gebhart/patrepeval huggingface dataset:
Intestinal Consumption of Intravenously Administered Fuels (1985)

Total parenteral nutrition has been extensively used to feed patients with a variety of gastrointestinal diseases, but little attention has focused on the nutritional requirements of the gut. To investigate intestinal consumption of intravenously administered nutrients, uptake of three principal fuels determined from in vitro studies was quantitated in seven awake, unrestrained dogs. Portal blood flow was measured by a dye dilution technique and, simultaneously, substrate samples were obtained from chronic indwelling arterial and portal venous catheters. Studies were performed during a postabsorptive basal period and during separate infusions of glutamine (0.10 mmol/kg X min), glucose (0.10 mmol/kg X min), and beta-hydroxybutyrate, (0.40 mmol/kg X min). During the basal period there was a significant arterial-portal vein gradient for glucose (144 +/- 26 mumol/liter) and glutamine (49 +/- 11 mumol/liter). These substances were taken up by the gut at rates of 4.11 +/- 1.23 and 1.43 +/- 0.19 mumol/kg X min, respectively. No significant uptake of beta-hydroxybutyrate was determined in the basal studies (0.27 +/- 0.10 mumol/kg X min). During substrate infusion, gut glucose uptake was unchanged (2.68 +/- 1.67 mumol/kg X min, NS), but consumption of glutamine (4.60 +/- 0.66 mumol/kg X min, p less than 0.001) and beta-hydroxybutyrate (4.33 +/- 0.71 mumol/kg X min, p less than 0.001) increased significantly. During parenteral feedings in patients with gastrointestinal disorders, circulating levels of beta-hydroxybutyrate and glutamine are often low, and glutamine is absent from standard amino acid solutions. Current parenteral formulation may not provide appropriate fuels for the gastrointestinal tract.
Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma (2005)

We report the results of a phase 2 trial using lenalidomide plus dexamethasone (Rev/Dex) as initial therapy for myeloma. Thirty-four patients were enrolled. Lenalidomide was given orally 25 mg daily on days 1 to 21 of a 28-day cycle. Dexamethasone was given orally 40 mg daily on days 1 to 4, 9 to 12, and 17 to 20 of each cycle. Objective response was defined as a decrease in serum monoclonal protein level by 50% or greater and a decrease in urine M protein level by at least 90% or to a level less than 200 mg/24 hours, confirmed by 2 consecutive determinations at least 4 weeks apart. Thirty-one of 34 patients achieved an objective response, including 2 (6%) achieving complete response (CR) and 11 (32%) meeting criteria for both very good partial response and near complete response, resulting in an overall objective response rate of 91%. Of the 3 remaining patients not achieving an objective response, 2 had minor response (MR) and one had stable disease. Forty-seven percent of patients experienced grade III or higher nonhematologic toxicity, most commonly fatigue (15%), muscle weakness (6%), anxiety (6%), pneumonitis (6%), and rash (6%). Rev/Dex is a highly active regimen with manageable side effects in the treatment of newly diagnosed myeloma.
Catalysis of RNA Cleavage by a Ribozyme Derived from the Group I Intron of Anabaena Pre-tRNALeu (1994)

