gebhart/patrepeval huggingface dataset:
Targeting of DEC-205 on human dendritic cells results in efficient MHC class II–restricted antigen presentation (2010)

The use of dendritic cells (DCs) in therapeutic cancer vaccination requires their loading with tumor-specific antigen(s). DEC-205, a phagocytosis receptor mediating antigen uptake, is associated with CD8(+) T-cell responses in mice. Here we fused an anti-DEC-205scFv to an HLA-DP4-restricted epitope from the tumor antigen MAGE-A3, and examined the suitability and efficacy of DEC-205 to deliver a helper epitope to human monocyte-derived DCs (moDCs). The construct specifically bound DEC-205 on human moDCs without negative impact on DC phenotype and function. We measured antigen presentation with specific autologous CD4(+) T cells, generated by TCR-RNA transfection. DEC-205 targeting resulted in significant major histocompatibility complex class II-restricted antigen presentation, and was superior to loading DCs by electroporation of mRNA encoding endosome-targeted MAGE-A3-DCLAMP or by direct peptide pulsing. Anti-DEC-205scFv-MAGE-A3 was presented 100 times more efficiently than the control constructs. DC maturation before or during incubation with anti-DEC-205scFv-MAGE-A3 reduced the interleukin-10/interleukin-2 ratio. Moreover, we successfully applied the DEC-205 targeting strategy to moDCs from malignant melanoma patients. Again, DEC-205-targeted mature DCs (mDCs) presented the antigen more efficiently than peptide-pulsed DCs and maintained their stimulatory capacity after cryoconservation. Thus, DEC-205 targeting represents a feasible and effective method to deliver helper epitopes to DCs in anticancer vaccine strategies, which may also be suitable for DC targeting in vivo.
A morphometric study of bone marrow angiogenesis in hairy cell leukaemia with clinicopathological correlations (2003)

Bone marrow angiogenesis has recently been implicated in the pathophysiology and course of various haematological malignancies. Little is known, however, about the significance of this phenomenon in hairy cell leukaemia (HCL). We evaluated various morphometric characteristics of microvessels, highlighted by means of anti-CD34 immunohistochemistry, in the bone marrow of 44 patients with typical HCL, before and after treatment with interferon-alpha (IFN-alpha). Overall, bone marrow from 103 HCL patients and 20 controls was examined. Microvessel density (MVD) and several size- and shape-related parameters were quantified in the region of most intense vascularization using image analysis. MVD, size-related parameters and the percentage of branching microvessels were higher in HCL than in controls. Likewise, perimeter counts were higher in partial/non-responders than in complete responders. Achievement of complete response was accompanied by smaller calibre microvessels. IFN-alpha induced a decrease in MVD and branching values in cases with diffuse marrow involvement. In univariate analysis, progression-free survival was adversely affected by MVD, branching and major axis length. Multivariate analysis indicated that MVD/branching independently affected progression-free survival and the likelihood of complete response. Our data suggest that the generation of bone marrow microvessels indicated an increased risk of progression and IFN-alpha treatment failure in HCL. Furthermore, the prognostic significance of angiogenesis requires the concomitant assessment of MVD and the complexity of the microvascular network.
Nephron Sparing Surgery for Appropriately Selected Renal Cell Carcinoma Between 4 and 7 Cm Results in Outcome Similar to Radical Nephrectomy (2004)

There were no statistically significant differences in cancer specific survival and distant metastases-free survival between patients treated with NSS and RN for 4 to 7 cm RCC after adjusting for important pathological features. NSS for 4 to 7 cm RCC results in excellent outcome in appropriately selected patients.
The Role of Kinase Inhibitors in the Treatment of Patients with Acute Myeloid Leukemia (2013)

Multiple small molecule kinase inhibitors are currently undergoing development for the treatment of acute myeloid leukemia (AML). Recently, selective and potent FLT3 inhibitors such as AC220 (quizartinib) have proven clinically effective in patients with AML with FLT3 internal tandem duplication (ITD) mutations, but inhibitors of other pathologically activated kinases in AML such as c-KIT and JAK2 have achieved less clinical success. Other classes of inhibitors currently undergoing clinical development target mediators of downstream signaling pathways such as mTOR and MEK or cell cycle machinery such as aurora kinases, PLK1, or cyclin-dependent kinases. Other than FLT3 inhibitors, most inhibitors have achieved only rare bone marrow responses, and kinase inhibitor therapy in AML remains investigational. Continuing efforts to develop kinase inhibitors for the treatment of AML will require careful selection of patients for clinical trials, translational studies to characterize responders, and investigation of combination therapy that may be capable of improving response rates and duration.
Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment (2002)

