gebhart/patrepeval huggingface dataset:
Primary Structures of the Genes, faoA and faoB, from Pseudomonas fragi B-0771 Which Encode the Two Subunits of the HDT Multienzyme Complex Involved in Fatty Acid β-Oxidation1 (1992)

Three enzyme activities involved in fatty acid beta-oxidation, i.e., those of enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, and 3-oxoacyl-CoA thiolase, are exhibited by one multienzyme complex (HDT) composed of two molecules each of two peptides in Pseudomonas fragi. Using specific antisera against the two subunits of HDT, we isolated the genes encoding the subunits of HDT and designated them "faoA" (for the alpha-subunit) and "faoB" (for the beta-subunit). Their complete nucleotide sequences were determined and it was revealed that faoA and faoB, both with individual putative S.D. sequences at suitable positions, formed a cluster, in that order. The amino acid sequences deduced from the nucleotide sequences of the two genes indicated that the alpha-subunit, encoded by faoA, is a polypeptide of 715 amino acid residues, and that the beta-subunit, encoded by faoB, consists of 390 amino acid residues lacking the first methionine of the primary product encoded by faoB. Immunoblotting of cell lysates prepared from Escherichia coli transformants carrying plasmids which possess the faoA and/or faoB gene with antisera against the subunits of HDT showed that both the faoA and faoB genes were transcribed and translated in E. coli. The overall activities of 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase were increased in the E. coli cells transformed with the plasmid possessing the faoA gene, suggesting that both the hydratase and dehydrogenase activities may be exhibited by the alpha-subunit of HDT.(ABSTRACT TRUNCATED AT 250 WORDS)
Intermediate Dose Thalidomide (200 mg Daily) has Comparable Efficacy and Less Toxicity than Higher Doses in Relapsed Multiple Myeloma (2003)

Thalidomide at doses >200 mg has 100% grade 1-2 and 25% grade 3-4 toxicities requiring discontinuation. We report a retrospective study of relapsed myeloma patients treated with thalidomide 200 mg with no dose escalation. Thirty patients were identified; 43% of patients responded with paraprotein decline >75% -- 2 (6%), 50-75% -- 7 (23%), 25-50% -- 4 (14%) and 2 (6%) were stable. All five patients with 13q deletion responded. Only 54% reported grade 1-2 toxicities (none reporting > grade 2) with 5 (17%) discontinuing treatment due to toxicity. Thalidomide 200 mg daily with no dose escalation appears as effective and better tolerated than escalated doses for relapsed myeloma patients.
Clinical applications of (18)F-FDG in oncology. (2002)

PET has emerged as a powerful diagnostic tool for the evaluation of cancer patients. Currently, most of these studies are performed with the glucose analog (18)F-FDG, which has been shown to accumulate avidly in most tumors. (18)F-FDG PET is now routinely used in the diagnosis, staging, and posttherapy evaluation of oncologic patients. After reading this paper, the reader should understand the physiologic basis of using (18)F-FDG in patients with different tumors, describe the role of this radiopharmaceutical in the management of oncologic patients, and identify those malignancies for which (18)F-FDG has proved to be effective in diagnosis and follow-up.
Targeting EGFR in Colorectal Cancer (2008)

In the United States, cancer is the most common cause of death among people under the age of 85 years, and colorectal cancer is the second most common cause of death from cancer.1 Chemotherapy for colorectal cancer has until recently typically consisted of the empirical use of cytotoxic agents guided by the results of controlled clinical trials. Cancer therapy has now entered a new era, however, owing to remarkable advances in our understanding of the nature of molecular and biochemical events involved in the process of carcinogenesis and tumor growth. Biologically targeted therapies are now commonly used as part of . . .
Synthesis, Structure, and Resolution of Exceptionally Twisted Pentacenes (2006)

