gebhart/patrepeval huggingface dataset:
Elevated levels of circulating plasma matrix metalloproteinase 9 in non-small cell lung cancer patients. (1999)

Elevated expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 have been implicated as playing important roles in tumor invasion and metastasis in various tissues. We investigated the relationship between circulating plasma MMP-9, its expression in tumor samples, and other clinical features in patients with non-small cell lung cancer (NSCLC). A series of 73 patients (45 men and 28 women) who underwent surgery for NSCLC was used in this study. Preoperative plasma concentrations of MMP-9 were examined using a one-step sandwich enzyme immunoassay. Expression levels of MMP-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 were measured in 24 tumor samples by immunohistochemistry. The plasma concentration of MMP-9 in NSCLC patients (71.0 +/- 60.2 ng/ml) was significantly elevated compared to that of healthy volunteers (P < 0.0001). MMP-9 concentrations were elevated in 33 of 73 cases (45.2%), compared with a cutoff value of the mean +/- 2 SD in healthy volunteers. There were statistically significant differences in MMP-9 concentration in adenocarcinoma versus squamous cell carcinoma (P = 0.014) and adenocarcinoma versus large cell carcinoma (P = 0.014). Five of 24 patients (20.8%) had positive immunohistochemical MMP staining of the tumor cell cytoplasm, and two cases had positive staining in the surrounding stromal cells. Plasma MMP-9 concentrations were elevated in 45.2% of NSCLC patients; however, this elevation did not seem to correlate with MMP-9 production by cancer and stromal cells. We concluded that the MMP-9 ELISA could be a beneficial adjunct for assessing the tumor burden of NSCLC, especially for types of squamous cell carcinoma and large cell carcinoma.
Complex-type N -glycan recognition by potent broadly neutralizing HIV antibodies (2012)

Broadly neutralizing HIV antibodies (bNAbs) can recognize carbohydrate-dependent epitopes on gp120. In contrast to previously characterized glycan-dependent bNAbs that recognize high-mannose N-glycans, PGT121 binds complex-type N-glycans in glycan microarrays. We isolated the B-cell clone encoding PGT121, which segregates into PGT121-like and 10-1074-like groups distinguished by sequence, binding affinity, carbohydrate recognition, and neutralizing activity. Group 10-1074 exhibits remarkable potency and breadth but no detectable binding to protein-free glycans. Crystal structures of unliganded PGT121, 10-1074, and their likely germ-line precursor reveal that differential carbohydrate recognition maps to a cleft between complementarity determining region (CDR)H2 and CDRH3. This cleft was occupied by a complex-type N-glycan in a "liganded" PGT121 structure. Swapping glycan contact residues between PGT121 and 10-1074 confirmed their importance for neutralization. Although PGT121 binds complex-type N-glycans, PGT121 recognized high-mannose-only HIV envelopes in isolation and on virions. As HIV envelopes exhibit varying proportions of high-mannose- and complex-type N-glycans, these results suggest promiscuous carbohydrate interactions, an advantageous adaptation ensuring neutralization of all viruses within a given strain.
Phase IB clinical trial of the oligosaccharide processing inhibitor swainsonine in patients with advanced malignancies. (1997)

The indolizidine alkaloid swainsonine, a potent inhibitor of Golgi alpha-mannosidase II, has been shown to reduce tumor cell metastasis, enhance cellular immune responses, and reduce solid tumor growth in mice. In our previous Phase I study, swainsonine administered by 5-day continuous infusion inhibited L-phytohemagglutinin-reactive N-linked oligosaccharide expression on peripheral blood lymphocytes. Significant toxicities included edema and elevated serum aspartate aminotransferase (AST). One patient with head and neck cancer had objective (>50%) tumor remission. Two patients showed symptomatic improvement. The objectives of this Phase IB trial were to examine the pharmacokinetics, toxicities, and biochemical effects of bi-weekly oral swainsonine at escalating dose levels (50-600 microgram/kg) in 16 patients with advanced malignancies and 2 HIV-positive patients unsuitable for conventional therapy. Eastern Cooperative Oncology Group performance status was </=2. The maximum tolerated dose was defined as 300 microgram/kg/day due primarily to serum AST abnormalities and dyspnea. Other adverse events present in >20% of patients included increase in serum AST (all patients), fatigue (n = 9), anorexia (n = 6), dyspnea (n = 6), and abdominal pain (n = 4). Inhibition of Golgi alpha-mannosidase II occurred in a dose-dependent manner. Examination of immunological parameters revealed a transient decrease in CD25(+) peripheral blood lymphocytes and, in seven of eight patients, an increase in CD4(+):CD8(+) ratios at 2 weeks. Serum drug levels peaked 3-4 h following a single oral dose in most patients and were proportional to dose at levels >/=150 microgram/kg. We conclude that oral swainsonine is tolerated by chronic intermittent administration at doses up to 150 microgram/kg/day. Adverse events considered drug related were similar to those observed in the infusional study but with fatigue and neurological effects also noted. Investigations of alternative dosing schedules with low starting doses are suggested for further clinical testing.
Experimental verification of waveguide-mode resonant transmission filters (1999)

