gebhart/patrepeval huggingface dataset:
The gene for B7, a costimulatory signal for T-cell activation, maps to chromosomal region 3q13.3-3q21 (1992)

B7 is an activation antigen expressed on activated B cells and gamma- interferon-stimulated monocytes. The B7 antigen is the natural ligand for CD28 on T cells. After engagement of T-cell receptor with antigen in association with major histocompatibility complex class II, a second signal mediated through the binding of B7 to CD28 greatly upregulates the production of multiple lymphokines. We have now mapped the B7 gene to human chromosome 3 using the technique of polymerase chain reaction on a panel of hamster x human somatic cell hybrid DNAs. We have further localized the gene to 3q13.3–3q21 using in situ hybridization on human metaphase chromosomes. Trisomy of chromosome 3 is a recurrent chromosome change seen in various lymphomas and lymphoproliferative diseases, particularly diffuse, mixed, small, and large cell lymphomas, human T-cell lymphotropic virus type I-induced adult T-cell leukemia, and angioimmunoblastic lymphadenopathy. A number of chromosomal defects involving 3q21 have been described in acute myeloid leukemia and also in myelodysplastic and myeloproliferative syndromes. The mapping of B7 may permit further insight into disease states associated with aberrant lymphocyte activation and lymphokine synthesis.
The Autoreactivity of Anti-Phosphorylcholine Antibodies for Atherosclerosis-Associated Neo-Antigens and Apoptotic Cells (2003)

Abs specific for phosphorylcholine (PC) are known to contribute to the immune defense against a variety of microbial infections. To assess for other types of binding interactions, we performed surveys of anti-PC Abs of diverse biologic origins and structural diversity and demonstrated a common autoreactivity for oxidatively modified low density lipoprotein and other oxidation-specific structures containing PC-Ags. We also found that cells undergoing apoptosis sequentially express a range of oxidation-specific neo-self PC determinants. Whereas natural Abs to PC recognized cells at early stages of apoptosis, by contrast, an IgG anti-PC Ab, representative of a T cell-dependent response, recognized PC determinants primarily associated with late stages of apoptosis. Cumulatively, these results demonstrate a fundamental paradigm in which Abs from both the innate and the T cell-dependent tiers of the B cell compartment recognize a minimal molecular motif arrayed both on microbes and as neo-self Ags linked to atherosclerosis and autoimmune disease.
HLA-B27 Misfolding in Transgenic Rats Is Associated with Activation of the Unfolded Protein Response (2005)

The mechanism by which the MHC class I allele, HLA-B27, contributes to spondyloarthritis pathogenesis is unknown. In contrast to other alleles that have been examined, HLA-B27 has a tendency to form high m.w. disulfide-linked H chain complexes in the endoplasmic reticulum (ER), bind the ER chaperone BiP/Grp78, and undergo ER-associated degradation. These aberrant characteristics have provided biochemical evidence that HLA-B27 is prone to misfold. Recently, similar biochemical characteristics of HLA-B27 were reported in cells from HLA-B27/human beta2-microglobulin transgenic (HLA-B27 transgenic) rats, an animal model of spondyloarthritis, and correlated with disease susceptibility. In this study, we demonstrate that the unfolded protein response (UPR) is activated in macrophages derived from the bone marrow of HLA-B27 transgenic rats with inflammatory disease. Microarray analysis of these cells also reveals an IFN response signature. In contrast, macrophages derived from premorbid rats do not exhibit a strong UPR or evidence of IFN exposure. Activation of macrophages from premorbid HLA-B27 transgenic rats with IFN-gamma increases HLA-B27 expression and leads to UPR induction, while no UPR is seen in cells from nondisease-prone HLA-B7 transgenic or wild-type (nontransgenic) animals. This is the first demonstration, to our knowledge, that HLA-B27 misfolding is associated with ER stress that results in activation of the UPR. These observations link HLA-B27 expression with biological effects that are independent of immunological recognition, but nevertheless may play an important role in the pathogenesis of inflammatory diseases associated with this MHC class I allele.
A Cyanobacterial Phytochrome Two-Component Light Sensory System (1997)

The biliprotein phytochrome regulates plant growth and developmental responses to the ambient light environment through an unknown mechanism. Biochemical analyses demonstrate that phytochrome is an ancient molecule that evolved from a more compact light sensor in cyanobacteria. The cyanobacterial phytochrome Cph1 is a light-regulated histidine kinase that mediates red, far-red reversible phosphorylation of a small response regulator, Rcp1 (response regulator for cyanobacterial phytochrome), encoded by the adjacent gene, thus implicating protein phosphorylation-dephosphorylation in the initial step of light signal transduction by phytochrome.
The lung as a route for systemic delivery of therapeutic proteins and peptides (2001)