9,10,11,20,21,22-hexaphenyltetrabenzo[a,c,l,n]pentacene (2) and a dimethyl derivative (2m) were prepared by the reaction of 1,3-diphenylphenanthro[9,10-c]furan with bisaryne equivalents generated from 1,2,4,5-tetrabromo-3,6-diarylbenzenes in the presence of n-butyllithium, followed by deoxygenation of the double adducts with low-valent titanium. Both are bright red solids with a strong orange fluorescence in solution. The X-ray structures of these compounds show them to be the most highly twisted polycyclic aromatic hydrocarbons known. Compound 2 has an end-to-end twist of 144 degrees , and the two crystallographically independent molecules of 2m have twists of 138 degrees and 143 degrees. Both molecules were resolved by chromatography on chiral supports, and the pure enantiomers have extremely high specific rotations (for 2, [alpha]D = 7400 degrees; for 2m, 5600 degrees), but the molecules racemize slowly at room temperature (DeltaG++rac = 24 kcal/mol). Both the experimental geometry and the observed racemization barrier for 2 are in good agreement with computational studies of the molecule at a variety of levels. Attempts to prepare compound 2 by reaction of tetraphenylbenzyne with 9,10,12,13-tetraphenyl-11-oxacyclopenta[b]triphenylene (3, a twisted isobenzofuran) gave no adducts, and attempts to prepare tetradecaphenylpentacene by reaction of hexaphenylisobenzofuran (11) with bisaryne equivalents gave only monoadducts.
DNA sequencing: present limitations and prospects for the future (1991)

As the human genome program gets under way, we examine the progress made since the first human genome meeting in Santa Cruz in 1985. The lessons of the last 5 years demonstrate that progress has been much slower than anticipated. The new technology being developed in 1985 was fluorescent sequencing and multiplexing. These techniques are now established, but they still have to produce a substantial sequence to rival those determined by conventional technology. Inspection of the EMBL and GenBank databases shows few large sequences have been determined and that there is a large discrepancy between what is theoretically possible and what has been achieved so far.
Cell-Mediated Protection against PulmonaryYersinia pestisInfection (2005)

Pulmonary infection with the bacterium Yersinia pestis causes pneumonic plague, an often-fatal disease for which no vaccine is presently available. Antibody-mediated humoral immunity can protect mice against pulmonary Y. pestis infection, an experimental model of pneumonic plague. Little is known about the protective efficacy of cellular immunity. We investigated the cellular immune response to Y. pestis in B-cell-deficient microMT mice, which lack the capacity to generate antibody responses. To effectively prime pulmonary cellular immunity, we intranasally vaccinated microMT mice with live replicating Y. pestis. Vaccination dramatically increased survival of microMT mice challenged intranasally with a lethal Y. pestis dose and significantly reduced bacterial growth in pulmonary, splenic, and hepatic tissues. Vaccination also increased numbers of pulmonary T cells, and administration of T-cell-depleting monoclonal antibodies at the time of challenge abrogated vaccine-induced survival. Moreover, the transfer of Y. pestis-primed T cells to naive microMT mice protected against lethal intranasal challenge. These findings establish that vaccine-primed cellular immunity can protect against pulmonary Y. pestis infection and suggest that vaccines promoting both humoral and cellular immunity will most effectively combat pneumonic plague.
Cystatin C is associated with inflammation but not atherosclerosis in systemic lupus erythematosus (2011)

Cystatin C was higher in patients with SLE than in control subjects even after adjustment for conventional measures of renal function. Cystatin C was significantly correlated with several markers of inflammation in SLE but was not associated with coronary atherosclerosis. Subtle renal dysfunction does not appear to be directly associated with accelerated atherosclerosis in SLE.
A Readily Available, Highly Potent E-Selectin Antagonist (2001)

A mix of accident, serendipity, and rational design led to compound 1, the most potent E-selectin inhibitor known to date. It was assembled in ten linear steps in an overall yield of >25 %. In a static assay it was 100-fold more potent than sialyl LewisX. In an even more relevant flow assay that mimics the dynamic in vivo conditions, 1 showed an IC50 of 1–2 μM, whereas sialyl LewisX did not inhibit at concentrations up to 1000 μM.
Effects of ion channel activity on development of dorsal root ganglion neurons (1998)

Studies of mouse dorsal root ganglion neurons in vitro demonstrate that ion channel function and regulation can influence a wide range of developmental processes. The work suggests that much as exposure to different trophic factors, the pattern of impulse activity a neuron experiences can have significant structural and functional effects during development. Studies concerning effects of ion channel activity on growth cone motility, axon fasciculation, synaptic plasticity, myelination, and intracellular signaling pathways regulating gene expression are presented in the context of changes in endogenous firing patterns during development.
Naltrexone and morphine alter the discrimination and plasma levels of ethanol (1999)

