Search

To investigate the muscarine receptor type mediating inhibition of [H]-noradrenaline release from the isolated rat and guinea-pig iris we have determined the potency of antimuscarinic drugs to antagonize the methacholine-induced inhibition of [H]-noradrenaline overflow evoked by field stimulation (3 Hz, 2 min). The prejunctional apparent affinities were compared with those obtained for postjunctional muscarine receptors mediating the methacholine-induced contraction of the isolated rabbit iris sphincter muscle. Prejunctional apparent affinity constants of pirenzepine (6.67), himbacine (8.51), methoctramine (7.92), 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, 8.00), hexahydro-difenidol enantiomers (6.92, (R); 5.77, (S)) in the rat iris and methoctramine (7.58) in the guinea-pig iris indicate the presence of M receptors. Although the post-junctional affinity constants in the rabbit iris sphincter of methoctramine (5.93), gallamine (3.92), and 4-DAMP (9.07) confirm our previous suggestions of the presence of M-like receptors, the results obtained with the hexahydro-difenidol enantiomers do not agree with that concept. The post-junctional affinity constants of the hexahydro-difenidol enantiomers were not different from the prejunctional values (6.86, (R); 5.55, (S)), indicating a similar and low degree of stereoselectivity for these stereoisomers at both receptor sites (14 and 17, (R)/(S)-ratios, respectively). Hence, the postjunctional muscarine receptor in the rabbit iris sphincter fails to exhibit the high degree of stereo selectivity observed for hexahydro-difenidol enantiomers at M receptors on other smooth muscles. [ABSTRACT FROM AUTHOR]

Alpha-acid glycoprotein (AAG) is one of the plasma proteins that bind basic drugs, like amitriptyline (AT) and its metabolite nortriptyline (NT). Two types of genetic polymorphism have been described for AAG: polymorphic forms which, on electrophoresis of the native protein, give four patterns with 5, 6, 7 or 8 bands, and the variants which on by electrophoresis of the desialysed protein, give three patterns with 2 bands, FF, FS and SS. In 31 depressive patients, treated daily with 150 mg AT for 3 weeks, free and total plasma AT and NT were determined, as well as the AAG polymorphic forms and variants. There was only a weak negative correlation between the free fractions of AT and NT and total plasma AAG, but free AT and NT were strongly correlated with the S form (but not the F form) of AAG variants. The differences in binding might be the expression of a further genetic factor determining the steady-state plasma levels of tricyclic drugs. [ABSTRACT FROM AUTHOR]

Linking clinical multi-omics with mechanistic studies may improve the understanding of rare cancers. We leverage two precision oncology programs to investigate rhabdomyosarcoma with FUS/EWSR1-TFCP2 fusions, an orphan malignancy without effective therapies. All tumors exhibit outlier ALK expression, partly accompanied by intragenic deletions and aberrant splicing resulting in ALK variants that are oncogenic and sensitive to ALK inhibitors. Additionally, recurrent CKDN2A/MTAP co-deletions provide a rationale for PRMT5-targeted therapies. Functional studies show that FUS-TFCP2 blocks myogenic differentiation, induces transcription of ALK and truncated TERT, and inhibits DNA repair. Unlike other fusion-driven sarcomas, TFCP2-rearranged tumors exhibit genomic instability and signs of defective homologous recombination. DNA methylation profiling demonstrates a close relationship with undifferentiated sarcomas. In two patients, sarcoma was preceded by benign lesions carrying FUS-TFCP2, indicating stepwise sarcomagenesis. This study illustrates the potential of linking precision oncology with preclinical research to gain insight into the classification, pathogenesis, and therapeutic vulnerabilities of rare cancers., (© 2024. The Author(s).)

The persistence of leukemic stem cells (LSCs) represents a problem in the therapy of chronic myeloid leukemia (CML). Hence, it is of utmost importance to explore the underlying mechanisms to develop new therapeutic approaches to cure CML. Using the genetically engineered ScltTA/TRE-BCR::ABL1 mouse model for chronic phase CML, we previously demonstrated that the loss of the docking protein GAB2 counteracts the infiltration of mast cells (MCs) in the bone marrow (BM) of BCR::ABL1 positive mice. Here, we show for the first time that BCR::ABL1 drives the cytokine independent expansion of BM derived MCs and sensitizes them for FcεRI triggered degranulation. Importantly, we demonstrate that genetic mast cell deficiency conferred by the Cpa3 Cre allele prevents BCR::ABL1 induced splenomegaly and impairs the production of pro-inflammatory cytokines. Furthermore, we show in CML patients that splenomegaly is associated with high BM MC counts and that upregulation of pro-inflammatory cytokines in patient serum samples correlates with tryptase levels. Finally, MC-associated transcripts were elevated in human CML BM samples. Thus, our study identifies MCs as essential contributors to disease progression and suggests considering them as an additional target in CML therapy. Mast cells play a key role in the pro-inflammatory tumor microenvironment of the bone marrow. Shown is a cartoon summarizing our results from the mouse model. BCR::ABL1 transformed MCs, as part of the malignant clone, are essential for the elevation of pro-inflammatory cytokines, known to be important in disease initiation and progression., (© 2023. The Author(s).)