Targeting the tyrosine kinase activity of BCR-ABL represents a very promising therapeutic strategy in chronic myeloid leukemia (CML). Despite strong efficacy of the tyrosine kinase inhibitor STI571, resistance has been observed in a significant proportion of patients in advanced CML stage or in Ph-positive acute lymphoid leukemia (ALL). We investigated in this study the mechanism of resistance to STI571 through point mutations in the tyrosine kinase domain and/or BCR-ABL gene amplification in 24 patients (16 in chronic phase and 8 in accelerated phase of the disease) who obtained no cytogenetic response to STI571 treatment. Screening for the already-described Thr315Ile point mutation in the ABL domain using a reverse transcription polymerase chain reaction restriction fragment length polymorphism (RT-PCR-RFLP) technique, 3 patients showed a proportion of mutated transcript at the time of resistance. The same technique failed to detect mutation at diagnosis, but a specific allele-specific oligonucleotide (ASO)-PCR on DNA for the Thr315Ile mutation and, after sequencing, for 2 newly described Phe311Leu and Met351Thr substitutions, showed the presence of rare mutated cells prior to STI571 therapy. Furthermore, the increased proportion of mutated cells during treatment detected by ASO-PCR strongly suggested clonal selection by the functional inhibiting effect of these mutations. Finally, no BCR-ABL gene amplification was detected by fluorescent in situ hybridization (FISH) in the 24 STI571-resistant patients. Our data support that in CML patients treated with STI571, ABL mutations are not restricted to the accelerated phase of the disease and that, at least in some cases, mutations seem to occur prior to STI571 therapy, probably as second mutational events during the course of CML.
Beneficial effects of antioxidants in diabetes: possible protection of pancreatic beta-cells against glucose toxicity. (1999)

Oxidative stress is produced under diabetic conditions and possibly causes various forms of tissue damage in patients with diabetes. The aim of this study was to examine the involvement of oxidative stress in the progression of pancreatic beta-cell dysfunction in type 2 diabetes and to evaluate the potential usefulness of antioxidants in the treatment of type 2 diabetes. We used diabetic C57BL/KsJ-db/db mice, in whom antioxidant treatment (N-acetyl-L-cysteine [NAC], vitamins C plus E, or both) was started at 6 weeks of age; its effects were evaluated at 10 and 16 weeks of age. According to an intraperitoneal glucose tolerance test, the treatment with NAC retained glucose-stimulated insulin secretion and moderately decreased blood glucose levels. Vitamins C and E were not effective when used alone but slightly effective when used in combination with NAC. No effect on insulin secretion was observed when the same set of antioxidants was given to nondiabetic control mice. Histologic analyses of the pancreases revealed that the beta-cell mass was significantly larger in the diabetic mice treated with the antioxidants than in the untreated mice. As a possible cause, the antioxidant treatment suppressed apoptosis in beta-cells without changing the rate of beta-cell proliferation, supporting the hypothesis that in chronic hyperglycemia, apoptosis induced by oxidative stress causes reduction of beta-cell mass. The antioxidant treatment also preserved the amounts of insulin content and insulin mRNA, making the extent of insulin degranulation less evident. Furthermore, expression of pancreatic and duodenal homeobox factor-1 (PDX-1), a beta-cell-specific transcription factor, was more clearly visible in the nuclei of islet cells after the antioxidant treatment. In conclusion, our observations indicate that antioxidant treatment can exert beneficial effects in diabetes, with preservation of in vivo beta-cell function. This finding suggests a potential usefulness of antioxidants for treating diabetes and provides further support for the implication of oxidative stress in beta-cell dysfunction in diabetes.
Angiotensin II Signal Transduction in Vascular Smooth Muscle (1997)

