gebhart/patrepeval huggingface dataset:
The role of epithelial Toll-like receptor signaling in the pathogenesis of intestinal inflammation (2007)

Emerging evidence suggests that the innate immune system, comprised of Toll-like receptors (TLRs) and their associated molecules, plays a pivotal role in the regulation of intestinal inflammation and in the response to invading pathogens. Although TLRs are thought to have predominantly beneficial effects in pathogen recognition and bacterial clearance by leukocytes, their dysregulation and unique signaling effects within intestinal epithelia in the setting of inflammation may have devastating consequences. For instance, activation of TLR4 in enterocytes leads to an inhibition of enterocyte migration and proliferation as well as the induction of enterocyte apoptosis-factors that would be expected to promote intestinal injury while inhibiting intestinal repair. TLR signaling has been shown to be abnormal in several intestinal inflammatory diseases, including Crohn's disease, ulcerative colitis, and necrotizing enterocolitis. This review serves to examine the evidence regarding the patterns of expression and signaling of TLRs in the intestinal mucosa at basal levels and during physiologic stressors to gain insights into the pathogenesis of intestinal inflammation. We conclude that the data reviewed suggest that epithelial TLR signaling-acting in concert with TLR signaling by leukocytes-participates in the development of intestinal inflammation. We further conclude that the evidence reviewed provides a rationale for the development of novel, epithelial-specific, TLR-based agents in the management of diseases of intestinal inflammation.
A Rapid and Simple Detection Method for the BRAF T1796A Mutation in Fine-Needle Aspirated Thyroid Carcinoma Cells (2004)

Fine-needle aspiration biopsy (FNAB) samples from thyroid tumor tissues were analyzed for the presence of the BRAF(T1796A) mutation by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) analysis. This assay utilized a specific mismatched primer and has proved to be a relatively simple, accurate, and highly sensitive method. The analysis of 130 aspirated samples from thyroid tumors (18 follicular adenomas, 72 papillary carcinomas [PTCs], 8 follicular carcinomas, 2 undifferentiated carcinomas, 1 medullary carcinoma, 2 malignant lymphomas, and 27 adenomatous goiters) revealed BRAF(T1796A) mutations in 37 (51.4%) of 72 PTCs, supporting the usefulness of this method. We examined BRAF(T1796A) in 21 patients with thyroid tumors using leftover cells in the needle at the preoperative FNAB. BRAF(T1796A) was detected in 4 patients, of which 3 cases were diagnosed as positive and 1 case as suspicious by cytologic examination. Furthermore, BRAF(T1796A) mutations were found to occur more often in tumors of 3 cm or larger in size. Our results indicate that the preoperative determination of the presence of a BRAF(T1796A) mutation by conventional PCR-RFLP may be potentially useful in the diagnosis of the most common thyroid malignancies.
Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018)

Melanoma, a skin cancer associated with high mortality rates, is highly radio- and chemotherapy resistant but can also be very immunogenic. These circumstances have led to a recent surge in research into therapies aiming to boost anti-tumor immune responses in cancer patients. Among these immunotherapies, neutralizing antibodies targeting the immune checkpoints T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are being hailed as particularly successful. These antibodies have resulted in dramatic improvements in disease outcome and are now clinically approved in many countries. However, the majority of advanced stage melanoma patients do not respond or will relapse, and the hunt for the "magic bullet" to treat the disease continues. This review examines the mechanisms of action and the limitations of anti-PD-1/PD-L1 and anti-CTLA-4 antibodies which are the two types of checkpoint inhibitors currently available to patients and further explores the future avenues of their use in melanoma and other cancers.
Phosphorylation and Action of the Immunomodulator FTY720 Inhibits Vascular Endothelial Cell Growth Factor-induced Vascular Permeability (2003)