The large surface area, good vascularization, immense capacity for solute exchange and ultra-thinness of the alveolar epithelium are unique features of the lung that can facilitate systemic delivery via pulmonary administration of peptides and proteins. Physical and biochemical barriers, lack of optimal dosage forms and delivery devices limit the systemic delivery of biotherapeutic agents by inhalation. Current efforts to overcome these difficulties in order to deliver metabolic hormones (insulin, calcitonin, thyroid-stimulating hormone [TSH], follicle-stimulating hormone [FSH] and growth hormones) systemically, to induce systemic responses (immunoglobulins, cyclosporin A [CsA], recombinant-methionyl human granulocyte colony-stimulating factor [r-huG-CSF], pancreatic islet autoantigen) and to modulate other biological processes via the lung are reviewed. Safety aspects of pulmonary peptide and protein administration are also discussed.
Structure of Poly(dA)·Poly(dT) is not Identical to the AT Rich Regions of the Single Crystal Structure of CGCGAATTBrCGCG. The Consequence of this to Netropsin Binding to Poly(dA)·Poly(dT) (1985)

The basic assumption of Dickerson and Kopka (J. Biomole. Str. Dyns. 2, 423, 1985) that the conformation of poly(dA).poly(dT) in solution is identical to the AT rich region of the single crystal structure of the Dickerson dodecamer is not supported by any experimental data. In poly(dA).poly(dT), NOE and Raman studies indicate that the dA and dT units are conformationally equivalent and display the (anti-S-type sugar)-conformation; incorporation of this nucleotide geometry into a double helix leads to a conventional regular B-helix in which the width of the minor groove is 8A. The derived structure is consistent with all available experimental data on poly(dA).poly(dT) obtained under solution conditions. In the crystal structure of the dodecamer, the dA and dT units have distinctly different conformations-dA residues adopt (anti, S-type sugar pucker), while dT residues belong to (low anti, N-type sugar pucker). These different conformations of the dA and dT units along with the large propeller twist can be accommodated in a double helix in which the minor groove is shrunk from 8A to less than 4A. In the conventional right handed B-form of poly(dA).poly(dT) with the 8A wide minor groove, netropsin has to bind asymmetrically along the dA strand to account for the NOE and chemical shift data and to generate a stereochemically sound structure (Sarma et al, J. Biomole. Str. Dyns. 2, 1085, 1985).
Heterologous Expression of Human Cholecystokinin in Saccharomyces cerevisiae (1997)

Precursors of the human regulatory peptide cholecystokinin (CCK) have been expressed in Saccharomyces cerevisiae, and the post-translational processing of secreted CCK-related products analyzed. Recombinant plasmids expressing native human prepro-CCK and a hybrid molecule encompassing the prepro leader of the yeast alpha-mating pheromone fused to pro-CCK were examined. The latter construct resulted in considerably higher levels of pro-CCK secretion and was therefore analyzed in more detail. Two of the protein modifications essential for CCK bioactivity, C-terminal alpha-amidation and tyrosyl sulfation, were not detected in S. cerevisiae. Proteolytic cleavage of pro-CCK occurred C-terminally of three basic sites; (i) Arg105-Arg106 which, upon exposure to carboxypeptidase activity, leads to the production of glycine-extended CCK; (ii) Arg95 to produce CCK-8 related processing intermediates; and (iii) Lys81 resulting in CCK-22 related products. To elucidate which protease(s) are involved in these endoproteolytic cleavage events, pro-CCK was expressed in yeast mutants lacking various combinations of the Mkc7, Yap3, and Kex2 proteases. Only in S. cerevisiae strains deficient in Kex2 function was any of the above mentioned pro-CCK cleavages abolished, namely processing at the Arg105-Arg106 and Arg95 sites. This suggests that mammalian Kex2-like serine proteases may process pro-CCK at single arginine residues. Our data suggests that an as yet uncharacterized endopeptidase(s) in the S. cerevisiae secretory pathway is responsible for the lysine-specific cleavage of pro-CCK.
Glutaraldehyde Inactivation of Exotic Animal Viruses in Swine Heart Tissue (1979)