In the cyanobacterium Anabaena PCC7120, the precursor to tRNA(Leu) contains a 249-nucleotide group I intron that undergoes efficient self-splicing in vitro. By deleting the 5' and 3' splice sites, this intron has now been converted to an RNA enzyme that uses a guanosine nucleophile to cleave substrate RNAs (S) with multiple turnover. This Anabaena ribozyme has a second-order rate constant for RNA cleavage (kcat/Km)S that is 250-500-fold smaller than that of the Tetrahymena ribozyme, and a multiple-turnover rate constant at saturating S [kcat(mt)] that is approximately 400-fold larger. Several lines of evidence, including kinetic analysis of cleavage of phosphorothioate- and deoxynucleotide-substituted substrates and pH dependence, support the conclusion that both (kcat/Km)S and kcat(mt) are limited by the actual chemical cleavage step. In contrast, for the Tetrahymena ribozyme, it has been shown that neither of these rate constants reflects the chemical step. These kinetic differences are expected from the shorter guide sequence-substrate pairing of the Anabaena ribozyme; for example, weaker binding of RNA speeds product release during multiple turnover and thereby overcomes the rate-limiting product release observed for the Tetrahymena ribozyme. Thus, the large kinetic differences represent superficial rather than fundamental differences between these ribozymes. Furthermore, the strength of the guanosine-binding interaction, the stereospecificity for Rp-phosphorothioate at the cleavage site, and the 10(3)-fold slower cleavage with a deoxyribonucleoside leaving group are properties conserved between the Anabaena and Tetrahymena ribozymes. Finally, log(kcat/Km)S increases linearly with pH in the acid range where chemistry is rate-limiting and becomes pH-independent above pH 7, perhaps because a conformational step becomes rate-limiting; again, these are characteristics shared with the Tetrahymena ribozyme. We conclude that two group I ribozymes, although differing in the identity of many of their active site nucleotides, nevertheless provide functionally similar active sites for sequence-specific RNA cleavage.
Family of Kunitz proteins from trophoblast: Expression of the trophoblast Kunitz domain proteins (TKDP) in cattle and sheep (2003)

Here we report the molecular cloning of several members of a family of novel proteins expressed by the ruminant trophoblast, known as the trophoblast Kunitz domain proteins (TKDPs). Each contains a carboxyl-terminal module of approximately 64 amino acids belonging to the Kunitz family of serine proteinase inhibitors. These Kunitz modules are preceded by one or more structurally related domains, each about 80 amino acids long. The function of these domains is unclear. The TKDPs differ considerably in sequence identity, with much of the diversity due to variability in the amino-terminal domains. However, nine of the ten Kunitz domains described here are themselves unique, ranging in amino acid sequence identity from 90% to 53% to each other and averaging only about 50% identity with bovine pancreatic trypsin inhibitor (BPTI). The "warhead" P1 residues, which govern specificity, are themselves variable and include some unusual amino acids, such as Asn, Thr, and Ile, as well as the more common Lys. The Kunitz domains of three of the TKDPs lack the conserved cysteines at positions 14 and 38 (BPTI numbering) that normally contribute to the orientation of the inhibitory loop. Northern blotting and reverse transcription-polymerase chain reaction (RT-PCR) demonstrated that the TKDP genes do not exhibit identical expression patterns during trophoblast development, although mostly are expressed maximally during early pregnancy. It is possible that the TKDPs provide a broad range of specificities against maternal proteinases that might be damaging to the trophoblast during pregnancy.
Cyclooxygenase-2 and Gastrointestinal Cancer (2004)

The cyclooxygenase (COX) enzymes (COX-1 and COX-2) are key enzymes of prostaglandin (PG) biosynthesis. Nonselective non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the enzymatic activity of both COX-1 and COX-2. Selective COX-2 inhibitors have been developed that appear to have 50% less gastrointestinal toxicity than traditional nonselective NSAIDs. Experimental evidence suggests that the COX pathway is involved in tumor promotion. Evidence to support this comes from both clinical and laboratory findings suggesting that chronic NSAID use reduces the relative risk for developing colorectal cancer (CRC). Although the precise mechanism or mechanisms by which these drugs affect tumor progression is not completely understood, it is likely that part of their anti-tumor effect is due to inhibition of the COX- 2 enzyme. COX-2 levels are increased in CRC as well as in several other solid malignancies. COX-2-derived bioactive lipid products promote tumor-associated n eovascularization, inhibit cell death, and stimulate cell proliferation and motility. Additionally, treatment with COX-2-selective inhibitors reduces polyp burden in animal models of intestinal neoplasia and in humans with familial adenomatous polyposis (FAP). Ongoing human clinical trails are under way to test the efficacy of COX-2-selective inhibitors in a number of human cancers.
Antitumor effect of interleukin (IL)-12 in the absence of endogenous IFN-gamma: a role for intrinsic tumor immunogenicity and IL-15. (2002)

