gebhart/patrepeval huggingface dataset:
Influence of the Molecular Charge on the Biodistribution of Bombesin Analogues Labeled with the [99mTc(CO)3]-Core (2008)

The overexpression of Bombesin (BBS) receptors on a variety of human cancers make them interesting targets for tumor imaging and therapy. Analogues of the neuropeptide BBS have been functionalized with the (NalphaHis)- chelator for labeling with the 99mTc-tricarbonyl core. The introduction of a betaAla-betaAla linker between the stabilized BBS binding sequence and the chelator led to increased tumor uptake but still rather unfavorable in ViVo properties. Novel polar linkers, with different charge, have been introduced in the molecule and tested for their influence on the biodistribution. The new analogues showed a shift in hydrophilicity from a Log D=0.9 to Log D values between 0.4 and -2.2. All compounds kept the increased stability in both human plasma (t(1/2)>16 h) and in tumor cells (t(1/2)=30-40 min). The compounds with Log D values between +1 and -1 showed the highest binding affinities with Kd values of <0.5 nM, as well as the highest cellular uptake. However, higher hydrophilicity (Log D < -1.8) led to lower affinity and a substantial decrease of internalization. The introduction of a positive charge (beta3hLys) resulted in unfavorable biodistribution, with increased kidney uptake. The introduction of an uncharged hydroxyl group (beta3hSer) improved the biodistribution, resulting in significantly better tumor-to-tissue ratios. The compound with one single negative charge (beta3hGlu) showed a significant increase in the tumor uptake (2.1+/-0.6% vs 0.80+/-0.35% ID/g in comparison to the betaAla-betaAla analogue) and also significantly higher tumor-to-tissue ratios. The specificity of the in ViVo uptake was confirmed by coinjection with natural BBS. Moreover, the analogue provided a much clearer image of the tumor xenografts in the SPECT/CT studies. The introduction of a single negative charge may be useful in the development of new BBS analogues to obtain an improved biodistribution profile, with increased tumor uptake and better imaging.
Inductively coupled plasma mass spectrometry of biological samples. Invited lecture (1993)

The determination of trace and ultra-trace amounts of elements in biological samples by inductively coupled plasma mass spectrometry is discussed. Most attention is paid to human serum, but other materials are also considered. Matrix effects and their correction using internal standards are discussed in detail, together with the determination of Zn, B, Mo and Sn in serum. An overview is also given of the results obtained on a ‘second generation’ serum reference material.
An oral dual inhibitor of IDO and TDO enhances anti-cancer immunity and synergizes with immune checkpoint blockade (2018)

Background: Indolamine 2,3-dioxygenase (IDO) blockade is a new therapeutic strategy to enhance cancer immunity. However, IDO blockade alone cannot completely block the immunosuppressive tryptophan-kynurenine (Trp-Kyn) pathway in the tumor microenvironment. Recent studies have demonstrated that Trp 2,3-dioxygenase (TDO) is an alternative enzyme employed by various tumors that can be used as a target for the Trp-Kyn pathway; therefore, here we developed an orally available dual inhibitor that targets IDO and TDO. Methods: Small-molecule inhibitors for IDO and TDO were synthesized and screened by in vitro IDO/TDO enzyme and cell-based assays. CT26 colon or 4T1 breast tumor-bearing mice were treated with CB548 either alone or in combination with an anti-PD1 antibody. We monitored tumor growth and analyzed the tumor microenvironment using flow cytometry, qPCR, and confocal microscopy. Results: A lead compound, CB548, showed potent inhibition of IDO and TDO in the enzyme and cell-based assays with various human and murine cancer cell lines. Oral administration of CB548 revealed a good pharmacokinetic profile, and the conversion of Trp to Kyn in tumors was effectively suppressed. Moreover, the CB548 monotherapy revealed a dose-dependent inhibition of CT26 colon or 4T1 breast cancer growth as well as markedly increased CD8+ T cell infiltration in the tumor microenvironment. Additionally, the combination immunotherapy of CB548 and anti-PD1 antibody suppressed tumor growth to a greater extent than did the monotherapy, and led to durable tumor regression. There was no significant systemic toxicity with the CB548 treatment. Conclusions: Overall, our study demonstrates that CB548, a novel IDO/TDO dual inhibitor, can elicit a robust anti-cancer immunity and synergistically inhibit cancer progression in combination with an immune checkpoint inhibitor. Legal entity responsible for the study: CHA Bundang Medical Center. Funding: This work was supported by the Bio & Medical Technology Development Program of the National Research Foundation funded by the Ministry of Science & ICT of Republic of Korea. Disclosure: J.S. Kim: Employee of the CMG Pharmaceutical. All other authors have declared no conflicts of interest.
Deletion of the membrane anchoring region of tissue factor abolishes autoactivation of factor VII but not cofactor function. Analysis of a mutant with a selective deficiency in activity. (1992)

