gebhart/patrepeval huggingface dataset:
Improvement of Pharmacokinetics of Radioiodinated Tyr3-Octreotide by Conjugation with Carbohydrates (2002)

Among a variety of other factors, the clearance kinetics and routes of excretion of radiopharmaceuticals are of crucial importance for early and high tumor/background ratios and thus signal intensity in diagnostic imaging by single photon emission tomography (SPECT) or positron emission tomography (PET). To overcome the unfavorable pharmacokinetics of radiohalogenated octreotide analogues, we evaluated three carbohydrated conjugates of Tyr(3)-octreotide (TOC). Glucose ([(125)I]Gluc-TOC), maltose ([(125)I]Malt-TOC), and maltotriose ([(125)I]Mtr-TOC) derivatives of [(125)I]TOC were synthesized via Maillard reaction and subsequent radioiodination. In cells transfected with sst1-sst5, I-Malt-TOC, and I-Mtr-TOC show sst-subtype binding profiles similar to I-TOC with high affinity for sst2. Comparative biodistribution studies 10, 30, and 60 min pi in nude mice bearing rat pancreatic tumor xenografts showed fast blood clearance for all glycosylated derivatives. Due to their markedly increased hydrophilicity, [(125)I]Gluc-TOC and [(125)I]Malt-TOC were mainly cleared via the kidneys, which led to a significant decrease in activity accumulation in liver and intestine (5.3 and 1.4 versus 10.6%ID/g for [(125)I]TOC in the liver, 1.7 and 1.0 versus 3.8%ID/g for [(125)I]TOC in the intestine 60 min pi). For all compounds, hydrophilicity and uptake in liver and intestines correlate. Uptake of the carbohydrate conjugates in the kidney was comparable. Compared to the parent compound, the accumulation of the carbohydrated compounds in sst-rich tissues (pancreas, adrenals) was increased by a factor of 1.5-3.5. While tumor uptake of [(125)I]TOC (6.7 +/- 2.6%ID/g), [(125)I]Malt-TOC (5.3 +/- 1.9%ID/g), and [(125)I]Mtr-TOC (4.9 +/- 2.2%ID/g) at 30 min postinjection was comparable, accumulation of [(125)I]Gluc-TOC was significantly increased (10.1 +/- 2.8%ID/g at 30 min pi). Somatostatin receptor specificity of tumor uptake was confirmed by pretreatment, competition, and displacement experiments in vivo using 0.8 mg TOC/kg and gamma-camera imaging. Glycosylation proved to be a powerful tool for the development of high affinity sst ligands with excellent excretion profiles and improved tumor accumulation.
Sequential Application of Simplex Designs in Optimisation and Evolutionary Operation (1962)

A technique for empirical optimisation is presented in which a sequence of experimental designs each in the form of a regular or irregular simplex is used, each simplex having all vertices but one in common with the preceding simplex, and being completed by one new point. Reasons for the choice of design are outlined, and a formal procedure given. The performance of the technique in the presence and absence of error is studied and it is shown (a) that in the presence of error the rate of advance is inversely proportional to the error standard deviation, so that replication of observations is not beneficial, and (b) that the “efficiency” of the technique appears to increase in direct proportion to the number of factors investigated. It is also noted that, since the direction of movement from each simplex is dependent solely on the ranking of the observations, the technique may be used even in circumstances when a response cannot be quantitatively assessed. Attention is drawn to the ease with which second-order designs having the minimum number of experimental points may be derived from a regular simplex, and a fitting procedure which avoids a direct matrix inversion is suggested. In a brief appendix one or two new rotatable designs derivable from a simplex are noted.
Incomplete filling and incoordinate contraction as mechanisms of hypotension during ventricular tachycardia in man. (1983)

