gebhart/patrepeval huggingface dataset:
.alpha.-Aminoboronic acid derivatives: effective inhibitors of aminopeptidases (1986)

alpha-Aminoboronic acids and their derivatives have been synthesized as stable white solids. These compounds are effective inhibitors of human enkephalin degrading aminopeptidase, microsomal leucine aminopeptidase (EC 3.4.11.2), and cytosolic leucine aminopeptidase (EC 3.4.11.1) at micro- to nanomolar concentrations. The inhibition of cytosolic leucine aminopeptidase has been studied in some detail. Kinetic data correspond to the mechanism for biphasic slow-binding inhibition: E + I in equilibrium E.I in equilibrium E.I*, in which a rapid initial binding is followed by a slow transformation to a stable enzyme inhibitor complex. The initial and final binding constants are dependent on the nature of the side chain at the alpha-carbon atom but are independent of the protecting group on the boronic acid moiety and follow the trend for the hydrolysis of the corresponding amino acid amides. The first-order rate constant for the transformation of E.I to E.I* is similar for all four compounds studied. These data suggest that the slow-binding step represents the formation of tetrahedral boronate species from trigonal boronic acid.
Psychometric properties of patient reported outcome (PRO) instruments in patients with small cell lung cancer (SCLC) in RESILIENT part 1. (2021)

e24027 Background: The ongoing two-part phase 2/3 RESILIENT study (NCT03088813) is investigating the efficacy and safety of liposomal irinotecan monotherapy in patients with SCLC who have progressed on or after first line platinum-based chemotherapy. This exploratory analysis from RESILIENT part 1 was conducted to confirm the psychometric properties of established PRO instruments that had not previously been validated in patients with SCLC. Methods: Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) Core 30 (C30) and the EORTC QLQ Lung Cancer 13 (LC13) before treatment assignment (baseline), every 6 weeks thereafter, at treatment discontinuation and at the 30-day follow-up visit. Psychometric methods included descriptive statistics (items and scales), correlations (item-to-item and item-to-total), internal consistency (Cronbach’s α), test-retest reliability (intraclass correlation coefficient [ICC], two-way random effects model), construct validity and sensitivity to change. The analysis included patients who received at least one dose of study drug and completed at least one PRO assessment. Results: Thirty patients were enrolled in RESILIENT part 1 and included in the analysis. At baseline, 68% of patients reported ‘not severe’ or ‘mild’ symptoms. Floor effects (i.e. more than 25% of responses of ‘not at all’) were observed for several of the functioning/impact and symptom scales of the EORTC QLQ C30 and LC13. Moderate to strong correlations were found among most questionnaire items within their respective scales. Acceptable evidence for internal consistency and good test-retest reliability were observed. Selected results for the EORTC QLQ LC13, including dyspnea scales, are shown in the Table. The magnitude of correlations among PRO instruments supported evidence for convergent validity in this sample. Conclusions: In RESILIENT part 1, patients experienced low and tolerable symptoms at enrollment, limiting the potential for further improvement. Overall, these PRO instruments had acceptable psychometric properties (e.g. construct validity, reliability and ability to detect change) in this sample. However, these analyses should be repeated in a larger sample using data from RESILIENT part 2. Clinical trial information: NCT03088813. [Table: see text]
The Transformation Suppressor Pdcd4 Is a Novel Eukaryotic Translation Initiation Factor 4A Binding Protein That Inhibits Translation (2002)