A guided-mode resonance transmission filter is demonstrated experimentally. A five-layer fiberglass/air structure with a waveguide-grating in the center layer is designed, fabricated, and tested. A close match between theoretical and experimental spectral characteristics is found over the spectral range of 4-20 GHz. Guided-mode resonance transmission peaks occur at frequency locations which are in excellent agreement with theoretical predictions.
Strategic Analysis of Auctions (2021)

In many markets, transaction prices are determined in auctions. In the most common form, prospective buyers compete by submitting bids to a seller. Each bid is an offer to buy that states a quantity and a maximum price. The seller then allocates the available supply among those offering the highest prices exceeding the seller&amp;apos;s asking price. The actual price paid by a successful bidder depends on a pricing rule, usually selected by the seller: two common pricing rules are that each successful bidder pays the price bid; or they all pay the same price, usually the highest rejected bid or the lowest accepted bid. Auctions have been used for millennia, and remain the simplest and most famil-iar means of price determination for multilateral trading without intermediary `market makers &amp;apos; such as brokers and specialists. Their trading procedures, which simply process bids and offers, are direct extensions of the usual forms of bilateral bargaining. Auctions also implement directly the demand submission procedures used in Walrasian models of markets. They therefore have prominent roles in the theory of exchange and in studies of the effects of economic institutions on the volume and terms of trade. Their allocative ef-®ciency in many contexts ensures their continued prominence in economic theory. They are also favored in experimental designs investigating the predictive power of economic theories. Auctions are apt subjects for applications of game theory because they present ex-plicit trading rules that largely ®x the `rules of the game&amp;apos;. Moreover, they present sub-stantive problems of strategic behavior of practical importance. They are particularly valuable as illustrations of games of incomplete information because bidders &amp;apos; private information is the main factor affecting strategic behavior. The simpler forms of auctions induce normal-form games that are essentially `solved &amp;apos; by applying directly the basic
Developmental expression and functional characterization of the potassium-channel subunit Kv3.1b in parvalbumin-containing interneurons of the rat hippocampus (1996)

The expression of the voltage-gated K(+)-channel subunit Kv3.1b in the developing hippocampus was determined by immunoblot and immunohistochemical techniques. Kv3.1b protein was detected first at postnatal day (P) 8. The Kv3.1b-immunopositive cell number per tissue section reached a maximum at P14 and was maintained through P40. In contrast, the Kv3.1b protein content of isolated membrane vesicles in immunoblots progressively increased through P40, suggesting an increase in Kv3.1b content per cell throughout this time period. Kv3.1b protein was expressed selectively in the somata, proximal dendrites, and axons of cells lying within or near the pyramidal cell layer, consistent with their being GABAergic inhibitory interneurons. Kv3.1b was present in approximately 80% of parvalbumin-positive interneurons. The developmental onset of Kv3.1b and parvalbumin immunoreactivity was identical. In contrast, Kv3.1b was mostly absent from the subset of somatostatin-positive inhibitory interneurons. Electrophysiological recordings were made from stratum pyramidale interneurons in which morphology and Kv3.1b-positive immunoreactivity were confirmed post hoc. Outward currents had voltage-dependent and biophysical properties resembling those of channels formed by Kv3.1b. The current blocked by low concentrations of 4-aminopyridine (4-AP) showed marked inactivation, suggesting that Kv3.1b may coassemble with other members of the Kv3 subfamily. In current-clamp recordings, concentrations of 4-AP that blocked the current through Kv3.1b channels allowed us tentatively to assign a role to Kv3.1b-containing channels in action-potential repolarization. These data demonstrate that Kv3.1b is regulated developmentally in a specific subpopulation of hippocampal interneurons and that channels containing this subunit may be a major determinant in imparting "fast-spiking" characteristics to these and other cells throughout the central nervous system containing the Kv3.1b subunit.
Bunazosin, a Selective α1 ‐Adrenoceptor Antagonist, as an Anti‐glaucoma Drug: Effects on Ocular Circulation and Retinal Neuronal Damage (2005)