Ferromagnetic La 0.7 Sr 0.3 Mn 1- x Ru x O 3 epitaxial multilayers with controlled variation of the Ru/Mn content were synthesized to engineer canted magnetic anisotropy and variable exchange interactions, and to explore the possibility of generating a Dzyaloshinskii-Moriya interaction. The ultimate aim of the multilayer design is to provide the conditions for the formation of domains with nontrivial magnetic topology in an oxide thin film system. Employing magnetic force microscopy and Lorentz transmission electron microscopy in varying perpendicular magnetic fields, magnetic stripe domains separated by Néel-type domain walls as well as Néel skyrmions smaller than 100 nm in diameter were observed. These findings are consistent with micromagnetic modeling, taking into account a sizable Dzyaloshinskii-Moriya interaction arising from the inversion symmetry breaking and possibly from strain effects in the multilayer system.

SrRuO 3 , a 4d ferromagnet with multiple Weyl nodes at the Fermi level, offers a rich playground to design epitaxial heterostructures and superlattices with fascinating magnetic and magnetotransport properties. Interfacing ultrathin SrRuO 3 layers with large spin-orbit coupling 5d transition-metal oxides, such as SrIrO 3 , results in pronounced peaklike anomalies in the magnetic field dependence of the Hall resistivity. Such anomalies have been attributed either to the formation of Néel-type skyrmions or to modifications of the Berry curvature of the topologically nontrivial conduction bands near the Fermi level of SrRuO 3 . Here, epitaxial multilayers based on SrRuO 3 interfaced with 5d perovskite oxides, such as SrIrO 3 and SrHfO 3 , were studied. This work focuses on the magnetotransport properties of the multilayers, aiming to unravel the role played by the interfaces with 5d perovskites in the peaklike anomalies of the Hall resistance loops of SrRuO 3 layers. Interfacing with large band gap insulating SrHfO 3 layers did not influence the anomalous Hall resistance loops, while interfacing with the nominally paramagnetic semimetal SrIrO 3 resulted in pronounced peaklike anomalies, which have been lately attributed to a topological Hall effect contribution as a result of skyrmions. This interpretation is, however, under strong debate and lately alternative causes, such as inhomogeneity of the thickness and the electronic properties of the SrRuO 3 layers, have been considered. Aligned with these latter proposals, our findings reveal the central role played in the anomalies of the Hall resistivity loops by electronic inhomogeneity of SrRuO 3 layers due to the interfacing with semimetallic 5d 5 SrIrO 3 ., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Coronaviruses (CoVs) are important human and animal pathogens that induce fatal respiratory, gastrointestinal and neurological disease. The outbreak of the severe acute respiratory syndrome (SARS) in 2002/2003 has demonstrated human vulnerability to (Coronavirus) CoV epidemics. Neither vaccines nor therapeutics are available against human and animal CoVs. Knowledge of host cell proteins that take part in pivotal virus-host interactions could define broad-spectrum antiviral targets. In this study, we used a systems biology approach employing a genome-wide yeast-two hybrid interaction screen to identify immunopilins (PPIA, PPIB, PPIH, PPIG, FKBP1A, FKBP1B) as interaction partners of the CoV non-structural protein 1 (Nsp1). These molecules modulate the Calcineurin/NFAT pathway that plays an important role in immune cell activation. Overexpression of NSP1 and infection with live SARS-CoV strongly increased signalling through the Calcineurin/NFAT pathway and enhanced the induction of interleukin 2, compatible with late-stage immunopathogenicity and long-term cytokine dysregulation as observed in severe SARS cases. Conversely, inhibition of cyclophilins by cyclosporine A (CspA) blocked the replication of CoVs of all genera, including SARS-CoV, human CoV-229E and -NL-63, feline CoV, as well as avian infectious bronchitis virus. Non-immunosuppressive derivatives of CspA might serve as broad-range CoV inhibitors applicable against emerging CoVs as well as ubiquitous pathogens of humans and livestock.