Pdcd4 is a novel transformation suppressor that inhibits tumor promoter-induced neoplastic transformation and the activation of AP-1-dependent transcription required for transformation. A yeast two-hybrid analysis revealed that Pdcd4 associates with the eukaryotic translation initiation factors eIF4AI and eIF4AII. Immunofluorescent confocal microscopy showed that Pdcd4 colocalizes with eIF4A in the cytoplasm. eIF4A is an ATP-dependent RNA helicase needed to unwind 5' mRNA secondary structure. Recombinant Pdcd4 specifically inhibited the helicase activity of eIF4A and eIF4F. In vivo translation assays showed that Pdcd4 inhibited cap-dependent but not internal ribosome entry site (IRES)-dependent translation. In contrast, Pdcd4(D418A), a mutant inactivated for binding to eIF4A, failed to inhibit cap-dependent or IRES-dependent translation or AP-1 transactivation. Recombinant Pdcd4 prevented eIF4A from binding to the C-terminal region of eIF4G (amino acids 1040 to 1560) but not to the middle region of eIF4G(amino acids 635 to 1039). In addition, both Pdcd4 and Pdcd4(D418A) bound to the middle region of eIF4G. The mechanism by which Pdcd4 inhibits translation thus appears to involve inhibition of eIF4A helicase, interference with eIF4A association-dissociation from eIF4G, and inhibition of eIF4A binding to the C-terminal domain of eIF4G. Pdcd4 binding to eIF4A is linked to its transformation-suppressing activity, as Pdcd4-eIF4A binding and consequent inhibition of translation are required for Pdcd4 transrepression of AP-1.
Hypoglycemic Properties of Polysaccharides Extracted from Ganoderma lucidum in Alloxan-Induced Diabetic Rats (2004)

A recent randomized and double-blind placebo-controlled clinical study has indicated that Ganoderma lucidum polysaccharides (GLP) decrease blood glucose in patients with type II diabetes. The aim of this study was to investigate the effect of the GLP extract in alloxan-induced diabetic rats. Oral administration of GLP at 0.25, 0.5 and 1.0 g/kg for 4 weeks resulted in a reduction of blood glucose levels by 12.5, 18.7 and 33.7% respectively, while glibenclamide treatment brought the hyperglycemic value down to normal. The hypoglycemic effect was supported by a significant decrease in glycosylated haemoglobin and increased plasma insulin levels (p＜0.01) in a dose- and time-dependent manner. This study showed that GLP has similar hypoglycemic effects as glibenclamide in alloxan-induced diabetic rats.
Sialylation of IgG Fc domain impairs complement-dependent cytotoxicity (2015)

IgG molecules exert both pro- and antiinflammatory effector functions based on the composition of the fragment crystallizable (Fc) domain glycan. Sialylated IgG Fc domains have antiinflammatory properties that are attributed to their ability to increase the activation threshold of innate effector cells to immune complexes by stimulating the upregulation of the inhibitory Fcγ receptor IIB (FcγRIIB). Here, we report that IgG Fc sialylation of human monoclonal IgG1 molecules impairs their efficacy to induce complement-mediated cytotoxicity (CDC). Fc sialylation of a CD20-targeting antibody had no impact on antibody-dependent cellular cytotoxicity and did not change the affinity of the antibody for activating Fcγ receptors. In contrast, the presence of sialic acid abrogated the increased binding of C1q to Fc-galactosylated IgG1 and resulted in decreased levels of C3b deposition on the cell surface. Similar to monoclonal antibodies, sialic acid inhibited the increased C1q binding to galactosylated Fc fragments in human polyclonal IgG. In sera derived from patients with chronic inflammatory demyelinating polyneuropathy, an autoimmune disease of the peripheral nervous system in which humoral immune responses mediate tissue damage, induction of IgG Fc sialylation was associated with clinical disease remission. Thus, impairment of CDC represents an FcγR-independent mechanism by which Fc-sialylated glycovariants might limit proinflammatory IgG effector functions.
Intermediate cells in normal and malignant prostate epithelium express c‐MET: Implications for prostate cancer invasion (2002)

Intermediate cells in normal and malignant prostate epithelium express high c-MET levels, indicating that they are prone to stromal invasion in prostate carcinoma.
Carbohydrate Structures of Recombinant Human α-l-Iduronidase Secreted by Chinese Hamster Ovary Cells (1997)