IFN-gamma knockout mice (GKO) rejected C26 colon carcinoma cells transduced to secrete interleukin(IL)-12 but do not reject similarly transduced TSA mammary adenocarcinoma (C26/12 and TSA/12 cells, respectively). To determine whether such difference could be because of a different tumor response to IFN-gamma, we injected BALB/c mice with TSA, C26, and their IL-12-transduced counterparts rendered unresponsive to IFN-gamma by stable transduction of a dominant negative (DN), truncated IFN-gamma receptor alpha chain. TSA/DN and C26/DN showed the same in vivo growth kinetics as parental cells, whereas coexpression of IL-12 induced rejection independent of tumor-cell responsiveness to IFN-gamma. This suggests that the role of IFN-gamma is primarily in activating the host immune response, which appears to depend on the intrinsic immunogenicity of the target tumor. C26 and TSA share a common tumor-associated antigen, yet C26 cells are more immunogenic than TSA. C26/12 expressed 10-fold higher levels of class I MHC molecules and induced higher CTL activity compared with TSA/12 cells in GKO mice. Moreover, whereas in GKO mice the TSA/12 tumor was associated with a greater number of infiltrating T cells, only those infiltrating C26/12 tumor expressed the activation marker OX40. The search for cytokine(s) that might contribute in determining the different T-cell response to these IL-12-transduced tumors in GKO mice revealed a role of IL-15. In situ hybridization showed IL-15 expression in C26/12 but not in TSA/12 tumors. In addition, injection of GKO mice with soluble IL-15 receptor-alpha to block IL-15 expression prevented rejection of C26/12 cells. Together, the results suggest that in the absence of IFN-gamma, IL-12 can exert antitumor activity through alternative mechanisms, depending on the tumor cell type and the availability of cytokines that can replace IFN-gamma in sustaining T-cell functions.
A dormant TIL phenotype defines non-small cell lung carcinomas sensitive to immune checkpoint blockers (2018)

The biological determinants of sensitivity and resistance to immune checkpoint blockers are not completely understood. To elucidate the role of intratumoral T-cells and their association with the tumor genomic landscape, we perform paired whole exome DNA sequencing and multiplexed quantitative immunofluorescence (QIF) in pre-treatment samples from non-small cell lung carcinoma (NSCLC) patients treated with PD-1 axis blockers. QIF is used to simultaneously measure the level of CD3+ tumor infiltrating lymphocytes (TILs), in situ T-cell proliferation (Ki-67 in CD3) and effector capacity (Granzyme-B in CD3). Elevated mutational load, candidate class-I neoantigens or intratumoral CD3 signal are significantly associated with favorable response to therapy. Additionally, a "dormant" TIL signature is associated with survival benefit in patients treated with immune checkpoint blockers characterized by elevated TILs with low activation and proliferation. We further demonstrate that dormant TILs can be reinvigorated upon PD-1 blockade in a patient-derived xenograft model.
Low-Power Dynamic Memory Word Line Decoding for Static Random Access Memories (2008)

Conventional memory address decoders based on static CMOS gates incur high clock loading and unnecessary power dissipation in unselected banks. This paper presents a dynamic word line decoder which is fast, has reduced active and leakage power dissipation, and also enables faster race-free sense timing. In a multi-bank memory array with sixteen decoders, the energy-delay product of the dynamic decoder is 66% lower than a low-power static version. The design leverages the predictability of dynamic circuits to provide significant decoder leakage reduction in unselected banks. The dynamic decoder has been fabricated on a 90 nm bulk CMOS process. The measured test chip address to word line delay is 170 ps at 1.5 V and the measured leakage reduction is over 20x at <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">V</i> <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">DD</sub> greater than 0.8 V.
Diverse point mutations in the human glucose-6-phosphate dehydrogenase gene cause enzyme deficiency and mild or severe hemolytic anemia. (1988)