Bunazosin hydrochloride is a potent and selective alpha1-adrenoceptor antagonist that has been clinically used both as a systemic antihypertensive as well as an ocular hypotensive drug. In a number of studies, we have examined some effects of bunazosin hydrochloride that might indicate its potential as an anti-glaucoma drug. In normal rabbit eyes, topically instilled bunazosin hydrochloride reached the posterior retina by local penetration at concentrations sufficient to attenuate the phenylephrine- or endothelin-1 (ET-1)-induced constriction of retinal arteries. Furthermore, bunazosin hydrochloride improved the impairment of optic nerve head (ONH) blood flow, the prolongation of visual-evoked potentials (VEP) implicit time, the enlargement of the optic disk cup, and the decrease in the number of retinal ganglion cell layer cells induced by repeated injections of ET-1 in rabbits. Topically instilled bunazosin hydrochloride improved the reductions in ONH capillary blood flow and VEP amplitude induced in rabbit eyes by nitric oxide synthase inhibition. In rat primary retinal cultures, bunazosin hydrochloride reduced glutamate-induced neuronal cell death, presumably through a Na+ channel blocking effect. In healthy humans, topically instilled bunazosin hydrochloride reportedly increases blood velocity in the ONH, retina and choroid, without significantly altering either blood pressure or heart rate. These results indicate that bunazosin hydrochloride exerts both an improvement effect within the ocular circulation and a direct neuroprotective effect. Hence, bunazosin hydrochloride may be useful as a therapeutic drug against ischemic retinal diseases (such as glaucoma and retinal vascular occlusive diseases) that are associated with disturbances of the ocular circulation.
A Novel Human Polycomb Binding Site Acts As a Functional Polycomb Response Element in Drosophila (2012)

Polycomb group (PcG) proteins are key chromatin regulators implicated in multiple processes including embryonic development, tissue homeostasis, genomic imprinting, X-chromosome inactivation, and germ cell differentiation. The PcG proteins recognize target genomic loci through cis DNA sequences known as Polycomb Response Elements (PREs), which are well characterized in Drosophila. However, mammalian PREs have been elusive until two groups reported putative mammalian PREs recently. Consistent with the existence of mammalian PREs, here we report the identification and characterization of a potential PRE from human T cells. The putative human PRE has enriched binding of PcG proteins, and such binding is dependent on a key PcG component SUZ12. We demonstrate that the putative human PRE carries both genetic and molecular features of Drosophila PRE in transgenic flies, implying that not only the trans PcG proteins but also certain features of the cis PREs are conserved between mammals and Drosophila.
Bartonella henselae prevalence in domestic cats in California: risk factors and association between bacteremia and antibody titers (1995)

The isolation of Bartonella henselae, the agent of cat scratch disease, from the blood of naturally infected domestic cats and the demonstration that cats remain bacteremic for several months suggest that cats play a major role as a reservoir for this bacterium. A convenience sample of 205 cats from northern California was selected between 1992 and 1994 to evaluate the B. henselae antibody and bacteremia prevalences and to determine the risk factors and associations between bacteremia and antibody titers. B. henselae was isolated from the blood of 81 cats (39.5%). Forty-two (52%) of these bacteremic cats were found to be infected with > or = 1,000 CFU/ml of blood. Impounded or former stray cats were 2.86 (95% confidence interval [CI] = 1.94, 4.22) times more likely to be bacteremic than the pet cats. Young cats ( < 1 year old) were more likely than adult cats to be bacteremic (relative risk = 1.64; (95% CI = 1.19, 2.28). Bacteremic cats were more likely than nonbacteremic cats to be infested with fleas (relative risk = 1.64; 95% CI = 1.38, 1.96). No association between B. henselae infection and feline immunodeficiency virus antibody prevalence was observed. Eighty-one percent of the cats (166 of 205) tested positive for B. henselae antibodies, and titers were higher in bacteremic than in nonbacteremic cats. Multiple logistic regression analysis indicated that younger age and seropositivity for B. henselae antibodies were associated with bacteremia. Serological screening for Bartonella antibodies may not be useful for the identification of bacteremic cats (positive predictive value = 46.4%), but the lack of antibodies to B. henselae was highly predictive of the absence of bacteremia (negative predictive value = 89.7%). Seronegative cats may be more appropriate pets for immunocompromised individuals who are at increased risk for developing severe B. henselae disease.
Ex Vivo Large Scale Generation of Human Platelets from Cord Blood CD34+ Cells. (2005)