The opioid antagonist, naltrexone, reduces intake of, and operant responding for, ethanol, but reports of how the opioid agonist morphine alters these effects are conflicting. We examined the discrimination and plasma levels of ethanol with naltrexone and morphine pretreatments. Rats were trained to discriminate ethanol (1.5 g/kg; i.g.) from water, under a two-lever, food-reinforced procedure. Ethanol and pentobarbital, but not amphetamine, substituted for ethanol in a dose-related manner. Naltrexone reduced ethanol-induced, ethanol-appropriate responding to about 35%, but the peripherally-acting antagonist, naltrexone methobromide, was without effect. Morphine neither substituted for nor enhanced ethanol-appropriate responding. Rather, ethanol-induced, ethanol-appropriate responding was attenuated in a dose-related manner by morphine administration. Neither naltrexone nor morphine altered ethanol-appropriate responding to the substitution with pentobarbital. In another group of rats, both naltrexone and morphine decreased plasma ethanol levels, and delayed the time of peak concentrations, suggesting that opiates alter the behavioral effects of ethanol through both pharmacokinetic and pharmacodynamic mechanisms. The similarities between an opioid agonist and an antagonist suggest that either naltrexone has opioid agonist-like effects, or that these effects occur through non-opioidergic mechanisms.
Single‐dose intravenous iron infusion versus red blood cell transfusion for the treatment of severe postpartum anaemia: a randomized controlled pilot study (2016)

This pilot study shows that intravenous iron could be an attractive alternative to RBC transfusion in severe postpartum anaemia, and that a larger trial is needed and feasible.
Candidate driver genes in microsatellite‐unstable colorectal cancer (2011)

Defects in the mismatch repair system lead to microsatellite instability (MSI), a feature observed in ∼ 15% of all colorectal cancers (CRCs). Microsatellite mutations that drive tumourigenesis, typically inactivation of tumour suppressors, are selected for and are frequently detected in MSI cancers. Here, we evaluated somatic mutations in microsatellite repeats of 790 genes chosen based on reduced expression in MSI CRC and existence of a coding mononucleotide repeat of 6-10 bp in length. All the repeats were initially sequenced in 30 primary MSI CRC samples and whenever frameshift mutations were identified in >20%, additional 70 samples were sequenced. To distinguish driver mutations from passengers, we similarly analyzed the occurrence of frameshift mutations in 121 intronic control repeats and utilized a statistical regression model to determine cut-off mutation frequencies for repeats of all types (A/T and C/G, 6-10 bp). Along with several know target genes, including TGFBR2, ACVR2, and MSH3, six novel candidate driver genes emerged that harbored significantly more mutations than identical control repeats. The mutation frequencies in 100 MSI CRC samples were 51% in G8 of GLYR1, 47% in T9 of ABCC5, 43% in G8 of WDTC1, 33% in A8 of ROCK1, 30% in T8 of OR51E2, and 28% in A8 of TCEB3. Immunohistochemical staining of GLYR1 revealed defective protein expression in tumors carrying biallelic mutations, supporting a loss of function hypothesis. This is a large scale, unbiased effort to identify genes that when mutated are likely to contribute to MSI CRC development.
Nox2 and Rac1 Regulate H2O2-Dependent Recruitment of TRAF6 to Endosomal Interleukin-1 Receptor Complexes (2005)

Reactive oxygen species (ROS) generated by NADPH oxidases (Nox) have been implicated in the regulation of signal transduction. However, the cellular mechanisms that link Nox activation with plasma membrane receptor signaling remain poorly defined. We have found that Nox2-derived ROS influence the formation of an active interleukin-1 (IL-1) receptor complex in the endosomal compartment by directing the H2O2-dependent binding of TRAF6 to the IL-1R1/MyD88 complex. Clearance of both superoxide and H2O2 from within the endosomal compartment significantly abrogated IL-1beta-dependent IKK and NF-kappaB activation. MyD88-dependent endocytosis of IL-1R1 following IL-1beta binding was required for the redox-dependent formation of an active endosomal receptor complex competent for IKK and NF-kappaB activation. Small interfering RNAs to either MyD88 or Rac1 inhibited IL-1beta induction of endosomal superoxide and NF-kappaB activation. However, MyD88 and Rac1 appear to be recruited independently to IL-1R1 following ligand stimulation. In this context, MyD88 binding was required for inducing endocytosis of IL-1R1 following ligand binding, while Rac1 facilitated the recruitment of Nox2 into the endosomal compartment and subsequent redox-dependent recruitment of TRAF6 to the MyD88/IL-1R1 complex. The identification of Nox-active endosomes helps explain how subcellular compartmentalization of redox signals can be used to direct receptor activation from the plasma membrane.
Irreversible Inhibition of EGFR: Modeling the Combined Pharmacokinetic–Pharmacodynamic Relationship of Osimertinib and Its Active Metabolite AZ5104 (2016)