Glutaraldehyde, 0.2%, in a 1:100 (wt/vol) ratio, inactivated four animal viruses (foot-and-mouth disease, swine vesicular disease, African swine fever, hog cholera) in swine heart tissues during 11-day exposures at 22 to 26 degrees C.
Pathology of Layer V Pyramidal Neurons in the Prefrontal Cortex of Patients With Schizophrenia (2004)

These results indicate that abnormal dendritic outgrowth or maintenance contributes to reduced neuropil and prefrontal connectivity in schizophrenia. Short postmortem intervals and resulting high tissue quality suggest that these dystrophic changes reflect schizophrenia pathology rather than postmortem artifact.
Nucleotide sequence of human monocyte interleukin 1 precursor cDNA. (1984)

Interleukin 1 (IL-1) is a protein with several biological activities regulating host defense and immune responses. We report here the isolation of human IL-1 cDNA. It encodes a precursor polypeptide of 269 amino acids (30,747 Mr). mRNA isolated by hybridization to this cDNA was translated in a reticulocyte cell-free system, yielding immunoprecipitable IL-1. Furthermore, this hybrid-selected mRNA was injected into Xenopus laevis oocytes, which subsequently secreted biologically active IL-1. The cDNA nucleotide sequence suggests that IL-1 is initially translated as a precursor molecule that is subsequently processed into the 15,000-20,000 Mr protein usually associated with IL-1 activity.
Phase I study of biweekly liposome irinotecan (PEP02, MM-398) in metastatic colorectal cancer failed on first-line oxaliplatin-based chemotherapy. (2012)

613 Background: PEP02 (MM-398) is a nanoliposomal formulation of irinotecan (CPT-11) that has improved pharmacokinetics (PK) and tumor distribution of CPT-11 and its active metabolite, SN-38. PEP02 single agent q3w has shown preliminary efficacy and safety in Phase II pancreatic and gastric cancer studies. Since irinotecan is approved for metastatic colorectal cancer (mCRC) and biweekly regimens are widely used, the aims of this study are to determine the maximum tolerated dose (MTD), characterize the PK and pharmacogenetics (PGx), and explore the efficacy of PEP02 q2w in mCRC. Methods: Patients (pts) with disease progression after 1 st -line oxaliplatin-based chemotherapy, ECOG PS 0-1, and without prior exposure to irinotecan were eligible. PEP02 was given on day 1 and 15 of each 28 day treatment cycle. The starting dose was 80 mg/m 2 and escalated by 10 mg/m 2 to the target dose of 100 mg/m 2 . PK was evaluated during the 1 st cycle and the tumor response was assessed by RECIST. Results: A total of 18 pts (M/F 9/9; median age 57.5) were enrolled, with 6 at each dose level. Dose-limiting toxicity manifested as G3 diarrhea was observed in one pt per dose level. The target dose of 100 mg/m 2 was determined to be the MTD. Nine pts had dose delayed (4, 3, 2 at 80, 90, 100 mg/m 2 ), mostly because of neutropenia. The PK and PGx are being analysed. As of August 2011, there are 3 pts still on study treatment and 17 pts evaluable for tumor response. Four pts (2 at 80 mg/m 2 , 1 each at 90 and 100 mg/m 2 ) showed partial response (3 after 2 cycles and 1 after 8 cycles) and 8 pts (3 each at 80 and 90 mg/m 2 , 2 at 100 mg/m 2 ) maintained stable disease for at least 2 cycles, which resulted in a response rate (RR) of 23.5% and a disease control rate (DCR) of 70.6%. Current median progression-free survival (PFS) is 4 months and 8 pts (47%) had PFS ≥ 6 months. Conclusions: The MTD of biweekly PEP02 is 100 mg/m 2 . As a 2 nd -line monotherapy after oxaliplatin-based chemotherapy, the efficacy results indicate the potential benefit of PEP02 for mCRC (FOLFIRI-1 achieved only 4% RR, 34% DCR, and 2.5 months PFS in FOLFOX pretreated pts). A randomized Phase II study evaluating PEP02 plus 5-FU/LV (FUPEP regimen) vs. FOLFIRI is currently ongoing in France.
Concepts and strategies for human gene therapy (1992)

Methods of modern molecular genetics have been developed that allow stable transfer and expression of foreign DNA sequences in human and other mammalian somatic cells. It is therefore no surprise that the methods have been applied in attempts to complement genetic defects and correct disease phenotypes. Two decades of research have now led to the first clinically applicable attempts to introduce genetically modified cells into human beings to cure diseases caused at least partially by genetic defects. We discuss here some of the strategies being followed for both in vitro and in vivo application of therapeutic gene transfer and summarize some of the technical and conceptual difficulties associated with somatic-cell gene therapy.
Emergent issues in the genetics of intestinal neoplasia. (1995)