FTY720, a potent immunosuppressive agent, is phosphorylated in vivo into FTY720-P, a high affinity agonist for sphingosine 1-phosphate (S1P) receptors. The effects of FTY720 on vascular cells, a major target of S1P action, have not been addressed. We now report the metabolic activation of FTY720 by sphingosine kinase-2 and potent activation of vascular endothelial cell functions in vitro and in vivo by phosphorylated FTY720 (FTY720-P). Incubation of endothelial cells with FTY720 resulted in phosphorylation by sphingosine kinase activity and formation of FTY720-P. Sphingosine kinase-2 effectively phosphorylated FTY720 in the human embryonic kidney 293T heterologous expression system. FTY720-P treatment of endothelial cells stimulated extracellular signal-activated kinase and Akt phosphorylation and adherens junction assembly and promoted cell survival. The effects of FTY720-P were inhibited by pertussis toxin, suggesting the requirement for Gi-coupled S1P receptors. Indeed, transmonolayer permeability induced by vascular endothelial cell growth factor was potently reversed by FTY720-P. Furthermore, oral FTY720 administration in mice potently blocked VEGF-induced vascular permeability in vivo. These findings suggest that FTY720 or its analogs may find utility in the therapeutic regulation of vascular permeability, an important process in angiogenesis, inflammation, and pathological conditions such as sepsis, hypoxia, and solid tumor growth.
Effect of Temperature on the Production of Human Fibroblast Interferon (1982)

The effect of temperature upon interferon production in human fibroblasts was examined. Kinetic studies showed that exposing the cells to 37° for one hour before lowering the temperature to 30° resulted in a more prolonged period of production in comparison to cultures maintained at either 37° or 30°. These data suggest that a temperature-dependent event early in the production phase is responsible for the increased rates of synthesis in the later stages of production. The addition of cycloheximide (10 μg/ml) to the culture medium during the 37° period did not shorten the production period indicating that the extended period of production does not depend upon protein synthesis. In view of the improved yields observed, these studies may have applications to large-scale interferon production.
Functional Consequences of Interactions between FAK and Epithelial Membrane Protein 2 (EMP2) (2009)

The EMP2-FAK association represents a novel protein-protein interaction, not previously reported, that demonstrates significant functional cellular responses in the context of in vitro models of proliferative vitreoretinopathy (PVR).
Theoretical and Experimental Studies of Bending of Inorganic Electronic Materials on Plastic Substrates (2008)

Abstract This paper describes materials and mechanics aspects of bending in systems consisting of ribbons and bars of single crystalline silicon supported by sheets of plastic. The combined experimental and theoretical results provide an understanding for the essential behaviors and for mechanisms associated with layouts that achieve maximum bendability. Examples of highly bendable silicon devices on plastic illustrate some of these concepts. Although the studies presented here focus on ribbons and bars of silicon, the same basic considerations apply to other implementations of inorganic materials on plastic substrates, ranging from amorphous or polycrystalline thin films, to collections of nanowires and nanoparticles. The contents are, as a result, relevant to the growing community of researchers interested in the use of inorganic materials in flexible electronics.
The Tubal Fimbria Is a Preferred Site for Early Adenocarcinoma in Women With Familial Ovarian Cancer Syndrome (2006)

A proportion of adenocarcinomas in prophylactic adnexectomies (bilateral salpingo-oophorectomies [BSOs]) from women with BRCA mutations (BRCA positive) occur in the fallopian tube. We analyzed a consecutive series of BSOs from BRCA-positive women following an index case of fimbrial serous carcinoma. To determine if the fimbria is a preferred site of origin, we followed a protocol for Sectioning and Extensively Examining the FIMbria (SEE-FIM). Immunostaining for p53 and Ki-67 was also performed. Thirteen BRCA-positive women (cases) and 13 women undergoing BSOs for other disorders (controls) were studied. Tubal carcinoma was detected in 4 cases at the initial histologic evaluation and in no controls. A fifth carcinoma was discovered following further sectioning of the fimbriae. Three were BRCA2 positive and two BRCA1 positive. Three were in the fimbria, one in both the fimbria and proximal tube, and one involved the ampulla. Four were serous carcinomas, four were confined to the tube, and three were noninvasive (intraepithelial). No ovarian carcinomas were identified. All tumors were Ki-67 positive (>75% of cell nuclei), and excluding one endometrioid carcinoma, p53 positive (>75% cell nuclei); p53 positivity in the absence of elevated Ki-67 did not correlate with morphologic neoplasia. The fimbria was the most common location for early serous carcinoma in this series of BRCA-positive women. Protocols that extensively examine the fimbria (SEE-FIM) will maximize the detection of early tubal epithelial carcinoma in patients at risk for ovarian cancer. Investigative strategies targeting the fimbriated end of the fallopian tube should further define its role in the pathogenesis of familial and sporadic ovarian serous carcinomas.
Prognostic factors in primary breast cancer. (1986)