Glucose-6-phosphate dehydrogenase (G6PD; EC 1.1.1.49) deficiency is a common genetic abnormality affecting an estimated 400 million people worldwide. Clinical and biochemical analyses have identified many variants exhibiting a range of phenotypes, which have been well characterized from the hematological point of view. However, until now, their precise molecular basis has remained unknown. We have cloned and sequenced seven mutant G6PD alleles. In the nondeficient polymorphic African variant G6PD A we have found a single point mutation. The other six mutants investigated were all associated with enzyme deficiency. In one of the commonest, G6PD Mediterranean, which is associated with favism among other clinical manifestations, a single amino acid replacement was found (serine----phenylalanine): it must be responsible for the decreased stability and the reduced catalytic efficiency of this enzyme. Single point mutations were also found in G6PD Metaponto (Southern Italy) and in G6PD Ilesha (Nigeria), which are asymptomatic, and in G6PD Chatham, which was observed in an Indian boy with neonatal jaundice. In G6PD "Matera," which is now known to be the same as G6PD A-, two separate point mutations were found, one of which is the same as in G6PD A. In G6PD Santiago, a de novo mutation (glycine----arginine) is associated with severe chronic hemolytic anemia. The mutations observed show a striking predominance of C----T transitions, with CG doublets involved in four of seven cases. Thus, diverse point mutations may account largely for the phenotypic heterogeneity of G6PD deficiency.
Structural and Functional Correlation of the Trypsin-digested Ca2+ Release Channel of Skeletal Muscle Sarcoplasmic Reticulum (1989)

The effect of trypsin digestion on the (i) fragmentation pattern, (ii) activity, (iii) [3H]ryanodine binding, and (iv) sedimentation behavior of the skeletal sarcoplasmic reticulum (SR) ryanodine receptor-Ca2+ release channel complex has been examined. Mild tryptic digestion of heavy, junctional-derived SR vesicles resulted in the rapid disappearance of the high molecular weight (Mr approximately 400,000) Ca2+ release channel protein on sodium dodecyl sulfate gels and appearance of bands of lower Mr upon immunoblot analysis, without an appreciable effect on [3H]ryanodine binding or the apparent S value (30 S) of the 3-[3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (Chaps)-solubilized channel complex. Further degradation to bands of Mr greater than 70,000 on immunoblots correlated with a reduction of channel size from 30 S to 10-15 S and loss of high affinity [3H]ryanodine binding to the trypsinized receptor, while low affinity [3H]ryanodine binding and [3H]ryanodine bound prior to digestion were retained. Parallel 45Ca2+ efflux measurements also indicated retention of the Ca2+, Mg2+, and ATP regulatory sites, although Ca2+-induced 45Ca2+ release rates were changed. In planar lipid bilayer-single channel measurements, addition of trypsin to the cytoplasmic side of the high conductance (100 pS in 50 mM Ca2+), Ca2+-activated SR Ca2+ channel initially increased the fraction of channel open time and was followed by a complete and irreversible loss of channel activity. Trypsin did not change the unitary conductance, and was without effect on single channel activity when added to the lumenal side of the channel.
Heterocyclic Azo Dyes by Oxidative Coupling (1962)

Abstract New findings in the field of oxidative coupling reactions are reported. These involve: extension of this type of reaction to amidrazone system displaying (vinylogous) tautomerism and to unsymmetrical diarylhydrazines; elucidation of the coupling mechanism for these arylhydrazines and for the amidrazone systems previously described; the properties of some dyes, complexed with heavy metals, and the synthesis of tetraazapentamethine and penta‐azapentamethine dyes.
Heart-Rate Variability and Cardiac Autonomic Function in Diabetes (1990)

Cardiac autonomic function was measured in 25 subjects with insulin-dependent diabetes mellitus and 11 control subjects. Autonomic integrity was assessed with standard tests of autonomic function and a new technique of measuring heart-rate variability (HRV) for 24 h. All of the diabetic subjects were selected on the basis of peripheral or autonomic neuropathy or long-term poorly controlled diabetes. They were divided into groups according to presence or absence of vagal neuropathy based on the results of standard tests of autonomic function. Thirteen diabetic subjects had normal autonomic function tests (group 1), and vagal neuropathy was detected in 12 diabetic subjects (group 2). All subjects were monitored by ambulatory electrocardiograph, and the recordings were played back through an analyzer that identified and timed successive pulse (R-R) intervals. HRV was measured from the standard deviation of the successive differences between R-R intervals. HRV was significantly reduced in group 1 (mean +/- SE 73 +/- 9 ms) and group 2 (65 +/- 12 ms) diabetic subjects compared with the control group (138 +/- 10 ms). The standard tests of autonomic function did not distinguish the vagal dysfunction noted with HRV monitoring in group 1 diabetic subjects compared with control subjects. Measurement of 24-h HRV can detect small changes in cardiac autonomic function compared with currently available tests.
Treatment Guidelines for Patients With Hyperthyroidism and Hypothyroidism (1995)