alpha-L-Iduronidase is a lysosomal hydrolase that is deficient in Hurler syndrome and clinically milder variants. Recombinant human alpha-L-iduronidase, isolated from secretions of an overexpressing Chinese hamster ovary cell line, is potentially useful for replacement therapy of these disorders. Because of the importance of carbohydrate residues for endocytosis and lysosomal targeting, we examined the oligosaccharides of recombinant alpha-L-iduronidase at each of its six N-glycosylation sites. Biosynthetic radiolabeling showed that three or four of the six oligosaccharides of the secreted enzyme were cleaved by endo-beta-N-acetylglucosaminidase H, with phosphate present on the sensitive oligosaccharides and L-fucose on the resistant ones. For structural analysis, tryptic and chymotryptic glycopeptides were isolated by lectin binding and reverse phase high pressure liquid chromatography; their molecular mass was determined by matrix-assisted laser desorption-time of flight mass spectrometry before and after treatment with endo- or exoglycosidases or with alkaline phosphatase. Identification of the peptides was assisted by amino- or carboxyl-terminal sequence analysis. The major oligosaccharide structures found at each site were as follows: Asn-110, complex; Asn-190, complex; Asn-336, bisphosphorylated (P2Man7GlcNAc2); Asn-372, high mannose (mainly Man9GlcNAc2, some of which was monoglucosylated); Asn-415, mixed high mannose and complex; Asn-451, bisphosphorylated (P2Man7GlcNAc2). The Asn-451 glycopeptide was unexpectedly resistant to digestion by N-glycanase unless first dephosphorylated, but it was sensitive to endo-beta-N-acetylglucosaminidase H and to glycopeptidase A. The heterogeneity of carbohydrate structures must represent the accessibility of the glycosylation sites as well as the processing capability of the overexpressing Chinese hamster ovary cells.
Cysteines in CH1 Underlie Retention of Unassembled Ig Heavy Chains (2005)

Conformation, structure, and oligomeric state of immunoglobulins not only control quality and functional properties of antibodies but are also critical for immunoglobulins secretion. Unassembled immunoglobulin heavy chains are retained intracellularly by delayed folding of the C(H)1 domain and irreversible interaction of BiP with this domain. Here we show that the three C(H)1 cysteines play a central role in immunoglobulin folding, assembly, and secretion. Remarkably, ablating all three C(H)1 cysteines negates retention and enables BiP cycling and non-canonical folding and assembly. This phenomenon is explained by interdependent formation of intradomain and interchain disulfides, although both bonds are dispensable for secretion. Substituting Cys-195 prevents formation not only of the intradomain disulfide, but also of the interchain disulfide bond with light chain, BiP displacement, and secretion. Mutating the light chain-interacting Cys-128 hinders disulfide bonding of intradomain cysteines, allowing their opportunistic bonding with light chain, without hampering secretion. We propose that the role of C(H)1 cysteines in immunoglobulin assembly and secretion is not simply to engage in disulfide bridges, but to direct proper folding and interact with the retention machinery.
Human CD4+ lymphocytes for antigen quantification: Characterization using conventional flow cytometry and mass cytometry (2012)

To transform the linear fluorescence intensity scale obtained with fluorescent microspheres to an antibody bound per cell (ABC) scale, a biological cell reference material is needed. Optimally, this material should have a reproducible and tight ABC value for the expression of a known clinical reference biomarker. In this study, we characterized commercially available cryopreserved peripheral blood mononuclear cells (PBMCs) and two lyophilized PBMC preparations, Cyto-Trol and PBMC-National Institute for Biological Standard and Control (NIBSC) relative to freshly prepared PBMC and whole blood samples. It was found that the ABC values for CD4 expression on cryopreserved PBMC were consistent with those of freshly obtained PBMC and whole blood samples. By comparison, the ABC value for CD4 expression on Cyto-Trol is lower and the value on PBMC-NIBSC is much lower than those of freshly prepared cell samples using both conventional flow cytometry and CyTOF™ mass cytometry. By performing simultaneous surface and intracellular staining measurements on these two cell samples, we found that both cell membranes are mostly intact. Moreover, CD4(+) cell diameters from both lyophilized cell preparations are smaller than those of PBMC and whole blood. This could result in steric interference in antibody binding to the lyophilized cells. Further investigation of the fixation effect on the detected CD4 expression suggests that the very low ABC value obtained for CD4(+) cells from lyophilized PBMC-NIBSC is largely due to paraformaldehyde fixation; this significantly decreases available antibody binding sites. This study provides confirmation that the results obtained from the newly developed mass cytometry are directly comparable to the results from conventional flow cytometry when both methods are standardized using the same ABC approach.
The receptor for urokinase type plasminogen activator polarizes expression of the protease to the leading edge of migrating monocytes and promotes degradation of enzyme inhibitor complexes. (1990)