The activation of human blood coagulation factor VII can occur by the feedback activity of either factor VIIa (autoactivation) or factor Xa. Both of these reactions are known to be enhanced by the presence of tissue factor, an integral membrane protein and the cofactor for factor VIIa. We examine here the activation of 125I-factor VII by both factor VIIa and factor Xa employing a mutant soluble form of tissue factor which has had its transmembrane and cytoplasmic domains deleted (sTF1-219). This mutant soluble tissue factor retains cofactor activity toward factor VIIa in a single-stage clotting assay but shows a strong dependence on initial plasma levels of factor VIIa (from 1 to 10,000 ng/ml) when compared to wild-type tissue factor. We show that this dependence is due to a deficiency of sTF1-219 in ability to both promote autoactivation and enhance the factor Xa-catalyzed activation of 125I-factor VII. sTF1-219 does not, however, inhibit the tissue factor-independent activation of 125I-factor VII by factor Xa. The results strongly suggest that the phospholipid anchoring region of tissue factor is essential for autoactivation and beneficial for factor Xa-catalyzed activation of 125I-factor VII. In addition, when taken together with the dependence of clotting times on initial factor VIIa levels observed with sTF1-219, these results indicate that factor VII autoactivation may be of greater importance in the initiation of blood coagulation via tissue factor than has been previously realized.
Pharmacological properties of the stereoisomers of prizidilol: their use in analysis of reflex tachycardia and blood pressure control in normotensive cats, rats, and dogs. (1986)

Prizidilol, a combined vasodilator/beta-adrenoceptor antagonist, has two optical isomers. The pharmacological activities of these isomers have been established and heart rate/blood pressure responses to both isomers have been determined. Both the R and S isomers elicited similar blood pressure lowering and vasodilator activity in anaesthetised normotensive rats. S-Prizidilol was a substantially more potent beta-adrenoceptor antagonist in vitro and in vivo than R-prizidilol. Neither optical isomer showed any specificity for either beta 1- or beta 2-adrenoceptors. In conscious rats both isomers lowered blood pressure similarly with only marginal differences in heart rate. In conscious cats the importance of increased sympathetic drive in reflex tachycardia was emphasised by the incidence of tachycardia after R-prizidilol but not after S-prizidilol when administered at equieffective blood pressure lowering doses. In conscious dogs both isomers caused tachycardia although S-prizidilol tended to cause the greater fall in blood pressure.
Synthesis and Angiotensin II Receptor Antagonistic Activities of Benzimidazole Derivatives Bearing Acidic Heterocycles as Novel Tetrazole Bioisosteres (1996)

The design, synthesis, and biological activity of benzimidazole-7-carboxylic acids bearing 5-oxo-1,2,4-oxadiazole, 5-oxo-1,2,4-thiadiazole, 5-thioxo-1,2,4-oxadiazole, and 2-oxo-1,2,3,5-oxathiadiazole rings are described. These compounds were efficiently prepared from the key intermediates, the amidoximes 4. The synthesized compounds were evaluated for in vitro and in vivo angiotensin II (AII) receptor antagonistic activities. Most were found to have high affinity for the AT1 receptor (IC50 value, 10(-6)-10(-7)M) and to inhibit the AII-induced pressor response (more than 50% inhibition at 1 mg/kg po). The 5-oxo-1,2,4-oxadiazole, 5-oxo-1,2,4-thiadiazole, and 5-thioxo-1,2,4-oxadiazole derivatives showed stronger inhibitory effects than the corresponding tetrazole derivatives, while their binding affinities were weaker. This might be ascribed to their improved bioavailability by increased lipophilicity. The 5-oxo-1,2,4-oxadiazole derivative 2 (TAK-536) and 5-oxo-1,2,4-thiadiazole derivative 8f showed efficient oral bioavailability without prodrug formation. This study showed that the 5-oxo-1,2,4-oxadiazole ring and its thio analog, the 5-oxo-1,2,4-thiadiazole ring, could be lipophilic bioisosteres for the tetrazole ring in nonpeptide AII receptor antagonists.
Nutritional Support (1997)