A review and update of published studies on oestrogen receptor and progesterone receptor as prognostic factors in breast cancer supports the following conclusions. In stage I breast cancer the lack of oestrogen receptor seems to be the most important factor for predicting earlier recurrence and poorer survival. In stage II breast cancer, measurement of progesterone receptor appears to be better than measurement of oestrogen receptor for predicting disease-free survival, and is as important as the oestrogen receptor in predicting overall survival. The benefits of adjuvant endocrine therapy are better predicted by the presence or absence of progesterone receptor rather than by oestrogen receptor. Measurement of proliferative activity (DNA S-phase) by thymidine labelling or flow cytometry, and of aneuploidy by flow cytometry, also provides prognostic information. The strong correlations between tumour receptor content, per cent S-phase and aneuploidy suggest that these measurements in concert might identify a subset of stage I breast cancer patients at increased risk for recurrence, who would thus be potential candidates for adjuvant therapy.
The Heterogeneity of Human Chorionic Gonadotropin (hCG). II. Characteristics and Origins of Nicks in hCG Reference Standards* (1991)

hCG, the hormone produced by the trophoblast throughout pregnancy, has peptide bond cleavages, or nicks, in the beta-subunit. We sought to compare the nature of these nicks in standard reference preparations of hCG, to determine the enzymes that may be responsible for generating the peptide bond cleavages, and to devise means of separating nicked from intact hormone. The standard reference preparations of hCG, which are purified from a commercial product made from large pools of pregnancy urine, were found to have varying concentrations of nicked hormone. The preceding report showed that 11 of 13 hCG preparations isolated from individual pregnancy urine samples were nicked at the beta 47-48 bond, with 2 of 13 having a second nick at beta 44-45. As shown here, all of the hCG reference standards are nicked to similar extents at both the beta 47-48 bond and the beta 44-45 bond. The percentage of peptide bond nicking in the various hCG standard preparations ranged from 10-20% and appeared higher in the more recent preparations. We showed that human leukocyte elastase is capable of specifically cleaving the beta 44-45 bond, and in extended digests it can also cleave the beta 48-49 and beta 51-52 peptide bonds. Thus, human leukocyte elastase may be the origin of some of these cleavages in the individual samples and the reference standards. Furthermore, we report that a monoclonal antibody directed to hCG alpha-beta dimer binds preferentially to nonnicked hCG and much less to nicked hCG.
Purification of Na+,K+-ATPase Expressed in Pichia pastoris Reveals an Essential Role of Phospholipid-Protein Interactions (2005)

Na+,K+-ATPase (porcine alpha/his10-beta) has been expressed in Pichia Pastoris, solubilized in n-dodecyl-beta-maltoside and purified to 70-80% purity by nickel-nitrilotriacetic acid chromatography combined with size exclusion chromatography. The recombinant protein is inactive if the purification is done without added phospholipids. The neutral phospholipid, dioleoylphosphatidylcholine, preserves Na+,K+-ATPase activity of protein prepared in a Na+-containing medium, but activity is lost in a K+-containing medium. By contrast, the acid phospholipid, dioleoylphosphatidylserine, preserves activity in either Na+- or K+-containing media. In optimal conditions activity is preserved for about 2 weeks at 0 degrees C. Both recombinant Na+,K+-ATPase and native pig kidney Na+,K+-ATPase, dissolved in n-dodecyl-beta-maltoside, appear to be mainly stable monomers (alpha/beta) as judged by size exclusion chromatography and sedimentation velocity. Na+,K+-ATPase activities at 37 degrees C of the size exclusion chromatography-purified recombinant and renal Na+,K+-ATPase are comparable but are lower than that of membrane-bound renal Na+,K+-ATPase. The beta subunit is expressed in Pichia Pastoris as two lightly glycosylated polypeptides and is quantitatively deglycosylated by endoglycosidase-H at 0 degrees C, to a single polypeptide. Deglycosylation inactivates Na+,K+-ATPase prepared with dioleoylphosphatidylcholine, whereas dioleoylphosphatidylserine protects after deglycosylation, and Na+,K+-ATPase activity is preserved. This work demonstrates an essential role of phospholipid interactions with Na+,K+-ATPase, including a direct interaction of dioleoylphosphatidylserine, and possibly another interaction of either the neutral or acid phospholipid. Additional lipid effects are likely. A role for the beta subunit in stabilizing conformations of Na+,K+-ATPase (or H+,K+-ATPase) with occluded K+ ions can also be inferred. Purified recombinant Na+,K+-ATPase could become an important experimental tool for various purposes, including, hopefully, structural work.
Oral budesonide therapy for steroid‐dependent ulcerative colitis: a pilot trial (1997)

