gebhart/patrepeval huggingface dataset:
The influence of 'diastolic' length on the contractility of isolated cat papillary muscle. (1985)

Isometrically contracting cat papillary muscles were studied. Muscle length was changed during diastole and returned to control just before the next contraction such that developed force was always measured at the same length. When the diastolic length was increased from a control length, systolic force at the control length increased slowly over several minutes. When the muscle was then held at the increased length, there was an immediate increase in systolic force followed by a small secondary slow increase. Conversely, a decrease in diastolic length from a control length resulted in a slow decrease in systolic force at the control length. When the muscle was then held at the decreased length there was an immediate decrease in systolic force followed by a small secondary decrease. No change in the time course of contraction accompanied the slow force changes after a maintained change of length or a change of diastolic length alone. The magnitude of the slow change of force was proportional to the duration of time in each diastole for which the length was altered and independent of the onset time of a given duration of diastolic length change. The contractility changes were not linearly related to the amplitude of the diastolic length changes. The potentiating effect of a given stretch was greater than the depotentiating effect of a similar release. The development of inotropic changes as a result of diastolic length changes occurred whether or not the muscle was stimulated during the period of the length changes.
Genetic Changes That Correlate with Reduced Susceptibility to Daptomycin in Staphylococcus aureus (2006)

Daptomycin is a lipopeptide antibiotic with potent activity against gram-positive bacteria. Complete-genome comparisons of laboratory-derived Staphylococcus aureus with decreased susceptibility to daptomycin and their susceptible parent were used to identify genes that contribute to reduced susceptibility to daptomycin. Selective pressure of growth in sublethal concentrations of daptomycin resulted in the accumulation of mutations over time correlating with incremental decreases in susceptibility. Single point mutations resulting in amino acid substitutions occurred in three distinct proteins: MprF, a lysylphosphatidylglycerol synthetase; YycG, a histidine kinase; and RpoB and RpoC, the beta and beta' subunits of RNA polymerase. Sequence analysis of mprF, yycF, yycG, rpoB, and rpoC in clinical isolates that showed treatment-emergent increases in daptomycin MICs revealed point mutations in mprF and a nucleotide insertion in yycG, suggesting a role for these genes in decreased susceptibility to daptomycin in the hospital setting.
Candida albicans strains heterozygous and homozygous for mutations in mitogen-activated protein kinase signaling components have defects in hyphal development (1996)

The Candida albicans genes, CST20 and HST7, were cloned by their ability to suppress the mating defects of Saccharomyces cerevisiae mutants in the ste20 and ste7 genes, which code for elements of the mating mitogenactivated protein (MAP) kinase pathway. These Candida genes are both structural and functional homologs of the cognate Saccharomyces genes. The pattern of suppression in Saccharomyces is related to their presumptive position in the MAP kinase cascade. Null alleles of these genes were constructed in Candida. The Candida homozygous null mutants are defective in hyphal formation on some media, but are still induced to form hyphae by serum, showing that serum induction of hyphae is independent of the MAP kinase cascade. The Candida heterozygotes CST20/cst20 and HST7/hst7 are also defective in hyphal formation. This lack of dominance of the wild-type allele suggests that gene dosage is important in Candida.
Heterogenous Nature of Flow-Mediated Dilatation in Human Conduit Arteries In Vivo (2001)

Flow-mediated dilatation (FMD) of conduit arteries is dependent on an intact endothelium, although the mechanisms are not fully understood. Using high-resolution ultrasound, we examined the role of endothelial mediators in radial artery dilatation in response to transient (short period of reactive hyperemia) and sustained (prolonged period of reactive hyperemia, hand warming, or an incremental infusion of acetylcholine into the distal radial artery) hyperemia. After short episodes of reactive hyperemia, FMD was abolished by local infusion of the nitric oxide synthesis inhibitor N:(G)monomethyl-L-arginine (5.3+/-1.2% versus 0.7+/-0.7%, P:<0.001). In contrast, basal vessel diameter and dilatation after prolonged episodes of reactive hyperemia, hand warming, and distal infusion of acetylcholine were not attenuated by nitric oxide synthesis inhibition. Inhibition of cyclooxygenase or local autonomic nervous system blockade also had no effect on FMD. Patients with hypercholesterolemia exhibited reduced FMD in response to transient hyperemia, but the response to sustained hyperemia was normal. These data suggest heterogeneity of endothelial responses to blood flow that are dependent on the characteristics of the flow stimulus. Dilatation after brief episodes of hyperemia is mediated by release of nitric oxide, whereas dilatation during sustained hyperemia is unaffected by NO synthesis inhibition. Hypercholesterolemia seems to differentially affect these pathways with impairment of the nitric oxide-dependent pathway and preservation of non nitric oxide-mediated dilatation to sustained flow stimuli.
Human Primary CD4 + T Cells Activated in the Presence of IFN- α 2b Express Functional Indoleamine 2,3-Dioxygenase (2001)

Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting enzyme in the catabolism of tryptophan. By creating a local microenvironment in which levels of tryptophan are low, IDO-expressing antigen-presenting cells (APC) could regulate T cell activation. This may be relevant to control both viral and bacterial replication as well as neoplastic cell growth. Interferon-alpha (IFN-alpha) is an antiviral cytokine affecting cellular differentiation. In addition, it reduces proliferation of CD4(+) T cells by several molecular mechanisms. To dissect the molecular steps responsible for the INF-mediated antiproliferative activity, we sought to determine whether activated primary CD4(+) T cells in the presence of IFN-alpha would produce IDO. We demonstrate here that IDO mRNA is not present in resting CD4(+) T cells. Stimulation with anti-CD3 plus interleukin-2 (IL-2) induces expression of IDO mRNA (about 2000 copies/150,000 cells), as determined by semiquantitative RT-PCR. When cells were stimulated in the presence of IFN-alpha, expression of IDO mRNA was significantly increased (more than 12,000 copies/150,000 cells). Functional analysis of IDO activity paralleled the results obtained with RT-PCR, demonstrating increased production of active enzyme in CD4(+) T cells stimulated in the presence of IFN-alpha. Our results indicate that IFN-alpha modulates levels of IDO produced by activated CD4(+) T cells. This would likely affect bystander cells by modifying levels of tryptophan in the local microenvironment.
Overexpression of protein kinase C-α in the epidermis of transgenic mice results in striking alterations in phorbol ester-induced inflammation and COX-2, MIP-2 and TNF-α expression but not tumor promotion (1999)

Protein kinase Calpha (PKCalpha) is one of six PKC isoforms expressed in keratinocytes of mouse epidermis. To gain an understanding of the role of epidermal PKCalpha, we have localized its expression to specific cells of normal mouse skin and examined the effect of keratin 5 (K5) promoter directed expression of PKCalpha in transgenic mice. In normal mouse skin, PKCalpha was extensively expressed in the outer root sheath (ORS) keratinocytes of the anagen hair follicle and weakly expressed in keratinocytes of interfollicular epidermis. K5-targeted expression of PKCalpha to epidermal basal keratinocytes and follicular ORS keratinocytes resulted in a tenfold increase in epidermal PKCalpha. K5-PKCalpha mice exhibited no abnormalities in keratinocyte growth and differentiation in the epidermis. However, a single topical treatment with the PKC activator, 12-O-tetradecanoylphorbol-13-acetate (TPA) resulted in a striking inflammatory response characterized by edema and extensive epidermal infiltration of neutrophils that formed intraepidermal microabscesses in the epidermis. Compared to TPA-treated wild-type mice, the epidermis of TPA-treated K5-PKCalpha mice displayed increased expression of cyclooxygenase-2 (COX-2), the neutrophil chemotactic factor macrophage inflammatory protein-2 (MIP-2) mRNA and the proinflammatory cytokine TNFalpha mRNA but not IL-6 or IL-1alpha mRNA. To determine if K5-PKCalpha mice display an altered response to TPA-promotion, 7, 12-dimethylbenz[a]anthracene-initiated K5-PKCalpha mice and wild-type mice were promoted with TPA. No differences in papilloma incidence or multiplicity were observed between K5-PKCalpha mice and wild-type littermates. These results demonstrate that the overexpression of PKCalpha in epidermis increases the expression of specific proinflammatory mediators and induces cutaneous inflammation but has little to no effect on epidermal differentiation, proliferation or TPA tumor promotion.
Vasopressin in pediatric vasodilatory shock: a multicentred randomized controlled trial (2009)