The indications for providing nutrients by the enteral or intravenous route (nutritional support) are not well defined, and the efficacy of nutritional support in many circumstances is unproved. Nonetheless, nutritional support is widely used for several reasons: malnutrition is common in hospitalized patients,1,2 there is an association between malnutrition and increased morbidity3,4 and mortality,5 it seems intuitively likely that well-nourished patients will respond most favorably to treatment, nutritional support can be administered safely to most patients, and clinical trials indicate that it is beneficial in selected patients.610 Virtually all patients can be fed intravenously or enterally, because . . .
Impact of Technology and Voltage Scaling on the Soft Error Susceptibility in Nanoscale CMOS (2008)

With each technology node shrink, a silicon chip becomes more susceptible to soft errors. The susceptibility further increases as the voltage is scaled down to save energy. Based on analysis on cells from commercial libraries, we have quantified the increase in the soft error probability across 65 nm and 45 nm technology nodes at different supply voltages using the Qcrit based simulation methodology. The Qcrit for both bit cells and latches decreases by ~30% as the designs are scaled from 65 nm to 45 nm. This decrease is expected to continue with further technology scaling as well. The results show that at nominal voltage, the Qcrit for a latch is just ~20% more than that of the bit cell in sub-65nm technology nodes. Further, as the voltage is scaled from 1 V to 0.4 V, Qcrit decreases by ~5X which substantially increases the probability of an upset if a particle strike happens. This work shows that in sub-65 nm technology nodes with aggressive voltage scaling, it is equally critical to solve the soft error problems in logic (latches, flip-flops) as it is in SRAMs.
RNA-based gene therapies for myotonic dystrophy type 1 (2003)

La dystrophie myotonique de type 1 (DM1) est une maladie neuromusculaire grave qui engendre une perte d’autonomie des patients et diminue leur espérance de vie. Cette maladie est la plus fréquente des dystrophies musculaires chez l’adulte avec une incidence mondiale d’une personne atteinte sur 15 000. Au Québec, cette maladie est d’une importance particulière, car elle touche une personne sur 500 dans les régions du Saguenay et de Charlevoix. La DM1 est causée par l’expansion du triplet CTG situé dans la région 3’ non-codante de la myotonine protéine kinase (DMPK). Toutefois, il a été démontré que la grande part des symptômes de la maladie seraient liés à l’accumulation nucléaire de l’ARNm de DMPK portant l’expansion. Ces ARNm mutés se lient à des facteurs nucléaires formant des foci dans les noyaux des cellules DM1, engendrant des effets toxiques sur le métabolisme cellulaire et sur l’épissage alternatif de certains ARNm. \n\nNos travaux avaient comme but premier d’évaluer si la destruction de l’ARNm mutant de DMPK dans des myoblastes provenant de muscle squelettique DM1 permettrait de rétablir certaines fonctions et caractéristiques normales dans ces cellules. Trois technologies à base d’ARNs: les antisens, les ribozymes et les shRNAs ont diminué avec succès ces niveaux d’ARN mutés. Les ARNs antisens et les ribozymes, contrairement aux shRNA, ont permis un ciblage préférentiel des ARNs mutés de DMPK dans le noyau de myoblastes DM1. Ceci permet donc de maintenir un niveau basal de la protéine DMPK dans les myoblastes, un détail important advenant l’utilisation de ces molécules en thérapie génique chez l’humain. En utilisant les ribozymes, nous avons diminué la quantité et l’intensité des foci ce qui a permis de libérer les facteurs cellulaires se liant aux expansions de CUG. Ceci a eu comme effet de corriger un défaut d’épissage alternatif dans le récepteur à l’insuline. En exprimant de longs antisenses à l’ARNm de DMPK par un oncorétrovirus, nous avons constaté une restauration de la fusion cellulaire, de la capture de glucose ainsi qu’une diminution de CUGBP, un facteur d’épissage alternatif. Nous avons également démontré que la surexpression de hnRNP H, un facteur d’épissage liant les expansions de CUG, permettait aussi de diminuer les niveaux de CUGBP et ainsi corriger le défaut d’épissage alternatif du récepteur à l’insuline. Ces résultats démontrent donc pour la première fois le lien direct entre la rétention des ARNs mutés, la déplétion nucléaire d’un facteur d’épissage s’y liant et l’exacerbation de certaines caractéristiques du phénotype DM1. La somme de nos observations a permis deux choses importantes: en premier lieu, d’établir un nouveau modèle détaillé expliquant la pathogenèse de la DM1. En second lieu, nos résultats ont permi de valider la pertinence de détruire spécifiquement les transcrits mutés de DMPK afin de développer une thérapie génique efficace pour la DM1.\n
Interactions between splanchnic and vagus nerves in the control of mean intragastric pressure in the ferret. (1984)