Abstract To obtain a large quantity of platelets (PLTs) from cord blood stem cells (CBSC) in vitro, we employed three-phase culture system. We first expanded CBSC on a monolayer of human telomerase catalytic subunit gene-transduced human stromal cells (hTERT stroma) in serum-free medium supplemented with stem cell factor (SCF), Flt-3/Flk-2 ligand (FL) and thrombopoietin (TPO) for 14 days (1st phase), and then cultured them to differentiate into megakaryocytes for another 14 days with refreshing medium which contain interleukin-11 (IL-11) in addition to original cytokine cocktail (2nd phase). Subsequently, we transferred the cells to a liquid culture medium containing SCF, FL, TPO and IL-11, and cultured them for 5 days (3rd phase) to recover PLTs in the culture medium. The quantity of PLTs recovered from one CB unit (5 x 106 CD34+ cells) was calculated to be 10.5 units (2 x 1011 PLTs). These CB-derived PLTs exhibited quite similar feature as those from peripheral blood in morphology as revealed by electron micrograph and in functions as revealed by aggregation assay and by FACS detecting expression of P-selectin and activated glycoprotein IIb-IIIa antigens upon fibrinogen/ADP stimulation. Thus our three-phase culture system was considered to be useful for large scale generation of PLTs from CB for clinical usage.
Down-regulation of protein kinase C is due to an increased rate of degradation (1987)

The phorbol-ester-induced loss of protein kinase C that has been documented in many cell types appears to be a critical event in the generation of a cellular refractory state. We have investigated here the synthesis and degradation of the protein kinase C polypeptide in order to determine why its steady-state amounts are depleted in response to phorbol esters. These results indicate that depletion is due to an increased rate of degradation, with no change either in mRNA amounts or in rates of polypeptide synthesis.
Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Alters Mitochondrial Membrane Lipids (2005)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to have selective antitumor activity. TRAIL induces ubiquitous pathways of cell death in which caspase activation is mediated either directly or via the release of apoptogenic factors from mitochondria; however, the precise components of the mitochondrial signaling pathway have not been well defined. Notably, mitochondria constitute an important target in overcoming resistance to TRAIL in many types of tumors. Bid is considered to be fundamental in engaging mitochondria during death receptor-mediated apoptosis, but this action is dependent on mitochondrial lipids. Here, we report that TRAIL signaling induces an alteration in mitochondrial membrane lipids, particularly cardiolipin. This occurs independently of caspase activation and primes mitochondrial membranes to the proapoptotic action of Bid. We unveil a link between TRAIL signaling and alteration of membrane lipid homeostasis that occurs in parallel to apical caspase activation but does not take over the mode of cell death because of the concurrent activation of caspase-8. In particular, TRAIL-induced alteration of mitochondrial lipids follows an imbalance in the cellular homeostasis of phosphatidylcholine, which results in an elevation in diacylglycerol (DAG). Elevated DAG in turn activates the delta isoform of phospholipid-dependent serine/threonine protein kinase C, which then accelerates the cleavage of caspase-8. We also show that preservation of phosphatidylcholine homeostasis by inhibition of lipid-degrading enzymes almost completely impedes the activation of pro-caspase-9 while scarcely changing the activation of caspase-8.
Snake venom disintegrins: novel dimeric disintegrins and structural diversification by disulphide bond engineering (2003)