Osimertinib (AZD9291) is a potent, selective, irreversible inhibitor of EGFR-sensitizing (exon 19 and L858R) and T790M-resistant mutation. In vivo, in the mouse, it is metabolized to an active des-methyl metabolite, AZ5104. To understand the therapeutic potential in patients, this study aimed to assess the relationship between osimertinib pharmacokinetics, the pharmacokinetics of the active metabolite, the pharmacodynamics of phosphorylated EGFR reduction, and efficacy in mouse xenograft models of EGFR-driven cancers, including two NSCLC lines. Osimertinib was dosed in xenografted models of EGFR-driven cancers. In one set of experiments, changes in phosphorylated EGFR were measured to confirm target engagement. In a second set of efficacy studies, the resulting changes in tumor volume over time after repeat dosing of osimertinib were observed. To account for the contributions of both molecules, a mathematical modeling approach was taken to integrate the resulting datasets. The model was able to describe the pharmacokinetics, pharmacodynamics, and efficacy in A431, PC9, and NCI-H1975 xenografts, with the differences in sensitivity described by the varying potency against wild-type, sensitizing, and T790M-mutant EGFR and the phosphorylated EGFR reduction required to reduce tumor volume. It was inferred that recovery of pEGFR is slower after chronic dosing due to reduced resynthesis. It was predicted and further demonstrated that although inhibition is irreversible, the resynthesis of EGFR is such that infrequent intermittent dosing is not as efficacious as once daily dosing. Mol Cancer Ther; 15(10); 2378-87. ©2016 AACR.
Signaling Maximum SID Depth using Border Gateway Protocol Link-State (2017)

This document proposes a way to signal Maximum SID Depth (MSD)
supported by a node at node and/or link granularity by a BGP-LS
speaker. In a Segment Routing (SR) enabled network a centralized
controller that programs SR tunnels needs to know the MSD supported by
the head-end at node and/or link granularity to push the SID stack of
an appropriate depth. MSD is relevant to the head-end of a SR tunnel
or Binding-SID anchor node where Binding-SID expansions might result
in creation of a new SID stack.
A Fatal Relationship—Influenza Virus Interactions with the Host Cell (1999)

Influenza A viruses are important worldwide pathogens for humans and different animal species. The infectious agent is the prototype of the orthomyxoviridae which are characterized by a segmented negative strand RNA genome that is replicated in the nucleus of the infected cell. The genome has a combined coding capacity of about 13 kb and contains the genetic information for ten viral proteins. Despite this relatively small coding capacity--large DNA viruses like herpes or poxviruses express about 150-200 gene products--influenza A viruses are able to successfully infect and multiply in a wide range of mammalian and avian species. It is therefore not surprising that influenza A viruses extensively use and manipulate host cell functions. This includes multiple interactions of viral proteins with cellular proteins. In recent years an increasing amount of information about the identity of the cellular factors that are involved in viral transcription and replication, intracellular trafficking of viral components and assembly of the virus particle has accumulated. This article aims to review recent developments in this field with a focus on cellular factors and processes which are activated by the virus to either support viral replication or to counteract host-cell defense mechanisms.
Association of Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor-2 Genetic Polymorphisms With Outcome in a Trial of Paclitaxel Compared With Paclitaxel Plus Bevacizumab in Advanced Breast Cancer: ECOG 2100 (2008)

Our data support an association between VEGF genotype and median OS as well as grade 3 or 4 hypertension when using bevacizumab in metastatic breast cancer.
Structural and functional domains of the myb oncogene: requirements for nuclear transport, myeloid transformation, and colony formation (1988)