Vasopressin has been suggested as a useful vaso-active agent in the support of vasodilatory shock in adults; however, its effect in children is unclear. We hypothesized that low-dose vasopressin in this population, administered as an adjunctive vasoactive agent, would lead to more rapid reversal of vasodilatory shock when compared with placebo.
Phage Library-derived Human Anti-TETA and Anti-DOTA ScFv for Pretargeting RIT (1999)

Pretargeting techniques have promise for radioimmunotherapy (RIT) in cancer because of the potential for markedly increasing the therapeutic ratio. Human antibody fragments can be retrieved from phage libraries and used to realize this potential. The library can be used to select the genetic material required to generate molecules with binding sites for both radiochelates and tumor antigens. In this study, human anti-chelate scFvs (single-chain fragments) for two metal chelates (Cu-TETA and Y-DOTA) were selected from a large, naive human scFv library. These anti-chelate scFvs were intended to serve as one arm of bispecific pretargeting molecules and to bind radiochelates given subsequently as Cu-67-TETA or Y-90-DOTA. Phage that displayed the anti-chelate scFv were selected by absorption to antibody (Lym-1) bound Cu-TETA or Y-DOTA. Enzyme-linked immunosorbent assays (ELISA) were performed to assess the intensity and specificity of phage binding to the specific chelate. Ninety-six clones demonstrating metal chelate binding seven times greater than to Lym-1 alone were chosen for diversity analysis. BstN I restriction digests were performed on DNA from these clones. Twenty-three and 43 different DNA fingerprint patterns were identified for anti-TETA and anti-DOTA clones, respectively. DNA sequencing of 39 anti-TETA clones for 23 different BstN I fingerprint patterns revealed 22 distinct sequences. Eleven of the anti-TETA clones were selected for further study. Five hundred to 1000 microg (100 to 320 microg per liter of culture) of purified scFv was produced from each of the 11 anti-TETA clones. Preliminary studies by BIAcore demonstrated evidence of 25- to 200-nM affinities. Comparable examination of the anti-DOTA clones is in progress. This study provides evidence that human scFv against unique synthetic targets can be readily selected from a large, naive human immunoglobulin phage library. Selections against metal chelated antibodies provided a wealth of scFvs with diverse binding affinities useful for engineering molecules for pretargeting RIT.
Pretreatment patient factors predicting attrition from a multicenter randomized controlled treatment study for panic disorder (1998)

This study examined pretreatment factors associated with attrition from a clinical trial for panic disorder. The study group consisted of 162 patients who began 11-visit treatments. Six domains (demography, panic disorder severity, psychiatric comorbidity, illness/treatment attributions, coping styles, and personality styles) with 52 variables were used to predict attrition. One hundred twenty-two patients completed and 40 dropped out from treatment. Final multivariate regression analyses showed that the following two variables were independently associated with attrition: lower household income and negative treatment attitudes; attributing the panic disorder to life stressors and greater age were independently associated with attrition at the trend level. Preliminary analyses suggested, in addition, associations between attrition and lower education, shorter length of prior treatment, higher anxiety sensitivity, lower agoraphobic avoidance, and a coping style of seeking social support that were not confirmed by best predictor analysis. Psychiatric comorbidity and personality styles were unrelated to attrition. The implications of these findings for future research and clinical practice are discussed.
Hemolytic properties of lytic peptides active against the sporozoites of Cryptosporidium parvum. (1992)

Cryptosporidium parvum is a protozoan parasite that causes mildto-severe diarrheal disease in animals and humans. There are currently no effective chemotherapeutic agents available for the treatment of cryptosporidiosis. Recently, small, naturally occurring antimicrobial lytic peptides with anti-protozoal activities have been described. In the present study, we compare the in vitro anti-cryptosporidial activities of synthetic lytic peptides and their corresponding hemolytic activities after a 30 min incubation at 37 degrees C. Sporozoite viability was assessed microscopically by the uptake of the vital dyes fluorescein diacetate (FDA) and propidium iodide (PI). Hemolysis was assessed spectrophotometrically by the release of soluble hemoglobulin. The most active peptide, Hecate-1, reduced sporozoite viability by 85.5% with a corresponding hemolytic activity of 21.5% at a concentration of 10 microM.
Localisation of proteins of iron metabolism in the human placenta and liver (2006)