Background: Embolic protection during SVG interventions using distal balloon occlusion and aspiration has shown to reduce periprocedural complications compared to unprotected SVG interventions. A similar effect is expected from filter wires., Patients and Methods: A total of 174 SVG interventions carried out with (group A; n=87) or without distal filter wire protection (group B; n=87) were retrospectively matched for the location of distal graft anastomosis and analyzed for baseline and procedural characteristics, for TIMI flow grade before and after PCI, for the post-procedural CK elevation, and for major adverse cardiac events at 30 days and 6 months (primary end point). Location of distal graft anastomosis was the left anterior descending artery in 19.6%, the left diagonal branch in 6.9%, the left marginal branch in 17.2%, the left posterolateral branch in 24.2%, the mid-segment of the right coronary artery in 28.7%, and the posterior descending artery in 3.4%., Results: Baseline clinical demographics showed no relevant differences between both the groups. Mean age of vein grafts was 11.7+/- 4.3 years in group A versus 10.6+/- 4.9 years in group B (P=0.15). The number of stents per lesion was 1.4+/- 0.8 in group A versus 1.0+/- 0.8 in group B (P<0.01). The total length of stents was 32.2+/- 16.2 mm in group A versus 20.9+/-12.1 mm in group B (P<0.01). TIMI flow grade pre was 2.5+/-0.8 in group A versus 2.7+/- 0.6 in group B (P<0.05). TIMI flow grade post was 2.9+/- 0.3 versus 2.9+/- 0.2. Improvement of TIMI flow grade after SVG intervention was 0.4+/- 0.7 in group A versus 0.2+/- 0.6 in group B (P<0.05). Post-procedural CK-MB elevations were observed in 17 patients of group A versus 14 patients of group B (P=0.18). At 30 days, there were no myocardial infarctions (MIs) and no deaths in either group. One patient of group A had to be reoperated and four patients of group A underwent repeat PCI (4.6%) versus one patient of group B (1.2%). At 6 months, there were again no MIs and no deaths in either group. Target lesion revascularization rate was 17.3% in group A versus 11.5% in group B (P <0.02)., Conclusion: When distal filter wire protection is used in high risk SVG lesions, the clinical outcome of percutaneous interventions may be equal to low risk SVG lesions without filter wire protection., ((J Interven Cardiol 2005;18:475-479).)

Background: The widespread use of drug-eluting stents in patients with coronary artery disease (CAD) is hampered by unequal regulations for reimbursement. Identification of patients with maximal benefit from this technology may be achieved by assessing long-term clinical outcome after implantation of uncoated bare metal stents., Patients and Methods: A consecutive series of 1,000 patients with CAD treated with bare metal coronary stents of various designs from January 1995 to December 1995 was retrospectively followed over 4 years. The primary end points of the study were major adverse cardiac events., Results: The mean age of patients was 62 +/- 10.3 years, 77.5% were male, and 18% were diabetic. Clinical follow-up was obtained in 821 patients (82.1%) after 4.6 +/- 1.1 years. During this period of time, 31.8% were admitted for repeat PCI, 15.1% underwent CABG operation, 3.5% had myocardial infarctions, and 3.7% died. At 4 years, 46.3% of diabetic patients survived without event versus 57.6% of nondiabetic patients (P < 0.05). Patients with CAD I survived without event in 65.3% versus 54.0% of patients with CAD II and 48.5% of patients with CAD III (P < 0.02)., Conclusion: Implantation of uncoated stents provides the worst long-term clinical outcome in patients with diabetes and those with multivessel CAD. Both groups of patients appear to be primary candidates for the use of drug-eluting stents.

The importance of the identification of depressions in clinical practice is emphasised. The author suggests the use of modern operationalized diagnostic criteria. In atypical depressions and depressions with comorbid psychiatric disorders the diagnosis is sometimes missed. Occasionally, it is impossible to decide if a depression is present or not. In such cases it is in general indicated to try antidepressive treatment.

The publication gives an overview of disorders defined according to ICD-10 in which anxiety represents one symptom or the main symptom. The number of possible diagnoses is rather high. The proper classification has important consequences for the therapy to be chosen.

The EPs to bilaterally presented non-verbal and non-cognitive visual and auditory stimuli were studied in 15 schizophrenics and 15 normal subjects. Many anomalies of exogenous components of VEPs and AEPs were observed in schizophrenics in comparison with control subjects, pointing to an abnormal cerebral functioning. So, the patients presented: (1) a less interhemispheric difference in latency of P100 component of VEPs over the occipital area; (2) a decrease or a lack of left hemispheric predominance of P2 component of AEPs over the central area; (3) a lower interhemispheric waveform similarity both for VEPs and AEPs. These results suggest a lower hemispheric specialization and interhemispheric synchronization of EPs in schizophrenics.