In patients with c-GCS-dependent ulcerative colitis, a dose of 9 mg budesonide daily in an oral pH-modified-release formulation was well tolerated, significantly decreased the CAI, and rendered c-GCS unnecessary in the majority of cases.
Convergence analysis of canonical genetic algorithms (1994)

This paper analyzes the convergence properties of the canonical genetic algorithm (CGA) with mutation, crossover and proportional reproduction applied to static optimization problems. It is proved by means of homogeneous finite Markov chain analysis that a CGA will never converge to the global optimum regardless of the initialization, crossover, operator and objective function. But variants of CGA's that always maintain the best solution in the population, either before or after selection, are shown to converge to the global optimum due to the irreducibility property of the underlying original nonconvergent CGA. These results are discussed with respect to the schema theorem.
Randomized Clinical Trial Comparing OASIS Wound Matrix to Regranex Gel for Diabetic Ulcers (2005)

Although the sample size was not large enough to demonstrate that the incidence of healing in the OASIS group was statistically superior (P = .055), the study results showed that treatment with OASIS is as effective as Regranex in healing full-thickness diabetic foot ulcers by 12 weeks.
Chemical signatures and new drug targets for gametocytocidal drug development (2014)

Control of parasite transmission is critical for the eradication of malaria. However, most antimalarial drugs are not active against P. falciparum gametocytes, responsible for the spread of malaria. Consequently, patients can remain infectious for weeks after the clearance of asexual parasites and clinical symptoms. Here we report the identification of 27 potent gametocytocidal compounds (IC50 < 1 μM) from screening 5,215 known drugs and compounds. All these compounds were active against three strains of gametocytes with different drug sensitivities and geographical origins, 3D7, HB3 and Dd2. Cheminformatic analysis revealed chemical signatures for P. falciparum sexual and asexual stages indicative of druggability and suggesting potential targets. Torin 2, a top lead compound (IC50 = 8 nM against gametocytes in vitro), completely blocked oocyst formation in a mouse model of transmission. These results provide critical new leads and potential targets to expand the repertoire of malaria transmission-blocking reagents.
Autonomous Refresh of Floating-Body Cell due to Current Anomaly of Impact Ionization (2009)

Physics of autonomous refresh is presented, which explains the mechanism of a spontaneous recovery of degraded binary states of the floating-body cell (FBC). Input current to the floating body and output current from the body balance to generate an unstable stationary state that is accompanied by two stable stationary ones. The current anomaly of impact ionization is essential for the instability that brings about the bistability and is realized by positive feedback where impact ionization current input increases as the body voltage increases. Experiments with charge pumping current as output show that the autonomous refresh is possible on a single-cell basis. Necessary conditions for a high-density memory to be autonomously refreshed are derived and assessed for state-of-the-art FBCs. FBC is shown in simulation to become an SRAM cell when the autonomous refresh is applied, which uses gate direct tunneling current as output. This is an SRAM cell that is theoretically expected to have the simplest structure ever reported.
A systematic review of the clinical, public health and cost-effectiveness of rapid diagnostic tests for the detection and identification of bacterial intestinal pathogens in faeces and food (2007)