We sought to determine mechanisms for decrease of cardiac output and for hypotension during ventricular tachycardia (VT) in man. Two-dimensional and M mode echocardiograms and left ventricular pressure from micromanometer-tipped catheters were obtained in 20 patients before, during, and at the end of induced hypotensive VT. Patients were divided into two groups according to left ventricular function in sinus rhythm as assessed by angiographic ejection fraction (EF) before electrophysiologic study. Group 1 (n = 8) had angiographic EF greater than or equal to 50% in normal sinus rhythm, and group 2 (n = 12) had EF less than or equal to 40%. During VT, left ventricular cavity volume (as indexed by short- and long-axis two-dimensional end-diastolic cavity areas) was markedly reduced in group 1, from 19.7 +/- 2 to 8.6 +/- 2 cm2 (p less than .001) and from 32.0 +/- 8 to 22.5 +/- 7 cm2 (p less than .001), respectively, but was only slightly reduced in group 2, from 34.1 +/- 6 to 31.5 +/- 7 cm2 (p = .044) and from 45.0 +/- 8 to 49.4 +/- 7 cm2 (p = NS), respectively. Conversely, left ventricular systolic function during VT (as indexed by fractional reduction in two-dimensional short- and long-axis areas) was markedly depressed in group 2, from 25.6 +/- 6% to 4.2 +/- 4% (p = .005) and from 13.7 +/- 3% to 1.8 +/- 0.8% (p less than .001), respectively, but remained at control levels in group 1. Left ventricular end-diastolic pressures increased in group 1, from 11.8 +/- 2 to 27.7 +/- 8 mm Hg (p = .005) and did not change in group 2 during VT. Pressure-dimension loops from left ventricular pressure and M mode echocardiographically determined cavity dimensions generated from the end of the VT episodes showed that diastolic pressure-dimension relationships returned to control levels with the first prolonged diastolic interval in group 1 patients, indicating that incomplete relaxation was the mechanism responsible for reduction of cardiac output during VT in these patients. Coordination of contraction and relaxation (indicated by the percent ratio of the pressure-dimension loop area to the area of the rectangle just enclosing the loop) decreased from 37 +/- 11% to 16 +/- 13% in group 2 patients during VT (p = .013) but remained at control levels in group 1 patients. Thus, during VT patients with impaired left ventricular function in sinus rhythm (group 2) developed severe discoordination, and patients with normal or near-normal function (group 1) developed incomplete relaxation to account for stroke volume deterioration and hypotension.
Bax/Bcl-2 expression levels of 2-methoxyestradiol-exposed esophageal cancer cells (2005)

2-Methoxyestradiol (2ME), an endogenous metabolite of 17beta-estradiol, has been reported to play an active role in the induction of apoptosis in both proliferating endothelial and cancer cells. Since it has been indicated that an increased ratio of pro-apoptotic Bax protein to anti-apoptotic Bcl-2 protein expression can be associated with apoptosis, and since the exact action mechanism of 2ME is still not clearly defined and appears to vary according to cell type, the influence of 1 microM 2ME was investigated on Bax and Bcl-2 expression levels in squamous esophageal carcinoma cells. 2ME exposure led to statistically significant decreases (0.69 over DMSO controls) in Bcl-2 expression levels. In contrast, no statistically significant effects were observed on Bax expression levels after exposure to 2ME. The Bax/Bcl-2 ratio for 2ME-exposed cells was 1.45, normalised against Bcl-2 levels. Although the exact mechanisms of apoptosis induction in squamous esophageal cancer cells require further investigation, the present study suggests that this altered ratio in favor of Bax could lead to the induction of apoptosis in these cells.
국민기초생활보장법상 ‘부양의무자’의 법적 문제 (2012)

이 글에서는 민법상의 친족간의 부양과 국민기초생활보장법상의 부양을 비교하여 살펴보았다. 민법은 직계혈족 및 그 배우자 사이와 생계를 같이하는 친족 사이에는 서로 부양할 의무가 있다고 하면서, 다만 부양의무자에게는 부양의 능력이 있어야 하고, 부양권리자에게는 부양이 필요하다는 요건이 갖추어져야 한다고 규정하고 있다. 이에 비하여 국민기초생활보장법에서는...
AG-024322 is a multi-targeted CDK inhibitor with potent antitumor activity in vivo (2005)