Mutation of the APC gene may be a common denominator of all human colon cancer--polypoid and non-polypoid familial cancer as well as sporadic occurrences. Fearon and Vogelstein (1990) have described a series of molecular changes during the progression of human colon cancer, beginning with mutations in APC. Min is a strain of the laboratory mouse carrying a nonsense mutation in Apc, the mouse homologue of APC. The Min strain has been used to test the effect of germline alterations in certain genes identified in the progression pathway of Fearon and Vogelstein. A deficiency in DNA cytosine methylase leads to a reduction in the tumour multiplicity of Min mice contrary to the a priori expectation based on the global hypomethylation of the DNA of early colonic neoplasms. Alterations in Kras had no perceptible effect on the tumour multiplicity of Min mice but may not have been successfully directed to the proliferative cell population. Constitutional mutation of p53 did not influence the multiplicity or histopathology of early Min induced intestinal tumours. The cause and effect analysis of the genetics of colon cancer is clearly in an early phase. An unlinked genetic factor interacting with Min in controlling intestinal tumour multiplicity is Mom1. A central goal for the near future is to identify the Mom1 gene product and to identify other loci that can interact with the Min mutation and affect tumour multiplicity or progression. Mouse chimaeras will permit an analysis of the clonality and cell autonomy of Min induced neoplasms and also of the action of Mom1. The results of these analyses will inform investigators as to what modes of prevention and therapy might be designed for particular tumour types. The Min strain thereby presents an opportunity to discover protective factors against human colon cancer.
Structure-Activity Relationship Study of Antimicrobial Dermaseptin S4 Showing the Consequences of Peptide Oligomerization on Selective Cytotoxicity (2000)

To understand how peptide organization in aqueous solution might affect the activity of antimicrobial peptides, the potency of various dermaseptin S4 analogs was assessed against human red blood cells (RBC), protozoa, and several Gram-negative bacteria. Dermaseptin S4 had weak antibacterial activity but potent hemolytic or antiprotozoan effects. K(4)K(20)-S4 was 2-3-fold more potent against protozoa and RBC, yet K(4)K(20)-S4 was more potent by 2 orders of magnitude against bacteria. K(4)-S4 had similar behavior as K(4)K(20)-S4, but K(20)-S4 and analogous negative charge substitutions were as active as dermaseptin S4 or had reduced activity. Binding experiments suggested that potency enhancement was not the result of increased affinity to target cells. In contrast, potency correlated well with aggregation properties. Fluorescence studies indicated that K(20)-S4 and all negative charge substitutions were as aggregated as dermaseptin S4, whereas K(4)-S4 and K(4)K(20)-S4 were clearly less aggregated. Overall, the data indicated that N-terminal domain interaction between dermaseptin S4 monomers is responsible for the peptide's oligomerization in solution and, hence, for its limited spectrum of action. Moreover, bell-shaped dose-response profiles obtained with bacteria but not with protozoa or RBC implied that aggregation can have dramatic consequences on antibacterial activity. Based on these results, we tested the feasibility of selectivity reversal in the activity of dermaseptin S4. Tampering with the composition of the hydrophobic domains by reducing hydrophobicity or by increasing the net positive charge affected dramatically the peptide's activity and resulted in various analogs that displayed potent antibacterial activity but reduced hemolytic activity. Among these, maximal antibacterial activity was displayed by a 15-mer version that was more potent by 2 orders of magnitude compared with native dermaseptin S4. These results emphasize the notion that peptide-based antibiotics represent a highly modular synthetic antimicrobial system and provide indications of how the peptide's physico-chemical properties affect potency and selectivity.
Interstitial Cells of Cajal Are Involved in Neurotransmission in the Gastrointestinal Tract (2006)