In this review, the role of tyrosine kinases in angiotensin II-mediated signal transduction pathways in vascular smooth muscle is discussed. Angiotensin II was isolated by virtue of its vasoconstrictor abilities and has long been thought to play a critical role in hypertension. However, recent studies indicate important roles for angiotensin II in inflammation, atherosclerosis, and congestive heart failure. The expanding role of angiotensin II indicates that multiple signal transduction pathways are likely to be activated in a tissue-specific manner. Exciting recent data show that angiotensin II directly stimulates tyrosine kinases, including pp60(c-src) kinase (c-Src), focal adhesion kinase (FAK), and Janus kinases (JAK2 and TYK2). Angiotensin II may activate receptor tyrosine kinases, such as Axl and platelet-derived growth factor, by as-yet-undefined autocrine mechanisms. Finally, unknown tyrosine kinases may mediate tyrosine phosphorylation of Shc, Raf, and phospholipase C-gamma after angiotensin II stimulation. These angiotensin II-regulated tyrosine kinases appear to be required for angiotensin II effects, such as vasoconstriction, proto-oncogene expression, and protein synthesis, on the basis of studies with tyrosine kinase inhibitors. Thus, understanding angiotensin II-stimulated signaling events, especially those related to tyrosine kinase activity, may form the basis for the development of new therapies for cardiovascular diseases.
Tritiated D‐ala1‐peptide T binding: A pharmacologic basis for the design of drugs which inhibit HIV receptor binding (1988)

Abstract The HIV virus initiates its infectious cycle through a high‐affinity binding interaction between the envelope protein gp 120 and its receptor, the T4 (or CD4) molecule. An octapeptide sequence, termed peptide T, present in the second variable region of gp 120 from the ARV isolate, has been implicated as the attachement site. The core peptide required for activity has been further refined to a pentapeptide, and homologous pentapeptides are similarly positioned in 21 other sequenced HIV isolates. Utilizing a novel direct binding assay of 3 H‐D‐ala 1 ‐peptide T, we now report that synthetic peptides derived from these other isolates are potent competitors of peptide T binding to T4‐positive lymphocytes and brain membranes. Direct peptide T binding is also competable by purified virion gp 120, indicating that these ligands are interactive at the same receptor. Peptide T has sequence relatedness to the peptide vasoactive intestinal peptide (VIP), and VIP and its relevant homologous pentapeptide, VIP[7–11], are also potent inhibitors of peptide T binding. To determine the essential structural features responsible for receptor activity we have studied a series of synthetic peptides substituted with single D‐amino acid residues. These data reveal that the tyrosine of position 7 in peptide T, present in all natural viral isolates, is obligate for receptor activity. Structure/function analysis for a large number of analogs is presented. Significantly, this binding assay is highly correlated with peptide bioactivity in several independent systems, indicating that this methodology can be used for rapid screening of novel, potential anti‐AIDS therapeutics whose target is inhibition of virus gpl20 binding.
Experimental Inoculation of Conventional Pigs with Porcine Reproductive and Respiratory Syndrome Virus and Porcine Circovirus 2 (2002)

Postweaning multisystemic wasting syndrome (PMWS) is a disease of nursery and fattening pigs characterized by growth retardation, paleness of the skin, dyspnea, and increased mortality rates. Porcine circovirus 2 (PCV2) has been demonstrated to be the cause of PMWS. However, other factors are needed for full development of the syndrome, and porcine reproductive and respiratory syndrome virus (PRRSV) infection has been suggested to be one of them. Twenty-four conventional 5-week-old pigs were distributed in four groups: control (n = 5), PRRSV inoculated (n = 5), PCV2 inoculated (n = 7), and PRRSV and PCV2 inoculated (n = 7). The two groups inoculated with PRRSV showed growth retardation. Pigs inoculated with both PRRSV and PCV2 had increased rectal temperature. One of these pigs developed wasting, had severe respiratory distress, and died. The most important microscopic lesion in pigs inoculated with PCV2 was lymphocyte depletion with histiocytic infiltration of the lymphoid organs, more severe and in a wider range of tissues in doubly inoculated pigs. Interstitial pneumonia was observed in the three inoculated groups. PCV2 nucleic acid was found by in situ hybridization in larger amounts and in a wider range of lymphoid tissues in PRRSV- and PCV2-inoculated than in PCV2-inoculated pigs. TaqMan PCR was performed to quantify the PCV2 loads in serum during the experiment. PCV2 loads were higher in doubly inoculated pigs than in pigs inoculated with PCV2 alone. These findings indicate that severe disease can be reproduced in conventional 5-week-old pigs by inoculation of PRRSV and PCV2. Moreover, these results support the hypothesis that PRRSV infection enhances PCV2 replication.
Two Isoforms of NADPH:Cytochrome P450 Reductase inArabidopsis thaliana (1998)