4413 Deregulated cyclin-dependent kinase (CDK) activity is characterized by uncontrolled cell cycle progression, which is a hallmark of human cancer. AG-024322 is a multi-targeted (pan)-CDK inhibitor displaying potent inhibition of the cell cycle kinases CDK1, CDK2, and CDK4. In cellular assays AG-024322 inhibits phosphorylation of CDK substrates, causing induction of cell cycle arrest, broad-spectrum anti-proliferative activity and induction of apoptosis. In vivo experiments demonstrate that AG-024322 inhibits the growth of established human tumor xenografts of different origins. Significant anti-tumor efficacy was observed in 8 of the 9 tumor models tested, with tumor growth inhibition (TGI) ranging from 32% to 86.4%. In addition, the anti-tumor effects of AG-024322 are dose-dependent. At the maximum tolerated dose (MTD) of 20 mg/kg, AG-024322 causes a 65% TGI in the MV522 tumor model, 52% TGI at 1/2 of the MTD and only slight anti-tumor activity at 1/4 of the MTD. Direct evidence that AG-024322 antitumor activity correlates with modulation of the target was obtained by monitoring the phosphorylation status of the substrate Retinoblastoma (Rb) protein in tumor tissue. There is a clear dose dependent reduction in the level of phospho-Rb795, and this inhibition of Rb phosphorylation in vivo shows a strong correlation with the dose-dependent inhibition of tumor growth. In addition, treatment with AG-024322 causes dose-dependent apoptosis in tumors in vivo, as assessed by TUNEL staining of the excised tumors. Similarly, staining for Ki67, a common marker of cell proliferation, is significantly reduced after administration of AG-02322 at MTD levels. The sum of the in vivo data demonstrates that AG-024322 displays broad-spectrum anti-tumor activity and clear target modulation in vivo, as demonstrated by inhibition of Rb phosphorylation, anti-proliferative staining, and induction of apoptosis. Moreover, the extent of target modulation correlates with drug exposure in the pharmacodynamic model.
A Synthetic Recursive “+1” Pathway for Carbon Chain Elongation (2012)

Nature uses four methods of carbon chain elongation for the production of 2-ketoacids, fatty acids, polyketides, and isoprenoids. Using a combination of quantum mechanical (QM) modeling, protein-substrate modeling, and protein and metabolic engineering, we have engineered the enzymes involved in leucine biosynthesis for use as a synthetic "+1" recursive metabolic pathway to extend the carbon chain of 2-ketoacids. This modified pathway preferentially selects longer-chain substrates for catalysis, as compared to the non-recursive natural pathway, and can recursively catalyze five elongation cycles to synthesize bulk chemicals, such as 1-heptanol, 1-octanol, and phenylpropanol directly from glucose. The "+1" chemistry is a valuable metabolic tool in addition to the "+5" chemistry and "+2" chemistry for the biosynthesis of isoprenoids, fatty acids, or polyketides.
GSK-3 Inhibitors: Discoveries and Developments (2004)

Glycogen synthase kinase 3 (GSK-3) in the 21(st) century emerged as one of the most attractive therapeutic target for the development of selective inhibitors as new promising drugs for unmet pathologies including Alzheimer's disease, stroke, bipolar disorders, chronic inflammatory processes, cancer and diabetes type II. The full potential of GSK-3 inhibitors is just starting to be realized but the number of candidates in development provided by both academic centres and pharmaceutical companies have increased exponentially in the last two years. This review discloses recent discoveries and developments on peptides and small molecules targeting GSK-3. Focusing attention on this exciting target could thus reap considerable clinical and economic rewards.
Microwave signal processing and devices for adaptive beamforming (2002)

Adaptive array antennas offer a powerful beamforming functionality, i.e., the main beam is autonomously steered into the desired direction and nulls are steered into the directions from which interference or jamming waves are arriving. The essence of this functionality is complex weighting in each branch of the array and adaptive optimization of these weights. To suppress interference effectively, the weights must be continuously adjusted because deep nulls are likely to appear only in very narrow angles. This paper proposes that adaptive beamforming can be carried our in an analog manner. Three possible architectures are introduced for this purpose, and their topological schemes and electrical features of these architectures are discussed from the viewpoint of adaptive array applications. Key microwave signal processing devices and a blind weight optimization algorithm developed for analog adaptive beamforming are also described.
Liquid Growth Hormone: Preservatives and Buffers (2004)