The v-myb oncogene of avian myeloblastosis virus causes acute myelomonocytic leukemia in vivo and transforms only myeloid cells in vitro. Its product, p48v-myb, is a nuclear protein of unknown function. To determine structure-function relationships for this protein, we constructed a series of deletion mutants of v-myb, expressed them in retroviral vectors, and studied their biochemical and biological properties. We used these mutants to identify two separate domains of p48v-myb which had distinct roles in its accumulation in the cell nucleus. We showed that the viral sequences which normally encode both termini of p48v-myb were dispensible for transformation. In contrast, both copies of the highly conserved v-myb amino-terminal repeat were required for transformation. We also identified a carboxyl-terminal domain of p48v-myb which was required for the growth of v-myb-transformed myeloblasts in soft agar but not for morphological transformation.
The Body-Mass Index of Twins Who Have Been Reared Apart (1990)

To assess the relative importance of genetic and environmental effects on the body-mass index (weight in kilograms divided by the square of the height in meters), we studied samples of identical and fraternal twins, reared apart or reared together. The samples consisted of 93 pairs of identical twins reared apart, 154 pairs of identical twins reared together, 218 pairs of fraternal twins reared apart, and 208 pairs of fraternal twins reared together. The intrapair correlation coefficients of the values for body-mass index of identical twins reared apart were 0.70 for men and 0.66 for women. These are the most direct estimates of the relative importance of genetic influences (heritability) on the body-mass index, and they were only slightly lower than those for twins reared together in this and earlier studies. Similar estimates were derived from maximum-likelihood model-fitting analyses--0.74 for men and 0.69 for women. Nonadditive genetic variance made a significant contribution to the estimates of heritability, particularly among men. Of the potential environmental influences, only those unique to the individual and not those shared by family members were important, contributing about 30 percent of the variance. Sharing the same childhood environment did not contribute to the similarity of the body-mass index of twins later in life. We conclude that genetic influences on body-mass index are substantial, whereas the childhood environment has little or no influence. These findings corroborate and extend the results of earlier studies of twins and adoptees.
Glycosylation: Heterogeneity and the 3D Structure of Proteins (1997)

Glycoproteins generally exist as populations of glycosylated variants (glycoforms) of a single polypeptide. Although the same glycosylation machinery is available to all proteins that enter the secretory pathway in a given cell, most glycoproteins emerge with characteristic glycosylation patterns and heterogeneous populations of glycans at each glycosylation site. The factors that control the composition of the glycoform populations and the role that heterogeneity plays in the function of glycoproteins are important questions for glycobiology. A full understanding of the implications of glycosylation for the structure and function of a protein can only be reached when a glycoprotein is viewed as a single entity. Individual glycoproteins, by virtue of their unique structures, can selectively control their own glycosylation by modulating interactions with the glycosylating enzymes in the cell. Examples include protein-specific glycosylation within the immunoglobulins and immunoglobulin superfamily and site-specific processing in ribonuclease, Thy-1, IgG, tissue plasminogen activator, and influenza A hemagglutinin. General roles for the range of sugars on glycoproteins such as the leukocyte antigens include orientating the molecules on the cell surface. A major role for specific sugars is in recognition by lectins, including chaperones involved in protein folding. In addition, the recognition of identical motifs in different glycans allows a heterogeneous population of glycoforms to participate in specific biological interactions.
Low-dose thalidomide and donor lymphocyte infusion as adoptive immunotherapy after allogeneic stem cell transplantation in patients with multiple myeloma (2004)

To improve the antimyeloma effect of donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation in multiple myeloma, we investigated in a phase 1/2 study the effect of low-dose thalidomide (100 mg) followed by DLI in 18 patients with progressive disease or residual disease and prior ineffective DLI after allografting. The overall response rate was 67%, including 22% complete remission. Major toxicity of thalidomide was weakness grade I/II (68%) and peripheral neuropathy grade I/II (28%). Only 2 patients experienced mild grade I acute graft versus host disease (aGvHD) of the skin, while no grades II to IV aGvHD was seen. De novo limited chronic GvHD (cGvHD) was seen in 2 patients (11%). The 2-year estimated overall and progression-free survival were 100% and 84%, respectively. Adoptive immunotherapy with low-dose thalidomide and DLI induces a strong antimyeloma effect with low incidence of graft versus host disease.