Receptor-bound urokinase-type plasminogen activator (uPA) remains associated to the surface of human monocytes for many hours. Monocytes induced to migrate in a chemotactic gradient of f-Met-Leu-Phe rapidly polarize their uPA receptors to the leading front of the cells. Receptor-bound enzyme can be inhibited by plasminogen activator inhibitor 2 (PAI-2), with a kinetics comparable to that determined for the free enzyme, and uPA/PAI-2 complexes can bind to the uPA receptor. In contrast to the active enzyme, the uPA/PAI-2 complex is rapidly cleared from the monocyte cell surface; this involves an initial cleavage of the complex at the cell surface, followed by endocytosis and degradation. These results indicate that the uPA receptor can function both to focus plasmin-mediated extracellular matrix degradation in front of migrating cells, and to target uPA/PAI-2 enzyme/inhibitor complexes for degradation; they suggest that this receptor is a key determinant in the control of uPA-catalyzed extracellular proteolysis.
Protection against Cholera in Breast-Fed Children by Antibodies in Breast Milk (1983)

We performed a prospective study to examine whether the IgA antibodies against cholera that are present in breast milk protect breast-fed infants and children against colonization with Vibrio cholerae 01 and disease. Among families of patients with cholera, we collected breast milk from mothers who had not had diarrhea in the previous week and monitored them and their breast-fed children for cholera colonization and diarrhea for 10 days. Breast milk was assayed for IgA antibodies to cholera toxin and lipopolysaccharide. Ninety-three mother--child pairs were studied; 30 infants became colonized with V. cholerae 01 and disease developed in 19. There were no differences between the antibody levels in milk fed to children who became colonized and in milk fed to children who did not. However, among the children who became colonized, those who had diarrhea drank breast milk containing significantly lower levels of both kinds of cholera antibodies than were present in the milk consumed by children who had no symptoms. We conclude that breast-milk antibodies against cholera do not appear to protect children from colonization with V. cholerae 01 but do protect against disease in those who are colonized.
Body Part Detection for Human Pose Estimation and Tracking (2007)

Accurate 3-D human body pose tracking from a monocular video stream is important for a number of applications. We describe a novel hierarchical approach for tracking human pose that uses edge-based features during the coarse stage and later other features for global optimization. At first, humans are detected by motion and tracked by fitting an ellipse in the image. Then, body components are found using edge features and used to estimate the 2D positions of the body joints accurately. This helps to bootstrap the estimation of 3D pose using a sampling-based search method in the last stage. We present experiment results with sequences of different realistic scenes to illustrate the performance of the method.
New Dancing Couple: PD‐L1 and MicroRNA (2017)

Lung cancer (LC) is the most common cause of cancer death in the world. A great challenge in treating NSCLC is the discovery of advanced, molecular tools to diagnose the disease in early stages as well as the development of immunotherapy. MicroRNAs are regulatory molecules (~20 nt in length) with the ability to regulate the expression of genes. The recently described PD-1 and PD-L1 molecules have great importance for potential use in immunotherapy of many cancers. These molecules are associated with immune checkpoints and provide an opportunity for the treatment of advanced NSCLC patients with synthetic monoclonal antibodies. PD-L1 expression is strictly associated with microRNA function in lung cancer cells. The group of microRNAs related to PD-L1 includes, among others, miR-200, miR-197 or miRNA-34. Expression of these molecules may be useful in lung cancer diagnosis, qualification to anti-PD-1 or anti-PD-L1 antibody therapy and could be a potential therapeutic target. However, studies on PD-L1-related microRNAs are necessary to develop advanced targeted molecular therapies.
Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population (2004)

Despite the increasing prevalence of nonalcoholic fatty liver disease (NAFLD), the criteria used to diagnose the disorder remain poorly defined. Localized proton magnetic resonance spectroscopy (MRS) accurately measures hepatic triglyceride content (HTGC) but has been used only in small research studies. Here, MRS was used to analyze the distribution of HTGC in 2,349 participants from the Dallas Heart Study (DHS). The reproducibility of the procedure was validated by showing that duplicate HTGC measurements were high correlated (r = 0.99, P < 0.001) and that the coefficient of variation between measurements was low (8.5%). Intake of a high-fat meal did not significantly affect the measurements, and values were similar when measurements were made from the right and left hepatic lobes. To determine the "upper limit of normal" for HTGC, the distribution of HTGC was examined in the 345 subjects from the DHS who had no identifiable risk factors for hepatic steatosis (nonobese, nondiabetic subjects with minimal alcohol consumption, normal liver function tests, and no known liver disease). The 95th percentile of HTGC in these subjects was 5.56%, which corresponds to a hepatic triglyceride level of 55.6 mg/g. With this value as a cutoff, the prevalence of hepatic steatosis in Dallas County was estimated to be 33.6%. Thus MRS provides a sensitive, quantitative, noninvasive method to measure HTGC and, when applied to a large urban US population, revealed a strikingly high prevalence of hepatic steatosis.
Dual inhibition of MET and SRC kinase activity as a combined targeting strategy for colon cancer (2017)