Two anatomical sites that are important in human iron metabolism are the liver and placenta. Liver macrophages recycle iron from erythrocytes, and the placenta transfers iron from the mother to the fetus. The cellular distribution of proteins involved in iron transport in these two sites was studied. Transferrin receptor-1 (TfR1) and Ferroportin (FPN) expression was found on the placental syncytiotrophoblast (STB) and were polarised such that TfR1 was on the apical maternal-facing membrane and FPN was on the basal fetal-facing membrane, consistent with unidirectional iron transport from mother to fetus. Ferritin was strongly expressed in the stroma, suggesting that fetal tissue can store and accumulate iron. HFE was on some parts of the basal STB and, where present, HFE clearly colocalised with FPN but not TfR1. In the stroma, both HFE and FPN were present on CD68+ Hofbauer macrophage cells. In liver, the location of HFE is controversial. Using four mouse monoclonals and two polyclonal sera we showed that the pattern of HFE expression mirrored the distribution of CD68+ macrophage Kupffer cells. FPN was also most strongly expressed by CD68+ Kupffer cells. These findings contribute to understanding how iron is transported and stored in the human placenta and liver.
Analysis of changes in acute‐phase plasma proteins in an acute inflammatory response and in rheumatoid arthritis using two‐dimensional gel electrophoresis (1998)

Two-dimensional (2-D) gel analysis was used to examine differences in the levels of 19 plasma proteins: before and after an acute inflammatory reaction (parenteral typhoid vaccination) in normal subjects, between rheumatoid arthritis (RA) patients and normals and in RA patients treated with tenidap (120 mg) and piroxicam (20 mg). Typhoid vaccination increased levels of SAA, haptoglobin alpha1, haptoglobin alpha2, haptoglobin beta and alpha1-anti-chymotrypsin but decreased transthyretin and apolipoprotein E. In RA patients, serum amyloid A (SAA), haptoglobin alpha2, haptoglobin beta, alpha1-antichymotrypsin and C3 proactivator levels were elevated while apolipoprotein A-I, apolipoprotein A-IV, transthyretin, Gc-globulin, alpha2-HS glycoprotein, alpha2-macroglobulin and alpha1-B glycoprotein levels were decreased, compared to normals. Compared to piroxicam, tenidap lowered levels of alpha1-antiprotease and SAA but raised the levels of transthyretin, Gc-globulin, alpha2-HS-glycoprotein and alpha2-macroglobulin in RA patients. C-reactive protein (CRP) could not be quantified on 2-D gels but, when measured by rate nephelometry, levels were reduced after treatment with tenidap compared to piroxicam. The general pattern of the acute phase protein response to an acute inflammatory response to typhoid vaccination is similar to that in the chronic inflammatory condition, RA. The impact of tenidap on both positive and negative acute-phase proteins in RA patients could clearly be distinguished from that of piroxicam.
Steroids, retinoids, and wound healing. (1998)

Glucocorticoids (corticosteroids) cause dehiscence of surgical incisions, increased risk of wound infection, and delayed healing of open wounds. They produce these effects by interfering with inflammation, fibroblast proliferation, collagen synthesis and degradation, deposition of connective tissue ground substances, angiogenesis, wound contraction, and re-epithelialization. These actions are mediated by the antagonism of various growth factors and cytokines. Vitamin A restores the inflammatory response and promotes epithelialization and the synthesis of collagen and ground substances. However, vitamin A does not reverse the detrimental effects of glucocorticoids on wound contraction and infection. In this paper, the known mechanisms of the interaction of glucocorticoids and retinoids are reviewed. The mutually inhibitory interplay between glucocorticoids and retinoids may serve to regulate the processes of inflammation, immunity, and connective tissue repair.
Yondelis® (trabectedin, ET-743): the development of an anticancer agent of marine origin (2003)

