the p42/p44 and Negatively by the p38/HOG Pathway (1996)

We have previously shown that the persistent activation of p42/p44(MAPK) is required to pass the G1 restriction point in fibroblasts (Pagès, G., Lenormand, P., L'Allemain, G., Chambard, J. C., Meloche, S., and Pouysségur, J. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 8319-8323) and postulated that MAPKs control the activation of G1 cyclin-dependent complexes. We examined the mitogen-dependent induction of cyclin D1 expression, one of the earliest cell cycle-related events to occur during the G0/G1 to S-phase transition, as a potential target of MAPK regulation. Effects exerted either by the p42/p44(MAPK) or the p38/HOGMAPK cascade on the regulation of cyclin D1 promoter activity or cyclin D1 expression were compared in CCL39 cells, using a co-transfection procedure. We found that inhibition of the p42/p44(MAPK) signaling by expression of dominant-negative forms of either mitogen-activated protein kinase kinase 1 (MKK1) or p44(MAPK), or by expression of the MAP kinase phosphatase, MKP-1, strongly inhibited expression of a reporter gene driven by the human cyclin D1 promoter as well as the endogenous cyclin D1 protein. Conversely, activation of this signaling pathway by expression of a constitutively active MKK1 mutant dramatically increased cyclin D1 promoter activity and cyclin D1 protein expression, in a growth factor-independent manner. Moreover, the use of a CCL39-derived cell line that stably expresses an inducible chimera of the estrogen receptor fused to a constitutively active Raf-1 mutant (DeltaRaf-1:ER) revealed that in absence of growth factors, activation of the Raf > MKK1 > p42/p44MAPK cascade is sufficient to fully induce cyclin D1. In marked contrast, the p38(MAPK) cascade showed an opposite effect on the regulation of cyclin D1 expression. In cells co-expressing high levels of the p38(MAPK) kinase (MKK3) together with the p38(MAPK), a significant inhibition of mitogen-induced cyclin D1 expression was observed. Furthermore, inhibition of p38(MAPK) activity with the specific inhibitor, SB203580, enhanced cyclin D1 transcription and protein level. Altogether, these results support the notion that MAPK cascades drive specific cell cycle responses to extracellular stimuli, at least in part, through the modulation of cyclin D1 expression and associated cdk activities.