To determine whether splanchnic nerves relax the stomach by direct or indirect mechanisms, ramp inflations of the stomach, section and electrical stimulation of the vagus and greater splanchnic nerves, and step inflations of the duodenum were used. A high threshold, sustained inhibition of the gastric pressure response to ramp inflation was mediated by the vagus. Prior splanchnectomy increased vagal inhibition. The greater splanchnic nerves had no effect on gastric responses to inflation, although after vagotomy they were shown to be mediators of a low threshold, powerful but transient inhibition of the stomach. This was not dependent on intrinsic neurones with nicotinic receptors. Electrical stimulation of the greater splanchnic nerves produced a relaxation of the stomach, the magnitude of which was determined by resting pressure. Splanchnically mediated relaxation was not abolished by atropine, nor was it reduced by concurrent vagal stimulation. At submaximal levels of vagal stimulation the two nerves had a partially additive effective on relaxation. Duodenal inflation had an effect on intracorpus pressure similar to that of electrical stimulation of the greater splanchnic nerves on intragastric pressure. Reflex relaxation of the corpus evoked by duodenal distension was decreased by atropine but greatly increased by atropine coupled with vagotomy. These changes were caused by variations in resting pressure. It was concluded that the principal effect of splanchnic nerves on mean gastric pressure is direct and does not depend on inhibition of cholinergic neurones either centrally or peripherally. Evidence is presented for central interactions between the vagus and the greater splanchnic nerves in the anaesthetized ferret.
Human Pentraxin 3 Binds to the Complement Regulator C4b-Binding Protein (2011)

The long pentraxin 3 (PTX3) is a soluble recognition molecule with multiple functions including innate immune defense against certain microbes and the clearance of apoptotic cells. PTX3 interacts with recognition molecules of the classical and lectin complement pathways and thus initiates complement activation. In addition, binding of PTX3 to the alternative complement pathway regulator factor H was shown. Here, we show that PTX3 binds to the classical and lectin pathway regulator C4b-binding protein (C4BP). A PTX3-binding site was identified within short consensus repeats 1-3 of the C4BP α-chain. PTX3 did not interfere with the cofactor activity of C4BP in the fluid phase and C4BP maintained its complement regulatory activity when bound to PTX3 on surfaces. While C4BP and factor H did not compete for PTX3 binding, the interaction of C4BP with PTX3 was inhibited by C1q and by L-ficolin. PTX3 bound to human fibroblast- and endothelial cell-derived extracellular matrices and recruited functionally active C4BP to these surfaces. Whereas PTX3 enhanced the activation of the classical/lectin pathway and caused enhanced C3 deposition on extracellular matrix, deposition of terminal pathway components and the generation of the inflammatory mediator C5a were not increased. Furthermore, PTX3 enhanced the binding of C4BP to late apoptotic cells, which resulted in an increased rate of inactivation of cell surface bound C4b and a reduction in the deposition of C5b-9. Thus, in addition to complement activators, PTX3 interacts with complement inhibitors including C4BP. This balanced interaction on extracellular matrix and on apoptotic cells may prevent excessive local complement activation that would otherwise lead to inflammation and host tissue damage.
microRNAs expression in endometriosis and their relation to angiogenic factors (2011)

Expression levels of miRNAs related to angiogenesis were different in eutopic endometrium from that observed in ovarian endometrioma. This could influence the expression of angiogenic factors and play a role in the pathogenesis of endometriosis.
Lectins with Anti-HIV Activity: A Review (2015)