Hepatocyte growth factor (HGF)/MET signaling is implicated in the development of colorectal cancer (CRC) and possesses therapeutic value for various types of cancer. However, inhibition of MET alone has been demonstrated to have limited efficacy. The present study examined the combined inhibition of MET and SRC kinase activity in colon cancer cells. Furthermore, the role of the HGF/MET pathway in ligand-dependent and -independent activation was demonstrated. The single inhibition of MET by knockdown small interfering RNA or inhibitor indicated a limited anti-viability effects without inhibiting the basal phosphorylation levels of SRC, protein kinase B (AKT) or extracellular signal-regulated kinase (ERK). In view of the strong association between MET and SRC identified by direct regulation, growth factor-induced MET activation was suppressed by pretreatment with the SRC inhibitor, dasatinib, and downstream phosphorylation of AKT and ERK partially decreased, which suggested that SRC activation was essential for ligand-dependent and -independent activation of MET. Considering that both the activation of MET and SRC was required in ligand-dependent and -independent MET activation, the antitumor effect of concurrent inhibition of MET and SRC was examined, and it was demonstrated that combination treatment exerted increased viability inhibition and apoptosis enhancement in mutant and wild type RAS colon cancer cells. Therefore, combinational inhibition of MET and SRC may be a promising strategy for the treatment of CRC.
Blockade of endogenous B7‐H1 suppresses antibacterial protection after primary Listeria monocytogenes infection (2007)

B7-H1 (also known as CD274 and PD-L1) is a cosignalling molecule regulating T-cell immunity positively or negatively in vivo. However, little is known about the role of endogenous B7-H1 in bacterial infection. We found that B7-H1 expression was up-regulated in various cell populations including CD4+ and CD8+ T cells, natural killer (NK) cells and macrophages following Listeria monocytogenes infection. Administration of the antagonistic B7-H1 monoclonal antibody resulted in a significant increase in mortality in mice infected with a lethal dose of L. monocytogenes compared with mice given the control immunoglobulin. In vivo blockade of B7-H1 greatly inhibited the production of tumour necrosis factor (TNF)-alpha and nitric oxide, key effector molecules responsible for intracellular killing by macrophages. B7-H1 blockade also suppressed the expression of granzyme B and interferon (IFN)-gamma by NK cells. Interestingly, blocking of endogenous B7-H1 selectively inhibited CD8+ T cells rather than CD4+ T cells in response to L. monocytogenes infection, as evidenced by the reduction of IFN-gamma production and the expression of effector surface markers including CD62L(int/low) and CD44(high) in CD8+ T cells from mice given anti-B7-H1 monoclonal antibody. In addition, we found that the proliferation of listeriolysin-O (LLO)-specific and IFN-gamma-producing L. monocytogenes-reactive CD8+ T cells was significantly decreased not only in the effector phase but also in the memory phase in the presence of anti-B7-H1 antibody. Our findings thus suggest that endogenous B7-H1 can provide positive costimulatory signals for innate and adaptive immunity leading to protection against intracellular bacterial infection.
The therapeutic potential of novel aromatase inhibitors in breast cancer (1999)

For over 20 years, aromatase inhibitors have played a role in the treatment of breast cancer. However, until relatively recently, their utility has been limited by a lack of selectivity and significant toxicity. Several second and third generation aromatase inhibitors which are highly selective for the aromatase enzyme have reached clinical trials this decade. As a result of these initial studies, aromatase inhibitors are now established as second line agents in the treatment of postmenopausal women with advanced breast cancer. They are now under evaluation in several other settings, including adjuvant and neoadjuvant therapy, and as part of combination treatment in premenopausal women. This review focuses on recent and ongoing clinical trials and the effect these have had on the clinical use of aromatase inhibitors.