Growth hormone (GH) treatment is a successful medical therapy for children and adults with GH deficiency as well as for growth retardation due to chronic renal disease, Turner syndrome and in children born small for gestational age. For all of these conditions, treatment is long term and patients receive daily subcutaneous injections of GH for many years. Patient compliance is therefore of critical importance to ensure treatment benefit. One of the major factors influencing compliance is injection pain. Besides the injection device used, pain perception and local tissue reaction following injection are dependent on the preservative used in the formulation and the concentration of GH. Injection pain may also be related to the buffer substance and injection volume. A liquid formulation of GH, Norditropi SimpleXx, has been developed that dispenses with the need for reconstitution before administration. The formulation uses phenol (3 mg/ml) as a preservative (to protect product from microbial degradation or contamination) and histidine as a buffer. Alternative preservatives used in other GH formulations include m-cresol (9 mg/ml) and benzyl alcohol (3-9 mg/ml). Buffering agents include citrate and phosphate. Phenol has been successfully used as a preservative in drug formulations for more than 50 years and is considered a safe and effective agent which complies with strict international requirements for preservatives in drug formulations. In toxicological studies, no or only mild local reactions have been observed following subcutaneous administration of phenol (7.5 mg/ml), m-cresol (3-4 mg/ml) and benzyl alcohol (9 mg/ml). No general toxicity reactions were observed after subcutaneous administration of these agents. Clinical evaluation of the preservatives and buffers used in Norditropin SimpleXx showed that pain perception was similar between formulations containing phenol and benzyl alcohol, whereas m-cresol was associated with more painful injections than benzyl alcohol. Furthermore, patients reported more pain following injection of a citrate-buffered solution than after a histidine-buffered solution. More pain was also reported following large volume injections and following injections with solutions containing high protein concentrations. In summary, optimization of the preservative and buffer content of a liquid GH formulation may reduce injection pain and lead to improved patient compliance.
Human Bocavirus 1 Is a Novel Helper for Adeno-associated Virus Replication (2017)

Human bocavirus 1 (HBoV1) is an autonomous parvovirus that infects well-differentiated primary human airway epithelia (HAE) <i>in vitro</i> In human embryonic kidney HEK293 cells, the transfection of a duplex HBoV1 genome initiates viral DNA replication and produces progeny virions that are infectious in HAE. HBoV1 takes advantage of signaling pathways in the DNA damage response for efficient genome amplification in both well-differentiated (nondividing) HAE and dividing HEK293 cells. On the other hand, adeno-associated virus 2 (AAV2) is a helper-dependent dependoparvovirus, and productive AAV2 replication requires coinfection with a helper virus (e.g., adenovirus or herpesvirus) or treatment with genotoxic agents. Here, we report that HBoV1 is a novel helper virus for AAV2 replication. Coinfection by HBoV1 and AAV2 rescued AAV2 replication in HAE cells. The helper function of HBoV1 for AAV2 is not limited to HAE cells but also includes HEK293 and HeLa cells. Importantly, the helper function of HBoV1 for AAV2 relies on neither HBoV1 replication nor the DNA damage response. Following transfection of HEK293 cells, the minimal requirements for the replication of the AAV2 duplex DNA genome and the production of progeny virions included the HBoV1 NP1 and NS4 proteins and a newly identified viral long noncoding RNA (BocaSR). However, following infection of HEK293 and HeLa cells with AAV2 virions, HBoV1 NS2 (but not NS4), NP1, and BocaSR were required for AAV2 DNA replication and progeny virion formation. These new methods for packaging the AAV2 genome may be useful for generating recombinant AAV-packaging cell lines and the directed evolution of AAV capsids.<b>IMPORTANCE</b> We first report that an autonomous parvovirus, HBoV1, helps the replication of a dependoparvovirus, AAV2, in differentiated human airway epithelia. We identified the minimal sets of HBoV1 genes required to facilitate the replication of the AAV2 duplex genome and for AAV2 infection. Notably, together with the expression of the <i>NP1</i> and <i>BocaSR</i> genes, HBoV1 <i>NS2</i> is required for the productive infection of HEK293 and HeLa cells by AAV2, whereas NS4 is sufficient for viral DNA replication of an AAV2 duplex genome. The identification of HBoV1 as a helper virus for AAV2 replication has implications for the improvement of recombinant AAV production in HEK293 cells and cell types that do not express the adenovirus <i>E1</i> gene as well as for the rescue of wild-type AAV genomes from tissues during directed evolution in the absence of wild-type adenovirus. A further understanding of the mechanism underlying HBoV1 helper-dependent AAV2 replication may also provide insights into its functions in HBoV1 replication.
JBP1 and JBP2 are two distinct thymidine hydroxylases involved in J biosynthesis in genomic DNA of African trypanosomes (2009)