We report the isolation and amino acid sequences of six novel dimeric disintegrins from the venoms of Vipera lebetina obtusa (VLO), V. berus (VB), V. ammodytes (VA), Echis ocellatus (EO) and Echis multisquamatus (EMS). Disintegrins VLO4, VB7, VA6 and EO4 displayed the RGD motif and inhibited the adhesion of K562 cells, expressing the integrin alpha5beta1 to immobilized fibronectin. A second group of dimeric disintegrins (VLO5 and EO5) had MLD and VGD motifs in their subunits and blocked the adhesion of the alpha4beta1 integrin to vascular cell adhesion molecule 1 with high selectivity. On the other hand, disintegrin EMS11 inhibited both alpha5beta1 and alpha4beta1 integrins with almost the same degree of specificity. Comparison of the amino acid sequences of the dimeric disintegrins with those of other disintegrins by multiple-sequence alignment and phylogenetic analysis, in conjunction with current biochemical and genetic data, supports the view that the different disintegrin subfamilies evolved from a common ADAM (a disintegrin and metalloproteinase-like) scaffold and that structural diversification occurred through disulphide bond engineering.
Cytogenetic analysis of pancreatic carcinomas: Intratumor heterogeneity and nonrandom pattern of chromosome aberrations (1998)

Twenty-nine nonendocrine pancreatic carcinomas (20 primary tumors and nine metastases) were studied by chromosome banding after short-term culture. Acquired clonal aberrations were found in 25 tumors and a detailed analysis of these revealed extensive cytogenetic intratumor heterogeneity. Apart from six carcinomas with one clone only, 19 tumors displayed from two to 58 clones, bringing the total number of clones to 230. Karyotypically related clones, signifying evolutionary variation, were found in 16 tumors, whereas unrelated clones were present in nine, the latter finding probably reflecting a distinct pathogenetic mechanism. The cytogenetic profile of pancreatic carcinoma was characterized by multiple numerical and structural changes. In total, more than 500 abnormal chromosomes, including rings, markers, homogeneously stained regions, and double minutes, altogether displaying 608 breakpoints, were detected. This complexity and heterogeneity notwithstanding, a nonrandom karyotypic pattern can be discerned in pancreatic cancer. Chromosomes 1, 3, 6, 7, 8, 11, 12, 17, and 19 and bands 1q12, 1q21, 3q11, 6p21, 6q21, 7q11, 7q22, 7q32, 11q13, 13cen, 14cen, 17q11, 17q21, and 19q13 were most frequently involved in structural rearrangements. A total of 19 recurrent unbalanced structural changes were identified, 11 of which were not reported previously: del(1)(q11), del(3)(p11), i(3)(q10), del(4)(q25), del(11)(p13), dup(11)(q13q23), i(12)(p10), der(13;15)(q10;q10), del(18)(q12), del(18)(q21), and i(19)(q10). The main karyotypic imbalances were entire-copy losses of chromosomes 18, Y, and 21, gains of chromosomes 7, 2, and 20, partial or whole-arm losses of 1p, 3p, 6q, 8p, 9p, 15q, 17p, 18q, 19p, and 20p, and partial or whole-arm gains of 1q, 3q, 5p, 6p, 7q, 8q, 11q, 12p, 17q, 19q, and 20q. In general, the karyotypic pattern of pancreatic carcinoma fits the multistep carcinogenesis concept. The observed cytogenetic heterogeneity appears to reflect a multitude of interchangeable but oncogenetically equivalent events, and the nonrandomness of the chromosomal alterations underscores the preferential pathways involved in tumor initiation and progression.
Guidelines for the welfare and use of animals in cancer research (2010)

Animal experiments remain essential to understand the fundamental mechanisms underpinning malignancy and to discover improved methods to prevent, diagnose and treat cancer. Excellent standards of animal care are fully consistent with the conduct of high quality cancer research. Here we provide updated guidelines on the welfare and use of animals in cancer research. All experiments should incorporate the 3Rs: replacement, reduction and refinement. Focusing on animal welfare, we present recommendations on all aspects of cancer research, including: study design, statistics and pilot studies; choice of tumour models (e.g., genetically engineered, orthotopic and metastatic); therapy (including drugs and radiation); imaging (covering techniques, anaesthesia and restraint); humane endpoints (including tumour burden and site); and publication of best practice.