We have investigated two NADPH-cytochrome (Cyt) P450 reductase isoforms encoded by separate genes (AR1 and AR2) in Arabidopsis thaliana. We isolated AR1 and AR2 cDNAs using a mung bean (Phaseolus aureus L.) NADPH-Cyt P450 reductase cDNA as a probe. The recombinant AR1 and AR2 proteins produced using a baculovirus expression system showed similar Km values for Cyt c and NADPH, respectively. In the reconstitution system with a recombinant cinnamate 4-hydroxylase (CYP73A5), the recombinant AR1 and AR2 proteins gave the same level of cinnamate 4-hydroxylase activity (about 70 nmol min-1 nmol-1 P450). The AR2 gene expression was transiently induced by 4- and 3-fold within 1 h of wounding and light treatments, respectively, and the induction time course preceded those of CYP73A5 and a phenylalanine ammonia-lyase (PAL1) gene. On the contrary, the AR1 expression level did not change during the treatments. Analysis of the AR1 and AR2 gene structure revealed that only the AR2 promoter contained three putative sequence motifs (boxes P, A, and L), which are involved in the coordinated expression of CYP73A5 and other phenylpropanoid pathway genes. These results suggest the possibility that AR2 transcription may be functionally linked to the induced levels of phenylpropanoid pathway enzymes.
Time division duplex transmission of direct sequence spread spectrum signals in multipath channels (2002)

The time division duplex (TDD) mode of transmission of direct sequence spread spectrum (DS-SS) signals is proposed for systems operating in multipath channels. It is shown that the TDD systems are simpler, can facilitate efficient power control, consume less power and can operate with simpler mobile unit receivers. In the proposed TDD method, both reverse and forward links use the same frequency band and thus have a highly correlated fading pattern. The reciprocity of fading patterns of forward and reverse links provides for a non-feedback power control technique to improve system performance under multipath fading. In systems where the multipaths are created artificially by using multiple antennas, such as indoor distributed antenna systems, the characteristic of the channel as seen by each antenna can be estimated at base station. The best situated antenna can then be selected and used for transmission, creating in effect a pre-selection diversity combining system at the base station. The function of power control is still carried out at mobile units. Computer simulation results show the performance of a power controlled two-path selection diversity to be within 4 dB of static channel performance at bit error rate (BER) of 10/sup -4/.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Extending Vase Life of Carnations with Aminooxyacetic Acid, Polyamines, EDU, and CCCP1 (1980)

Abstract Aminooxyacetic acid (AOAA) at a concentration of 0.5 mM extended the vase life of carnations ( Dianthus caryophyllus L. cv. White Sim) to a degree comparable to that shown by 0.1 mM aminoethoxyvinylglycine (AVG) (71 to 94%). Increases in vase life ranging from 22 to 53% were also obtained with N-[2-(2-oxo-l-imidazolidinyl) ethyl]-N’-phenylurea (EDU), carbonylcyanide m -chlorophenyl-hydrazone (CCCP), spermidine, putrescine, or spermine. Combinations of AVG and EDU or AOAA and EDU further extended the vase life 134 to 140% over that of the control flowers. These increases were additive to the beneficial effects obtained from the control preservative solution, which contained 2% sucrose and 200 ppm 8-hydroxyquinoline citrate.
Enterovirus D68 Antivirals: Past, Present, and Future (2020)