Interstitial cells of Cajal (ICC) are important cells which coordinate gastrointestinal motility. ICC express Kit receptor tyrosine kinase, and Kit immunohistochemistry reveals ICC morphology and distribution in the gastrointestinal musculature. ICC show a highly branched morphology and form unique networks. Myenteric ICC (ICC-MY) are located at the layer of the myenteric plexus and serve as electrical pacemakers. Intramuscular ICC (ICC-IM) and ICC in the deep muscular plexus (ICC-DMP) are distributed within the muscular layers, and are densely innervated by excitatory and inhibitory enteric motor neurons and in close contact with nerve terminals. Recent studies combined with morphological and functional techniques directly revealed that ICC-IM and ICC-DMP are mediators of enteric motor neuro-transmission. These types of ICC express several receptors for neurotransmitters such as acetylcholine and substance P and show responses to excitatory nerve stimulations. ICC also express receptive mechanisms for nitric oxide, which is an inhibitory neurotransmitter in the gastrointestinal tract. They can respond to nitrergic nerve stimulation by cyclic GMP production. Kit mutant mice lack ICC-IM and show attenuated postsynaptic responses after intrinsic nerve stimulation. These findings indicate the importance for ICC in neurotransmission in the gastrointestinal tract.
GLYCINE UPTAKE IN RAT CENTRAL NERVOUS SYSTEM SLICES AND HOMOGENATES: EVIDENCE FOR DIFFERENT UPTAKE SYSTEMS IN SPINAL CORD AND CEREBRAL CORTEX (1971)

Abstract— Evidence is presented that glycine is taken up by two different transport systems in rat CNS tissue slices; one system has relatively low affinity for glycine (K m = 300 μ m ) and predominates in cerebral cortex, cerebellum and mid‐brain, the other has a higher affinity for glycine (K m = 40 μ m ) and is detectable only in spinal cord, medulla and pons. The low affinity transport system appears to be shared by other small neutral amino acids, whereas the high affinity system is very specific for glycine. Both transport systems were shown to be present in particles in homogenates of CNS tissue by incubation with glycine in vitro , and subcellular fractionation studies suggested that synaptosomes were partly responsible for such uptake. Various substances were tested as inhibitors of the high affinity uptake system for glycine in spinal cord slices; the most potent inhibitors were p ‐chloro‐mercuriphenylsulphonate, N ‐ethylmaleimide, chlorpromazine, imipramine, desipramine, hydrazinoacetic acid and haloperidol. No competitive inhibitors of the high affinity glycine uptake were found. It is suggested that the high affinity transport system is associated with inhibitory synapses where glycine is a transmitter.
Protein Interaction Domain Mapping of Human Kinetochore Protein Blinkin Reveals a Consensus Motif for Binding of Spindle Assembly Checkpoint Proteins Bub1 and BubR1 (2011)

The kinetochore is a supramolecular structure essential for microtubule attachment and the mitotic checkpoint. Human blinkin/human Spc105 (hSpc105)/hKNL1 was identified originally as a mixed-lineage leukemia (MLL) fusion partner and later as a kinetochore component. Blinkin directly binds to several structural and regulatory proteins, but the precise binding sites have not been defined. Here, we report distinct and essential binding domains for Bub1 and BubR1 (here designated Bubs) at the N terminus of blinkin and for Zwint-1 and hMis14/hNsl1 at the C terminus. The minimal binding sites for Bub1 and BubR1 are separate but contain a consensus KI motif, KI(D/N)XXXF(L/I)XXLK. RNA interference (RNAi)-mediated replacement with mutant blinkin reveals that the Bubs-binding domain is functionally important for chromosome alignment and segregation. We also provide evidence that hMis14 mediates hNdc80 binding to blinkin at the kinetochore. The C-terminal fragment of blinkin locates at kinetochores in a dominant-negative fashion by displacing endogenous blinkin from kinetochores. This negative dominance is relieved by mutations of the hMis14 binding PPSS motif on the C terminus of blinkin or by fusion of the N sequence that binds to Bub1 and BubR1. Taken together, these results indicate that blinkin functions to connect Bub1 and BubR1 with the hMis12, Ndc80, and Zwint-1 complexes, and disruption of this connection may lead to tumorigenesis.
Expression of PD-1 on CD4+Tumor-Infiltrating Lymphocytes in Tumor Microenvironment Associated with Pathological Characteristics of Breast Cancer (2018)

CD4<sup>+</sup>/PD-1<sup>+</sup> or CD4<sup>+</sup>/PD-1<sup>-</sup> tumor-infiltrating lymphocytes showed diverse association with pathological features of breast cancer. CD4<sup>+</sup>/PD-1<sup>+</sup> tumor-infiltrating lymphocytes had a significant relationship with Ki-67 expression whereas CD4<sup>+</sup>/PD-1<sup>-</sup> tumor-infiltrating lymphocytes had a significant relationship with E-cadherin expression. Further studies are warranted to explore the immunomodulatory effects of phenotypes of CD4<sup>+</sup> T cell subsets in breast cancer.