Genomic DNA of African trypanosomes contains a hypermodified thymidine residue termed base J (beta-d-glucosyl-HOMedU). This modified base is localized primarily to repetitive DNA, namely the telomeres, and is implicated in the regulation of antigenic variation. The base is synthesized in a two-step pathway. Initially, a thymidine residue in DNA is hydroxylated by a thymidine hydroxylase (TH). This intermediate (HOMedU) is then glucosylated to form base J. Two proteins involved in J synthesis, JBP1 (J binding protein 1) and JBP2, contain a putative TH domain related to the family of Fe(2+)/2-oxoglutarate-dependent hydroxylases. We have previously shown that mutations in the TH domain of JBP1 kill its ability to stimulate J synthesis. Here we show that mutation of key residues in the TH domain of JBP2 ablate its ability to induce de novo J synthesis. While the individual JBP1 null and JBP2 null trypanosomes have reduced J levels, the deletion of both JBP1 and JBP2 generates a cell line that completely lacks base J but still contains glucosyl-transferase activity. Reintroduction of JBP2 in the J-null trypanosome stimulates HOMedU formation and site-specific synthesis of base J. We conclude that JBP2 and JBP1 are the TH enzymes involved in J biosynthesis.
Anti-CD2 receptor antibodies activate the HIV long terminal repeat in T lymphocytes (1991)

The CD2 T lymphocyte glycoprotein surface molecule mediates both cell to cell adhesion and T cell activation, two processes that are involved in the spread of HIV infection. Treatment of chronically HIV-infected PBMC with anti-CD2 mAb has been shown to induce the expression of infectious virus from these cultures. In this study we investigated the mechanisms whereby anti-CD2 antibodies stimulate viral production. We demonstrate that treatment of transiently transfected T lymphocytes with anti-CD2 antibodies results in activation of the HIV long terminal repeat. Furthermore, CAT assays using mutated HIV long terminal repeat-CAT constructs and gel shift assays demonstrate that this activation is dependent on the NF-kappa B enhancer. These studies suggest that interaction of CD2 with its natural ligand, LFA-3, may play a role in regulation of HIV expression.
Optimization of instruction fetch mechanisms for high issue rates (1995)

Recent superscalar processors issue four instructions per cycle. These processors are also powered by highly-parallel superscalar cores. The potential performance can only be exploited when fed by high instruction bandwidth. This task is the responsibility of the instruction fetch unit. Accurate branch prediction and low I-cache miss ratios are essential for the efficient operation of the fetch unit. Several studies on cache design and branch prediction address this problem. However, these techniques are not sufficient. Even in the presence of efficient cache designs and branch prediction, the fetch unit must continuously extract multiple, non-sequential instructions from the instruction cache, realign these in the proper order, and supply them to the decoder. This paper explores solutions to this problem and presents several schemes with varying degrees of performance and cost. The most-general scheme, the collapsing buffer, achieves near-perfect performance and consistently aligns instructions in excess of 90% of the time, over a wide range of issue rates. The performance boost provided by compiler optimization techniques is also investigated. Results show that compiler optimization can significantly enhance performance across all schemes. The collapsing buffer supplemented by compiler techniques remains the best-performing mechanism. The paper closes with recommendations and suggestions for future.
Antifibrotic properties of caveolin-1 scaffolding domain in vitro and in vivo (2008)

Lung fibrosis involves the overexpression of ECM proteins, primarily collagen, by alpha-smooth muscle actin (ASMA)-positive cells. Caveolin-1 is a master regulator of collagen expression by cultured lung fibroblasts and of lung fibrosis in vivo. A peptide equivalent to the caveolin-1 scaffolding domain (CSD peptide) inhibits collagen and tenascin-C expression by normal lung fibroblasts (NLF) and fibroblasts from the fibrotic lungs of scleroderma patients (SLF). CSD peptide inhibits ASMA expression in SLF but not NLF. Similar inhibition of collagen, tenascin-C, and ASMA expression was also observed when caveolin-1 expression was upregulated using adenovirus. These observations suggest that the low caveolin-1 levels in SLF cause their overexpression of collagen, tenascin-C, and ASMA. In mechanistic studies, MEK, ERK, JNK, and Akt were hyperactivated in SLF, and CSD peptide inhibited their activation and altered their subcellular localization. These studies and experiments using kinase inhibitors suggest many differences between NLF and SLF in signaling cascades. To validate these data, we determined that the alterations in signaling molecule activation observed in SLF also occur in fibrotic lung tissue from scleroderma patients and in mice with bleomycin-induced lung fibrosis. Finally, we demonstrated that systemic administration of CSD peptide to bleomycin-treated mice blocks epithelial cell apoptosis, inflammatory cell infiltration, and changes in tissue morphology as well as signaling molecule activation and collagen, tenascin-C, and ASMA expression associated with lung fibrosis. CSD peptide may be a prototype for novel treatments for human lung fibrosis that act, in part, by inhibiting the expression of ASMA and ECM proteins.