Yondelis (trabectedin, ET-743) is a novel antitumor agent derived from a marine source, the Caribbean tunicate Ecteinascidia turbinata. Preclinical studies demonstrated activity at low concentrations against a variety of tumors. The mechanism by which ET-743 exerts its antitumor activity has not been completely elucidated yet. Binding to the minor groove of DNA which causes a bend towards the major groove has been demonstrated. Furthermore, ET-743 interferes with DNA binding proteins and transcription factors. Clinical studies have been initiated as phase I dose-finding studies at four different treatment regimens. Dose-limiting toxicities were hematological, including neutropenia and thrombocytopenia. Furthermore, significant liver toxicity was observed, especially as a rise in transaminase levels. Antitumor activity in phase I and phase II trials was studied in multiple tumor types, including soft tissue sarcomas, melanomas and breast cancer. ET-743 is currently being extensively investigated in advanced soft tissue sarcomas. The present review describes the development of ET-743, highlighting chemical properties, mode of action, metabolism and preclinical and clinical studies.
T cell chemotaxis to lysophosphatidylcholine through the G2A receptor (2003)

G2A is an immunoregulatory G protein-coupled receptor predominantly expressed in lymphocytes and macrophages. Ectopic overexpression studies have implicated G2A as a receptor for the bioactive lysophospholipid, lysophosphatidylcholine (LPC). However, the functional consequences of LPC-G2A interaction at physiological levels of receptor expression, and in a cellular context relevant to its immunological role, remain largely unknown. Here, we show impaired chemotaxis to LPC of a T lymphoid cell line in which G2A expression was chronically down-regulated by RNA interference technology. Rescuing this phenotype by reconstitution of the physiological level of receptor expression further supports a functional connection between LPC-G2A interaction and cellular motility. Overexpression of G2A in the T lymphoid cell line significantly enhanced chemotaxis to LPC. It also modified migration toward the LPC-related molecule, lysophosphatidic acid, indicating the possibility of crosstalk between G2A and endogenous lysophosphatidic acid receptors. The role of G2A in LPC-mediated cell migration may be relevant to the autoimmune syndrome associated with genetic inactivation of this G protein-coupled receptor in mice. The experimental system described here can be useful for understanding the structural requirements for LPC recognition by G2A and the signaling pathways regulated by this ligand-receptor pair.
Physiologically Based Pharmacokinetic Model Qualification and Reporting Procedures for Regulatory Submissions: A Consortium Perspective (2018)

This work provides a perspective on the qualification and verification of physiologically based pharmacokinetic (PBPK) platforms/models intended for regulatory submission based on the collective experience of the Simcyp Consortium members. Examples of regulatory submission of PBPK analyses across various intended applications are presented and discussed. European Medicines Agency (EMA) and US Food and Drug Administration (FDA) recent draft guidelines regarding PBPK analyses and reporting are encouraging, and to advance the use and acceptability of PBPK analyses, more clarity and flexibility are warranted.
Increased expression of signaling lymphocytic activation molecule in patients with rheumatoid arthritis and its role in the regulation of cytokine production in rheumatoid synovium (1997)

In the present study the expression and function of signaling lymphocytic activation molecule (SLAM) in lymphocytes from patients with rheumatoid arthritis (RA) were investigated. The expression levels of SLAM were significantly up-regulated on synovial fluid and synovial tissue T cells from patients with RA compared with peripheral blood T cells from the same patients or from healthy volunteers. In addition, the expression of SLAM on peripheral blood B cells from patients with RA was elevated compared with that in healthy volunteers. SLAM+ T cells in synovial fluid coexpressed CD45RO and demonstrated decreased expression of CD27, indicative of a primed phenotype. In addition, the activation state of SLAM+ T cells was enhanced, as judged by increased expression of CD25, CD28, CD69, and CD95 on these cells. Interestingly, SLAM expression on activated CD4+ and CD8+ T cells from both patients and healthy individuals could be down-regulated by IL-10, which has been previously shown to function as an anti-inflammatory molecule in rheumatoid synovium. Furthermore, anti-SLAM mAbs increased the production of IL-10, IFN-gamma, and TNF-alpha by in vitro activated synovial fluid mononuclear cells, supporting the idea that signaling through SLAM may play a role in the regulation of synovial inflammation in patients with RA. Given the fact that SLAM was recently shown to be a high affinity self ligand, our data suggest that synovial T cells may stimulate their own cytokine production through homophilic SLAM-SLAM interactions.