Enterovirus D68 (EV-D68) is an RNA virus that causes respiratory illnesses mainly in children. In severe cases, it can lead to neurological complications such as acute flaccid myelitis (AFM). EV-D68 belongs to the enterovirus genera of the Picornaviridae family, which also includes many other significant human pathogens such as poliovirus, enterovirus A71, and rhinovirus. There are currently no vaccines or antivirals against EV-D68. In this review, we present the current understanding of the link between EV-D68 and AFM, the mechanism of viral replication, and recent progress in developing EV-D68 antivirals by targeting various viral proteins and host factors that are essential for viral replication. The future directions of EV-D68 antiviral drug discovery and the criteria for drugs to reach clinical trials are also discussed.
Tungsten (IV) carbenes for the metathesis of olefins. Direct observation and identification of the chain carrying carbene complexes in a highly active catalyst system (1982)

On addition of aluminium halides to the carbene complexes W(CHBut)(OCH2But)2X2 conversion into highly active catalysts for olefin metathesis occurs; the nature of the initiating and propagating species in olefin metathesis has been identified by n.m.r. spectroscopy.
F X Nottingham and F X Taunton Two Novel Mutations in Factor X Resulting in Loss of Functional Activity and an Interpretation Using Molecular Modelling (2001)

We report two novel mutations in the Factor X gene which result in a bleeding tendency in two unrelated Caucasian families. Although the mutations occur at adjacent codons in exon 8 and result in reduced functional activity with normal antigen levels, the patterns of inheritance appear to be quite distinct. Factor X Nottingham (alanine 404 threonine) appears to be associated with an autosomal recessive pattern of inheritance. In contrast, Factor X Taunton (arginine 405 glycine) results in a mode of inheritance consistent with an autosomal dominant pattern, all five of the heterozygotes in this family being clinically affected. Molecular modelling studies suggest that, in the case of Factor X Nottingham, a drastic conformational change causes major unfolding of the protein. For Factor X Taunton, less extreme conformational changes occur causing loss of functional activity such that substrate binding sites might be maintained. It is proposed that competition with wild type for substrate binding could occur leading to a dominant negative effect.
Optical coherence tomography (OCT): a review (1999)

This paper reviews the state of the art of optical coherence tomography (OCT), an interferometric imaging technique that provides cross-sectional views of the subsurface microstructure of biological tissue. Following a discussion of the basic theory of OCT, an overview of the issues involved in the design of the main components of OCT systems is presented. The review concludes by introducing new imaging modes being developed to extract additional diagnostic information.
Application of an acoustofluidic perfusion bioreactor for cartilage tissue engineering (2014)

Cartilage grafts generated using conventional static tissue engineering strategies are characterised by low cell viability, suboptimal hyaline cartilage formation and, critically, inferior mechanical competency, which limit their application for resurfacing articular cartilage defects. To address the limitations of conventional static cartilage bioengineering strategies and generate robust, scaffold-free neocartilage grafts of human articular chondrocytes, the present study utilised custom-built microfluidic perfusion bioreactors with integrated ultrasound standing wave traps. The system employed sweeping acoustic drive frequencies over the range of 890 to 910 kHz and continuous perfusion of the chondrogenic culture medium at a low-shear flow rate to promote the generation of three-dimensional agglomerates of human articular chondrocytes, and enhance cartilage formation by cells of the agglomerates via improved mechanical stimulation and mass transfer rates. Histological examination and assessment of micromechanical properties using indentation-type atomic force microscopy confirmed that the neocartilage grafts were analogous to native hyaline cartilage. Furthermore, in the ex vivo organ culture partial thickness cartilage defect model, implantation of the neocartilage grafts into defects for 16 weeks resulted in the formation of hyaline cartilage-like repair tissue that adhered to the host cartilage and contributed to significant improvements to the tissue architecture within the defects, compared to the empty defects. The study has demonstrated the first successful application of the acoustofluidic perfusion bioreactors to bioengineer scaffold-free neocartilage grafts of human articular chondrocytes that have the potential for subsequent use in second generation autologous chondrocyte implantation procedures for the repair of partial thickness cartilage defects.
Dysregulated expression of Fau and MELK is associated with poor prognosis in breast cancer (2009)

The combination of in vitro functional studies with the analysis of gene expression in clinical breast cancer samples indicates that three functionally interconnected genes, Fau, Bcl-G and MELK, are crucially important in breast cancer and identifies them as attractive targets for improvements in breast cancer risk prediction, prognosis and therapy.