Despite the relatively poor quality of reporting of studies evaluating rapid detection methods, the reviewed evidence shows that PCR for Campylobacter, Salmonella and E. coli O157 is potentially very successful in identifying pathogens, possibly detecting more than the number currently reported using culture. Less is known about the benefits of testing for B. cereus, C. perfringens and S. aureus. Further investigation is needed on how clinical outcomes may be altered if test results are available more quickly and at a greater precision than in the current practice of bacterial culture.
Untersuchungen zum circadianen Sekretionszyklus der neurosekretorischen Kerngebiete der Maus* (1975)

Abstract Investigations on the circadian cycle of secretion in the neurosecretory nuclei of mouse. The circadian cycle of secretion of both hypothalamic neurosecretory nuclei N. supraopticus and N. paraventricularis in mice was studied by histological, histochemical, biochemical and electron‐microscopical methods. Both areas undergo a circadian secretion cycle (24 h‐rhytm). The activity of metabolism increases at the beginning of night, whereas by day the cells are considered to be in a phase of restitution and transportation of the secretion. Especially increases the volume of the cell nuclei (synthesis of RNA and proteins) and the activity of the extralysosomal unspecific esterase rises to maximal values. From midnight till the beginning of the light‐phase the cells show a maximal volume of the nuclei and an increased secretion as well as higher activity of acid phosphatase and lactate dehydrogenase. Unspecific esterase activity, on the other hand, diminished. There was a noticable increase in the quantity of neurosecretion in both areas, it reached a maximum at the beginning of the light‐phase, whereas the volume of the nuclei and the activity of acid phosphatase and thiamine pyrophosphatase diminished. The neurosecretion is more and more transported to the hypophysis. The cells restitute during the light‐phase and reach their starting level.
Pharmacokinetics and body distribution of amiodarone and desethylamiodarone in rats after intravenous administration. (1992)

The pharmacokinetics and body distribution of amiodarone and desethylamiodarone were studied in rats after single oral administration of 100 mg/kg and 200 mg/kg of amiodarone. The time-course of the concentrations of the drug and its main metabolite was determined by high performance liquid chromatography in serum and tissues up to 24 h. The mean absorption half-life of amiodarone was 1.83 h for both dosages and the mean elimination half-life was 15 h after the 100 mg/kg dosage and 105 h after the 200 mg/kg dosage. The mean bioavailability of oral amiodarone ranged from 17% to 60% with an average of 39%. Desethylamiodarone, the major metabolite of amiodarone, was present over the 24 h period of observation in relatively low levels of 30 to 60 ng/ml after the 100 mg/kg dose and 50 to 110 ng/ml after the 200 mg/kg dose respectively, which is circa 4% and 7% of the corresponding parent drug level. Amiodarone is preferentially distributed in decreasing order in lung, liver, thyroid gland, kidney, heart, adipose tissue, muscle tissue and brain. The metabolite desethylamiodarone exhibited a distribution pattern comparable to the parent drug. However, its maximum concentrations in serum and tissues were consistently lower than the corresponding amiodarone concentrations and varied from 18 to 55% (mean 27%), depending on the acute oral dose applied and on the kind of tissue. The amiodarone tissue/serum concentration ratios were high in lung tissue (60-100) and moderate to high in the other tissues except brain (3-60), and indicate an extensive distribution of the drug with the lung as an organ with specific binding sites or uptake mechanisms and adipose tissue as a reservoir with a large storage capacity. The metabolite tissue/serum concentration ratios were very high in lung tissue (500-800), high in renal, thyroid, liver and adipose tissue (80-200) and moderate in the other tissues except for brain (20-60); they indicate a very extensive distribution of desethylamiodarone with, primarily, lung and to some lesser extent kidney, liver and thyroid gland as organs with sites of metabolism and/or specific binding sites or uptake mechanisms and fat as a reservoir for the drug. A marked increase in the accumulation of amiodarone and desethylamiodarone was observed in adipose tissue after chronic oral administration, whereas the rise in kidney and brain was less pronounced and in the remaining tissues it was insignificant. Our data suggest that the rat is a good model for describing the single oral dose pharmacokinetics and body distribution of amiodarone and desethylamiodarone in man.