<h3>Objective.</h3> —To develop a set of minimum clinical guidelines for use by primary care physicians in the evaluation and management of patients with hyperthyroidism and hypothyroidism. <h3>Participants.</h3> —Guidelines were developed by a nine-member ad hoc Standards of Care Committee of the American Thyroid Association (the authors of this article). The participants were selected by the committee chair and the president of the American Thyroid Association on the basis of their clinical experience. The committee members represented different geographic areas within the United States, in order to take into account different practice styles. <h3>Evidence.</h3> —Guidelines were developed on the basis of expert opinion of the participants, as well as on available published information. <h3>Consensus Process.</h3> —Input was obtained from all of the participants, each of whom wrote an initial section of the document. A complete draft document was then written by three participants (P.A.S., D.S.C., and E.G.L.) and resubmitted to the entire committee for revision. The revised document was then submitted to the entire membership of the American Thyroid Association for written comments, which were then reviewed (mainly by P.A.S., D.S.C., and E.G.L.). Many of the suggestions of the American Thyroid Association members were incorporated into the final draft, which was then approved by the Executive Council of the American Thyroid Association. The entire process, from initial drafts to final approval, took approximately 18 months. <h3>Conclusions.</h3> —A set of minimum clinical guidelines for the diagnosis and treatment of hyperthyroidism and hypothyroidism were developed by consensus of a group of experienced thyroidologists. The guidelines are intended to be used by physicians in their care of patients with thyroid disorders, with the expectation that more effective care can be provided, and at a cost savings. (<i>JAMA</i>. 1995;273:808-812)
Determination of human immunodeficiency virus RNA in plasma and cellular viral DNA genotypic zidovudine resistance and viral load during zidovudine-didanosine combination therapy (1995)

Eleven human immunodeficiency virus (HIV)-infected subjects on long-term zidovudine (ZDV) therapy had didanosine (ddI) added to their antiretroviral regimen. HIV RNA in plasma was quantitated by branched-DNA signal amplification assay. Peripheral blood mononuclear cell (PBMC) HIV viral DNA was quantitated by PCR. The relative amounts of wild-type (WT) sequence, ddI resistance-associated codon changes (reverse transcriptase [RT] gene codon 65 K-->R [RT K65R], RT 174V, RT I135K/T/V, and RT M184I/V), and ZDV resistance-associated codon change (RT T215Y/F) from HIV RNA in plasma and RT T215Y/F from PBMC viral DNA were determined by differential hybridization of PCR products from 10 of 11 subjects. All subjects had evidence of RT T215Y/F mutation in both RNA in plasma and PBMC DNA at baseline. Subjects with a mixture of WT and RT T215Y/F HIV RNA in plasma at baseline demonstrated a decline in RNA levels in plasma after the addition of ddI. However, after 6 months of ZDV-ddI therapy, WT HIV RNA in plasma was undetectable in all subjects who had demonstrated a mixture at baseline. Subjects with only RT T215Y/F RNA present in plasma at baseline remained so and demonstrated no decline in RNA levels in plasma. In all subjects, no significant changes in PBMC DNA viral load and RT T215Y/F or WT levels were seen. HIV RNA in plasma demonstrated a significantly higher RT T215Y/F mutant/WT ratio than that of PBMC viral DNA, both at baseline and after ZDV-ddI combination therapy in all subjects. No subjects developed mutations associated with ddI resistance at codons 65, 74, 135, and 184 during this study. This study suggests that determination of relative amounts of RT T215Y/F and WT species from HIV RNA in plasma at baseline may be predictive of virologic response during ZDV-ddI combination therapy.