Lectins including flowering plant lectins, algal lectins, cyanobacterial lectins, actinomycete lectin, worm lectins, and the nonpeptidic lectin mimics pradimicins and benanomicins, exhibit anti-HIV activity. The anti-HIV plant lectins include Artocarpus heterophyllus (jacalin) lectin, concanavalin A, Galanthus nivalis (snowdrop) agglutinin-related lectins, Musa acuminata (banana) lectin, Myrianthus holstii lectin, Narcissus pseudonarcissus lectin, and Urtica diocia agglutinin. The anti-HIV algal lectins comprise Boodlea coacta lectin, Griffithsin, Oscillatoria agardhii agglutinin. The anti-HIV cyanobacterial lectins are cyanovirin-N, scytovirin, Microcystis viridis lectin, and microvirin. Actinohivin is an anti-HIV actinomycete lectin. The anti-HIV worm lectins include Chaetopterus variopedatus polychaete marine worm lectin, Serpula vermicularis sea worm lectin, and C-type lectin Mermaid from nematode (Laxus oneistus). The anti-HIV nonpeptidic lectin mimics comprise pradimicins and benanomicins. Their anti-HIV mechanisms are discussed.
Concentrations of the acute phase reactants high‐sensitive C‐reactive protein and YKL‐40 and of interleukin‐6 before and after treatment in patients with acromegaly and growth hormone deficiency (2007)

Summary Background Acromegaly is accompanied by increased cardiovascular mortality and a cluster of proatherogenic risk factors. In the general population, ischaemic heart disease (IHD) is associated with elevated levels of inflammatory markers. The acute phase reactant (APR) C‐reactive protein (CRP) has been reported to be reduced in acromegaly and increase after treatment, suggesting that excess of GH/IGF‐I could have anti‐inflammatory effects. This is in accordance with results obtained in patients with growth hormone deficiency (GHD), where increased levels of CRP have been reported. Objective To investigate the hypothesis that the GH/IGF‐I system is a suppressive regulator of inflammatory processes. Subjects and methods Twenty‐one acromegalic patients and 19 GH‐deficient patients were studied. The two APRs CRP and YKL‐40 and the proinflammatory cytokine interleukin‐6 (IL‐6) were measured before and after treatment and in healthy matched controls. Results In acromegalic patients, serum concentrations of high‐sensitive CRP (hsCRP) and YKL‐40 were reduced compared to controls ( P &lt; 0·001) and increased ( P &lt; 0·001) after treatment, together with IL‐6 ( P = 0·021), to levels comparable with controls. Pretreatment serum YKL‐40 and IL‐6 showed a significant inverse correlation with IGF‐I and GH. In GH‐deficient patients, hsCRP and YKL‐40 were elevated compared to controls ( P = 0·001 and P = 0·048). During treatment, levels of both APRs showed a trend towards a decrease ( P = 0·087 and P = 0·060), and after treatment, levels of YKL‐40 no longer differed from that of controls. Serum IL‐6 was not different from controls and did not change during GH treatment. Conclusion The results point to the possibility of a relationship between GH disturbances and inflammatory processes.
The Use of Microcomputers and Microprocessors in Modern VTR Control (1979)

Microcomputers can be used in the design of time-code generators and editing systems. A time-code generator with a single-chip microcomputer and the layout of two editing systems having distributed processing are described. Here the microcomputer forms part of the master processor for both systems, one an “on-air” editing system and the other a production editing system. An intelligent control interface has been developed permitting a dialog between the master processor and the interface of the associated videotape recording equipment. A brief description of features of the on-line production editing system is given. A slow-motion programmer completes the line of peripheral videotape recording control equipment. It too uses an incorporated microcomputer for greater versatility.
Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals (2010)

Targeted therapy with imatinib in chronic myeloid leukemia (CML) prompted a new treatment paradigm. Unlike CML, chronic lymphocytic leukemia (CLL) lacks an aberrant fusion protein kinase but instead displays increased phosphatidylinositol 3-kinase (PI3K) activity. To date, PI3K inhibitor development has been limited because of the requirement of this pathway for many essential cellular functions. Identification of the hematopoietic-selective isoform PI3K-δ unlocks a new therapeutic potential for B-cell malignancies. Herein, we demonstrate that PI3K has increased enzymatic activity and that PI3K-δ is expressed in CLL cells. A PI3K-δ selective inhibitor CAL-101 promoted apoptosis in primary CLL cells ex vivo in a dose- and time-dependent fashion that was independent of common prognostic markers. CAL-101-mediated cytotoxicity was caspase dependent and was not diminished by coculture on stromal cells. In addition, CAL-101 abrogated protection from spontaneous apoptosis induced by B cell-activating factors CD40L, TNF-α, and fibronectin. In contrast to malignant cells, CAL-101 does not promote apoptosis in normal T cells or natural killer cells, nor does it diminish antibody-dependent cellular cytotoxicity. However, CAL-101 did decrease activated T-cell production of various inflammatory and antiapoptotic cytokines. Collectively, these studies provide rationale for the clinical development of CAL-101 as a first-in-class targeted therapy for CLL and related B-cell lymphoproliferative disorders.